Circadian rhythms and cancers: the intrinsic links and therapeutic potentials.

Background

It is well known that the rotation of the Earth is a near-24-h period which endows most organisms with an internal time-keeping system to adapt to the environmental changes. This evolutionarily conserved time-keeping mechanism termed circadian rhythm allows organisms to accommodate the changing environment, such as sleep and wake in animals and opening and closing of plant flowers [ 1 ]. As early as 1729, the French astronomer de Mairan firstly reported the endogenous rhythms associated with persistent movements of plant leaves even in constant darkness. He extended his observations to patients with sleep disorders in human beings [ 2 ]. However, since these initial observations, research on circadian rhythms was minimal until the discovery of circadian genes in Drosophila in the 1970s which opened the door for the in-depth understanding of circadian clocks [ 3 , 4 ]. In the 1990s, an explosion of data in this field contributed to the canonical action model of the circadian clock in which the Clock/Bmal1 and Per/Cry complexes play the central role [ 5 – 9 ]. Although the components of circadian rhythms are not conserved between species, the basic mechanisms are universal in almost all models which comprise various biological processes including anabolism and catabolism, cell division and cell cycle, immune cell functions, apoptosis and DNA damage repair [ 10 ]. Perturbation of circadian rhythms by environmental disturbances (e.g., shift work, jet lag) has been implicated in multiple pathological conditions, such as cardiovascular diseases, sleep disorders, neurodegenerative disorders, and cancers [ 11 – 13 ].

Several key biological processes are regulated by circadian rhythms. Thus, the disruption of the circadian clock may contribute to abnormal cell proliferation, increased gene mutation, and resistance to apoptosis, which are important hallmarks of cancer [ 14 , 15 ]. Based on the findings from epidemiology and laboratory studies, abnormal circadian rhythms have been listed as a potential carcinogen by the World Health Organization (WHO), which has increased the focus on defining the underlying mechanisms of circadian disruption-induced tumorigenesis [ 16 , 17 ]. Indeed, accumulating evidence has demonstrated that altered circadian rhythms are closely related to tumorigenesis in breast cancer, prostate cancer, colorectal cancer (CRC), pancreatic adenocarcinoma, liver cancer, lung cancer, and others [ 18 – 25 ]. In addition, therapeutic efficiency in cancer treatment is also partially dependent on the time of drug administration, which could be a new therapeutic chronotherapy strategy in cancer management [ 26 , 27 ]. The intrinsic links between circadian rhythms and tumorigenesis have therefore raised interest in manipulating these rhythms to prevent malignant transformation, to develop more efficacious therapies or novel adjuvant strategies, and ultimately improve the treatment outcome of cancer patients.

In this review, we will introduce the mechanism of disruptions of circadian rhythms-derived cancer progression and discuss the potential application of pharmacological modulation of the circadian clock and/or treating cancer using the clock as new therapeutic options for improved cancer management.

Regulation of circadian rhythms and their functions in cancer

In almost all models, the signaling pathways regulating circadian rhythms are universal regardless of non-conservation of the clock components [ 28 ]. In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus holds the “master clock”, which clocks with the environmental light cycle by directly coordinating the autonomic nervous system efferent and neuroendocrine signals [ 29 – 31 ]. In detail, several proteins involved in the clockwork of the cell associate closely with the negative and positive transcriptional feedback loops (Fig. 1 ). For example, circadian locomotor output cycles kaput (CLOCK) and brain and muscle aryl hydrocarbon receptor nuclear translocator 1 (BMAL1), which contain two basic helix-loop-helix domains, can bind to the Cryptochrome ( Cry ) and Period ( Per ) genes through their E-boxes, thus positively regulating circadian transcription [ 32 – 34 ]. In contrast, the mammalian CRY and PER proteins, as a heterodimer interacting with casein kinase Iε (CKIε), perform a negative effect for CLOCK/BMAL1-driven transcription [ 35 – 38 ]. In addition, the expression of circadian genes is transcriptionally modulated by the RORs (subfamilies of nuclear hormone receptors) and REV-ERB, resulting in the activation or repression of gene transcription for several clock genes [ 39 – 42 ]. Fig. 1 Regulation of circadian rhythms and their functions in cancer. a the master regulator of circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN coordinates several organ clocks in response to the environmental factors (including sleep/wake, eating/fasting, activity/rest, etc.), for controlling body homeostasis, such as heart rate, body temperature, and hormone levels. b at the molecular level, CLOCK and BMAL1 can bind to the CRY and PER genes through their E-boxes, thus positively regulating circadian transcription. But the mammalian CRY and PER proteins, as a heterodimer interacting with CKIε, perform a negative effect for CLOCK/BMAL1-driven transcription. In addition, the expression of circadian genes is transcriptionally modulated by the RORs and REV-ERB, resulting in the activation or repression of gene transcription for several clock genes. c , the mutation or deletion of core clock genes (including Per1/2 , Clock , Bmal1 , Cry1/2 and Rorc ) can accelerate the development of various tumors, such as liver, ovarian, lung, and colorectal cancer, and lymphoma. CLOCK: circadian locomotor output cycles kaput; BMAL1: brain and muscle aryl hydrocarbon receptor nuclear translocator 1; CRY: cryptochrome; PER: period; CKIε: casein kinase Iε

Growing evidence from both epidemiological research and preclinical data based on animal models supports the relationship between chronic disruption of the circadian clock and the occurrence of cancer [ 43 – 47 ]. Indeed, circadian disruption was listed as a probable human carcinogen in 2007 by the International Agency for Research on Cancer (IARC), part of the WHO [ 48 ].

For example, several studies have revealed that shift workers have a higher risk of developing breast and prostate cancers, as evidenced by a strong correlation between a long period (> 20 years) of shiftwork and increased cancer risk [ 49 – 52 ]. Furthermore, previous studies have indicated that people in modern society have undergone a sub-health lifestyle change, including excessive calories intake at midnight or continuous caloric intake over the 24 h throughout days, which mimics aspects of shiftwork and potentially promotes prostate and breast cancer risk [ 53 , 54 ].

Interestingly, rest/activity rhythm was also identified as a key factor due to the significant impact on the clinical treatment of metastatic CRC patients, who have a poor quality of life with erratic periods of rest/activity [ 55 , 56 ]. In line with this, the disruption of the core clock Per2 gene further aggravated CRC cancer cell proliferation in Apc Min/+ genetic mice [ 57 ]. In addition, disruption of Per2 also accelerated Kras G12D and Kras G12D / p53 −/− mutation-mediated lung cancer progression [ 23 ].

Additionally, mice with the core clock Per2 genes disrupted were more tumor-prone following treatment with the carcinogenic agent diethylnitrosamine (DEN) [ 58 , 59 ]. Moreover, irradiation stimuli promoted the development and progression of liver cancer and lymphoma in Per1 and Per2 mutant mice and Bmal1 −/ + mice [ 60 ]. Mice with deleted Cry1 and Cry2 or Rorc showed similar effects in lymphoma [ 60 , 61 ]. There has also been a report on a link between Clock mutation Clock Δ19/ + and Tp53 mutation-induced liver cancer and lymphoma [ 62 ].

However, some studies demonstrated that clock gene mutations (including Clock , Per1 −/− or Per2 −/− , Cry1 −/− and Cry2 −/− ) potentially led to an adverse influence on cancer progression [ 63 , 64 ]. In a RAS mutation-triggered cutaneous squamous tumor model, Bmal1 deletion protects from tumorigenesis [ 65 ]. In addition, previous studies have revealed CLOCK and BMAL1 as key regulators for acute myeloid leukemia (AML) by contributing to proliferation and stemness [ 66 , 67 ]. Moreover, deletions of Cry1 and Cry2 diminished tumor development in p53 null mice possibly due to triple mutant-induced genotoxic stress [ 68 , 69 ]. Taken together, the dual function of clock genes, either as oncogenes or as tumor suppressors, may be attributed to tissue-specific mechanisms and implies the existence of intricate clock-dependent networks, which are involved in the maintenance of homeostasis during different tumor stages.

In summary, these rhythms mainly emerge from the interplay between circadian clocks and sleep–wake cycles, eating–fasting cycles, and activity–rest cycles. These circadian rhythms are able to modulate several key aspects of cellular and organ functions with profound implications in cancer management. In the following sections, we will discuss the interplay between these cycles with cancer and describe the links involved.

The interplay between sleep–wake cycles and cancer

Disruption of sleep–wake circadian rhythm has a major impact on the entire neuroendocrine-immune system, which modulates immune defense and energy metabolism, thus contributing to normal physiological activity by coordinating the biological response to everyday stresses, as well as cognitive and physical performance (Fig. 2 ). Fig. 2 The interplay between sleep–wake cycles and cancer. a sleep–wake cycles regulate the immune system. During normal sleep–wake cycles, SWS sustains the function of immune system by maintaining the balance of T-helper1 (Th1) and T-helper2 (Th2) cell-derived cytokines (Th1 cytokines: IL-2, IFNγ, and IL-12; Th2 cytokines: IL-4 and IL-10), which benefit the antigen presenting process. b sleep–wake cycles regulate the inflammatory response. Disturbance of sleep continuity (sleep time and efficiency) and architecture (SWS and REM sleep) may lead to body inflammatory response, including abnormal systemic inflammation, cellular inflammation and inflammation transcriptional activity, which are associated with development of chronic inflammation related disease, such as cancers. c Sleep–wake cycles and endocrine. Endocrine factors, including growth hormone, prolactin, thyroid hormone, cortisol, gonadal steroids, insulin, and so on, have been identified to be secreted during certain time periods. Disruption of sleep–wake cycles may break these balances and influence their secretions. d Sleep–wake cycles regulate DNA damage and repair. On the one hand, sleep disruption can reduce the levels of melatonin, an important antioxidant, which may lead to increased oxidative DNA damage. On the other hand, sleep deprivation downregulates the expression of several genes involved in DNA repair, such as ERCC6, PARP1, and RAD50, which may ultimately promote tumorigenesis. e , Feedback from cancer to sleep–wake cycles. IL-1β in the brain can regulate REM and NREM sleep by modulating various molecules and neurotransmitters, including COX-2, GABA, and nitric oxide (NO), while IL-6 enhances SWS and decreases REM sleep. SWS: slow-wave sleep; REM: rapid eyes movement; TSH: thyroid-stimulating hormone; PRL: prolactin; RAAS: renin–angiotensin–aldosterone systems; COX-2: cyclooxygenase-2.

Sleep–wake cycles regulate the immune system

Rhythmical biological regulation of the immune system is mediated by intricate crosstalk between the nervous and endocrine systems [ 70 – 72 ]. Dysregulation of sleep–wake cycles, like prolonged sleep deprivation, disrupts the immune system, resulting in increased rates of viral infection and weak antigen processing and antibody formation [ 70 , 73 , 74 ].

During normal sleep–wake cycles, the immune system displays a biphasic shift that is linked with maintaining the balance of T-helper1 (Th1) and T-helper2 (Th2) cell-derived cytokines (Th1 cytokines: IL-2, IFNγ, and IL-12; Th2 cytokines: IL-4 and IL-10) [ 75 ]. Mechanically, Th1 activity in the initial hours of nighttime sleep is enhanced and accompanied by moderate promotion of interferon (IFN)-γ/IL-4-producing Th cells, while Th2 activity dominates in the late hours of sleep or before wake up [ 76 ]. Once this pattern is broken, cytokines are excessively produced and directly induce immune disturbances, which subsequently lead to chronic inflammation and tissue damage. In sleep-deprived individuals, including stressed persons, insomniacs, and the elderly, a switch toward Th2 activity has been reported [ 76 ]. Sleep deprivation-induced production of growth hormone and prolactin turning cytokine balance into Type 1 dominance, as well as cortisol and norepinephrine leading to Type 2 dominance, are all involved in immune response alteration [ 70 , 76 , 77 ].

In addition, decreased cellular immunity is also attributed to the elevation of sympathetic tone induced by sleep deprivation. During sleep, the number of monocytes producing IL-12 or IL-10 is normally increased or decreased, respectively, thus resulting in a circadian rhythm. However, when chronic wakefulness occurs, rhythmic temporal variations of IL-12 and IL-10 produced from monocytes are lost, causing dysregulation of the immune system [ 77 ]. Furthermore, Irwin and colleagues revealed that the lytic activity of natural killer (NK) cell was diminished by an average of 28% in people with sleep deprivation, i.e., wakefulness between 03:00 to 07:00 h, compared with blood sampling between 07:00 and 09:00 h from healthy men [ 78 ]. They then demonstrated that partial sleep deprivation potentially attenuates the natural immune response, evidenced by decreased numbers and weak lytic activity of NK cells, lymphokine-activated killer (LAK), and its precursors [ 79 ]. Notably, a marked decrease of CD8 + T cells (cytotoxic and memory), which are derived from tumor necrosis factor (TNFα) stimuli, is the most pronounced effect resulting from sleep deprivation, solidly implying an impaired immune response if exposed to carcinogenic risk [ 76 ]. These findings suggest that even modest disruption of sleep–wake cycles resulting from working the night shift can significantly induce the dysregulation of natural immune responses, T cell-cytokine production, etc. These dysregulations need more than a single day of sleep to recover to baseline and potentially lead to an increased risk of cancer [ 80 – 82 ].

Sleep–wake cycles regulate inflammatory responses

Inflammatory responses are abnormally activated following dysregulation of the immune system caused by disruption of sleep–wake cycles, which is characterized by the activation of soluble intercellular adhesions molecule (sICAM)-modulated NF-κB inflammatory signaling and the subsequent induction of inflammatory markers TNF-γ, IL-6, and C-reactive protein (CRP) [ 83 , 84 ]. In addition, sleep deprivation alters IL-6-mediated trans-signaling by changing the levels of soluble IL-6 (sIL-6) receptor in various types of brain cells and neighboring organs [ 85 ]. An analysis using a DNA microarray indicated that sleep-deprivation-induced upregulation of inflammatory genes in humans was a common response and might be not rapidly resolved [ 83 ]. Sleep restriction-triggered upregulation of proinflammatory cytokines (IL-6, IL-1β, IL-17, and CRP) were maintained at high expression levels even through two nights of recovery sleep [ 86 ]. In line with this, increased levels of CRP were also found in shift workers, indicating a progression of an inflammatory state and an increased risk of cancer [ 87 ].

Rigorous studies profiling inflammatory markers in the human sleep–wake cycle are limited to a few methodological studies that have looked at profiles of systemic and cellular inflammatory markers obtained repeatedly over the course of a regular sleep–wake cycle, compared with continuous wakefulness over 24 h [ 88 ]. These studies have shown a close association between the levels of several markers and sleep, the circadian oscillator, or both [ 70 ]. For example, IL-6 was reported to have a circadian profile whose levels peaked at 19:00 h and 05:00 h [ 89 ]. Furthermore, upregulation of IL-6 levels and production of TNF was attributed to nocturnal sleep [ 70 ]. A previous study indicated that experimental sleep deprivation during the nocturnal period resulted in an undersecretion of IL-6 and an attenuated secretion of TNF from Toll-like receptor 4 (TLR4)-induced monocytes [ 90 ]. Notably, sleep deprivation changed the nighttime pattern of IL-6 secretion into daytime, therefore resulting in an IL-6 oversecretion during the day [ 89 ]. Similarly, by investigating people with sleep disturbances, TLR4-mediated IL-6 production from monocytes was also found to be decreased at night and increased in the day [ 91 ]. Nevertheless, IL-6 levels were partially mediated by the circadian oscillator as indicated by the observation of transient (less than 1 h) peaks during nocturnal wakefulness [ 85 ].

Different stages of sleep, including slow-wave sleep (SWS) and rapid eyes movement (REM) sleep, differentially induced nocturnal changes of inflammatory cytokine activity. However, the levels of the inflammatory cytokines during the detailed period were not clear. The levels of inflammatory cytokines were reported to peak early in SWS, but higher levels of IL-6 were found during REM sleep compared with being awake [ 92 ]. Consistent with increased IL-6 during REM sleep, IL-6 and sIL-6R were upregulated later during the night, and the morning levels of TLR4-stimulated IL-6 production from monocytes were found to correlate with the amount of REM sleep [ 85 , 91 , 92 ].

In conclusion, sleep disruption may lead to abnormal inflammatory responses as evidenced by the upregulation of proinflammatory cytokines (especially IL-6 and CRP), which are potential risk factors for several cancers, including ovarian, brain, breast and colorectal cancers.

Sleep–wake cycles and endocrine factors

Endocrine factors, especially those governed by the hypothalamic-pituitary axis, have been identified to be regulated by circadian rhythms, therefore fluctuating over the day. These include growth hormone (GH), prolactin (PRL), thyroid hormone, cortisol, and gonadal steroids [ 93 – 95 ]. Insulin and adipokines, a form of nutrient-sensitive hormones, are also mediated by circadian rhythms (light/dark and feeding/fasting cycles) giving rise to varying circulating levels, partially controlled by time-of-day-dependent patterns [ 93 ].

Growth hormone and prolactin have been reported to change their secretory pattern due to exposure to acute sleep deprivation [ 96 ]. This treatment also mitigated nighttime peaks of growth hormone and prolactin, leading to dysregulation of the immune system [ 70 ]. Furthermore, a previous study demonstrated that the 24-h mean and amplitude of several endocrine factors modulated by the circadian clock, including thyroid-stimulating hormone, prolactin, and leptin, were suppressed by semi-chronic sleep deprivation with sleep debt during 6 days [ 93 ]. Sleep debt also influenced the circadian pattern of plasma cortisol, resulting in higher plasma levels in the afternoon and early evening [ 93 ].

Notably, hyperphagia and weight gain are closely associated with sleep deprivation. Mechanically, sleep deprivation triggers downregulation of the plasma concentration of the appetite-restraining adipokine leptin and upregulation of the plasma concentration of the appetite-stimulating peptide ghrelin, in which adipokine leptin and peptide ghrelin are produced in adipose tissue and the stomach, respectively [ 97 ]. Accordingly, this process leads to greater hunger and appetite, subsequently resulting in triglyceride metabolism and disturbed lipid levels [ 98 ]. Inhibition of appetite is required for the secretion and blood levels of leptin, which are positively regulated by daily sleep length and display significant reduction with sleep deprivation [ 97 , 99 ]. Indeed, overweight or obesity risk in shift workers is found to have a potential relationship with sleep deprivation-induced changes of the hormonal milieu. Numerous studies have comprehensively revealed that weight gain or various levels of obesity, defined by increased body mass index and/or elevated waist-hip ratio, was potentially mediated by prolonged shift work-induced circadian disruption [ 100 , 101 ]. In addition, marked weight gain was also confirmed, even 4–5 years after shift work exposure in prospective cohort studies [ 102 ]. However, weight modulation in shift work is a cumulative effect because it is also regulated by various factors, such as age, lifestyle as well as “night eating syndrome” [ 103 ]. Nevertheless, either overweight or obesity facilitated increased secretion of adipokines and release of macrophages from adipose tissue, thus triggering chronic inflammation and subsequent oxidative stress and DNA damage [ 104 ]. These events likely contribute to breast cancer promotion and poor prognosis at least in a subpopulation, for example, postmenopausal female shift workers [ 105 ].

Sleep–wake cycles regulate DNA damage and repair

Stress-induced DNA damage has long been recognized as an important risk factor for the development of several chronic diseases, including cancer [ 106 – 108 ]. Sleep disruption in shift workers may lead to increased oxidative DNA damage due to decreased secretion of melatonin (an important cellular antioxidant) caused by sleep disruption [ 109 – 112 ]. For example, urine samples from 217 dayshift workers and 223 nightshift workers were collected for analysis of 8-OH-dG (a marker of oxidative DNA damage) and aMT6s (a marker of circulating melatonin) levels by using high-performance liquid chromatography with electrochemical detection [ 113 ]. The results found that disruption of melatonin in nightshift workers is associated with impaired DNA repair machinery and increased cellular oxidative DNA damage, as evidenced by the positive correlation between aMT6s and urinary 8-OH-dG levels [ 113 ]. Another study also demonstrated that night work is associated with reduced DNA repair, and that this effect was probably due to melatonin suppression caused by night work, which raises the potential of melatonin supplementation for preventing DNA damage-induced chronic diseases [ 114 ]. Moreover, an observational study on 49 healthy doctors has found that nightshift doctors with sleep deprivation showed lower expression of DNA repair genes and increased DNA breaks compared with the dayshift colleagues, which was linked to the development of chronic disease [ 115 ]. In a recent controlled laboratory study, transcriptomic analysis of genes and associated pathways in circulating leukocytes obtained from night shift workers and healthy adults demonstrated a significantly impaired DNA repair pathway, which increased DNA damage and cancer risk in shift workers [ 116 ]. Taken together, these findings indicate that chronic disruption of sleep–wake cycles may cause increased DNA damage and decreased DNA repair, serving as potential risk factors for tumorigenesis [ 117 – 119 ].

Feedbacks from cancer to sleep–wake cycles

Various cytokines, such as TNF-α, TGF-β, IL-10, and especially IL-1β and IL-6, are well studied and have been shown to be involved in the complex crosstalk between cancer initiation/progression and sleep–wake cycles [ 120 , 121 ].

Notably, IL-1β can not only act as a pleiotropic cytokine to promote cancer progression in the tumor microenvironment but can also gain access to the brain through passive diffusion, subsequently interacting with IL-1R1 expressed on endothelial cells at the blood–brain barrier or vagal afferents [ 122 – 124 ]. Accordingly, IL-1β in the brain has been identified as the key mediator to affect rhythmical behavior. A previous study reported that both duration and delta power (~ 0.5–4 Hz oscillations) of NREM (non-rapid eye movement) sleep were markedly enhanced by injecting central or systemic IL-1β, which might play a role in hypnosis [ 125 ]. In contrast, spontaneous NREM sleep could be inhibited by the administration of IL-1β receptor antagonists or IL-1β neutralizing antibodies [ 126 , 127 ]. For REM sleep, IL-1β regulates it in a time and dose-dependent manner, shown by high levels of IL-1β inhibiting REM sleep, while low levels of IL-1β have no effect [ 121 ]. Moreover, IL-1β can influence sleep by modulating various molecules and neurotransmitters, including cyclooxygenase-2, NF-κB, GABA, nitric oxide (NO), prostaglandins, and adenosine [ 128 ]. For instance, inhibition of NO synthesis by an inhibitor, L-NAME, could decrease NO production and IL-1β-induced NREM sleep [ 129 ]. Notably, sleep deprivation could in turn stimulate the expression of IL-1β in the brain [ 130 ]. Overall, these studies suggest that IL-1β is under circadian and homeostatic control and has effects on multiple sleep nuclei.

IL-6 has been suggested to follow diurnal rhythms, but its detailed role is not yet totally clear [ 121 , 131 ]. Like IL-1β, IL-6 during wakefulness is normally at low levels and peaks during sleep [ 89 ]. Sleep deprivation elevates plasma levels of circulating IL-6 [ 92 ]. A study in humans revealed that IL-6 enhanced SWS and decreased REM sleep following subcutaneous injection [ 132 ]. Paradoxically, human recombinant IL-6 injected intracerebroventricularly into rabbits seemed to be not somnogenic but pyrogenic [ 133 ]. However, recombinant rat IL-6 reduced NREM sleep after temporarily enhancing NREM sleep in rat models [ 134 ]. In fact, the relationship between IL-6 and sleep–wake cycles is intricate. For example, sleep enhanced the levels of sIL-6R to over 70% of the wake levels at the termination of sleep, and simultaneously induced IL-6 trans-signaling regardless of classical/membrane-bound IL-6 signaling [ 85 ]. This process further supports the role of sleep in immune defense [ 135 , 136 ].

In summary, the above findings suggest that the disruption of sleep–wake cycles may serve as a potential risk factor for tumors mainly through modulating the neuroendocrine-immune system, the inflammatory responses, and the DNA damage repair systems. Moreover, increased levels of inflammatory cytokines secreted from tumors or tumor-associated leukocytes could in turn control the homeostasis of several sleep process, implying the complex crosstalk between cancers and sleep–wake cycles. Therefore, maintaining regular sleep pattern is highly encouraged in daily life for prevention of not only cancer but also other disorders.

The interplay between eating–fasting cycles and cancer

Dietary-related risk factors have been identified as one of the key determinants for cancer development [ 137 – 139 ]. In line with this notion, 14–20% of all cancer-related mortality in the USA is associated with obesity induced by dysregulation of eating–fasting cycles, and guidelines for nutrition administration that advocate maintaining eating–fasting cycles are thus suggested for reducing cancer incidence [ 138 , 139 ]. In addition, preclinical data have revealed that cancer cells with hyperproliferation usually fail to adapt to fasting conditions, implying the possibility that calorie-limited diets based on eating–fasting cycles could become a potential strategy for the prevention and treatment of cancer [ 140 , 141 ]. Notably, balancing eating–fasting cycles seems to improve acute and/or chronic side effects from treatments in cancer patients. Herein, we summarize the detailed mechanisms behind eating–fasting cycles-mediated signaling pathways for cancer initiation and development, and emphasis the important role of ordered eating–fasting cycles in cancer prevention or therapy (Fig. 3 ). Fig. 3 The interplay between eating–fasting cycles and cancer. a eating–fasting cycles regulate differential stress resistance and sensitization of cancer cells. Fasting triggers metabolic reprogramming of adipose tissue and muscle, which on the one hand sensitizes cancer cells to chemotherapy and other cancer therapies while on the other protects healthy cells from side effects from tumor therapy. b fasting or FMDs is able to decrease the levels of growth-promoting nutrients and factors, including glucose, IGF1 and insulin. Decreased glucose levels coupled with reduced glucose uptake via inhibition of GLUTs result in downregulated aerobic glycolysis and increased OXPHOS. This metabolic switch increases the accumulation of cellular ROS levels in cancer cells in response to chemotherapy, resultantly causing oxidative DNA damage and cell death. In addition, fasting or FMDs can also regulate IGF1R-mTOR-AMPK signaling to activate anticancer immunity by inducing autophagy. FMD: fasting-mimicking diets; GLUT: glucose transporter; OXPHOS: oxidative phosphorylation; ROS: reactive oxygen species

Effects of eating–fasting cycles on hormones and metabolites

The levels of metabolites and circulating hormones are changed in response to eating–fasting. This is characterized by downregulation of glucose, IGF1, leptin, and insulin, and upregulation of adiponectin, which contribute to either antitumor effects and/or protection from side effects [ 142 , 143 ]. Increasingly strong evidence is demonstrating that fasting or fasting-mimicking diets (FMDs) inhibits the effect of IGF1 and glucose against cancer [ 144 ]. Mechanistically, fasting or an FMD compromises various onco-pathways, such as cAMP-PKA and IGF1R-AKT-mTOR-S6K signaling, activates anticancer immunity, and enhances the tolerance of normal cells in stress conditions by inducing autophagy [ 145 – 147 ]. In addition, fasting has been revealed to induce ketone body accumulation, leading to mitigation of tumor proliferation and promotion of differentiation by inhibiting histone deacetylases (HDACs) [ 148 ].

Eating–fasting cycles regulate differential stress resistance and sensitization of cancer cells

Fasting triggers metabolic reprogramming of adipose tissue and muscle, where carbon-related metabolic pathways are modulated to change the levels of certain metabolites and circulating hormones. On the one hand these processes sensitize cancer cells to chemotherapy and other cancer therapies, while on the other they protect healthy cells from side effects from tumor therapy [ 140 , 141 ].

Several studies using animal models have demonstrated that short-term fasting (STF) promoted the anticancer effects of chemotherapeutic agents against numerous cancers, including pancreatic cancer, breast cancer, colorectal cancer, melanoma, and neuroblastoma, while simultaneously diminishing toxic effects of the treatments [ 149 – 151 ]. Furthermore, a 24–60-h fasting regime reinforced chemotoxicity tolerance of healthy cells, and further enhanced anticancer effects of chemotherapy compared to chemotherapy alone in different strains of mice with tumor xenografts [ 145 , 152 – 154 ]. The distinct outcomes derived from STF in healthy or tumor cells are termed differential stress resistance (DSR) [ 155 ]. Similarly, healthy cells faced with nutrient deprivation utilize energy for tissue repair that facilitates resistance to chemotherapy, while tumor cells still maintain hyperproliferation thus resulting in increased DNA damage and apoptosis during chemotherapy [ 141 , 152 , 156 ]. Thus, differential stress sensitization (DSS) is defined as a phenomenon whereby STF protects healthy cells from chemotherapy-induced toxicity and enhances the antitumor effect of chemotherapy.

Differential stress resistance (DSR)

The hypothesis that starvation plays an adverse effect in cancer compared to normal cells is reasonable, especially when the organism simultaneously faces cell stressors such as chemotherapy. In detail, healthy cells during starvation reduce global ribosome biogenesis and growth-related gene transcription which facilitates entry into the self-maintenance mode to resist damage caused by various cancer treatments. By contrast, the self-maintenance mode is terminated due to onco-pathways in cancer cells, thus leading to the reduction of stress response signaling [ 141 ]. This study also demonstrated that low-glucose triggered further cell death of mouse or human glioma and neuroblastoma cancer in hydrogen peroxide or cyclophosphamide-treated models, while protecting healthy glia cells from treatment-induced toxicity [ 141 ]. In line with these results, etoposide treatment markedly promoted the survival rate of neuroblastoma allograft-bearing mice following 2-day fasting, while resulting in only moderate effects in non-fasted mice [ 141 ].

A subsequent study indicated that fasting-triggered inactivation of IGF1 signaling protected glia and neurons from the oxidative stress agent cyclophosphamide and reduced doxorubicin-induced mouse embryonic fibroblasts, but not glioma and neuroblastoma cells [ 144 ]. Furthermore, mice with a conditional liver Igf1 gene deletion, which mimics fasting characterized by decreased levels of circulating IGF1, showed a toxicity-resistant ability against chemotherapeutic drugs, such as doxorubicin [ 157 ]. Histopathology studies suggested that compromised cardiac myopathy induced by doxorubicin was present in control mice but not in limited ingredient diet (LID)-treated mice [ 144 ]. Taken together, these data demonstrate that fasting-induced IGF1 downregulation is involved in increased tolerability to chemotherapy.

Fasting also contributes to overcoming the bottleneck for clinical application of both mTOR inhibitors and dexamethasone, which are used as anti-emetics and anti-allergics or as anticancer agents in cancer therapy, but have non-negligible side effects, such as hyperglycemia [ 149 ]. Indeed, the high glucose-induced cAMP-PKA pathway, which was attributed to both dexamethasone and rapamycin treatment, was revealed to enhance the toxicity of mouse cardiomyocytes from doxorubicin [ 149 ]. These results could possibly be reversed by decreasing circulating glucose concentration via fasting or insulin injections. In addition, fasting and/or FMD-triggered autophagy is also involved in the reduction of doxorubicin-induced cardiomyopathy by removing damaged mitochondria and toxic aggregates, therefore resulting in the reduction of reactive oxygen species (ROS) with protective effects on cardiomyocytes [ 158 ].

Differential stress sensitization (DSS)

Dietary treatment alone (like fasting and FMDs) shows limited effects on cancer. However, based on the DSS-derived mechanism, dietary interventions combined with canonical cancer therapy potentially display promising anticancer effects [ 159 – 161 ]. Previous observations on glioma, melanoma, and breast cancer indicated that fasting induced unexpected upregulation of ribosome biogenesis and expression of assembly genes or proliferation-related genes, which contribute to the activation of AKT and S6K and subsequent ROS accumulation and DNA damage, further increasing the effect of DNA-damaging drugs [ 140 ]. In fact, periodic cycles of fasting or FMDs in mice were reported to inhibit cell growth in several solid tumors and lymphoid leukemia [ 147 , 159 ]. Notably, periodic fasting or FMDs were also revealed to enhance the anticancer effects of chemo- or radiotherapy and tyrosine kinase inhibitors (TKIs) [ 162 – 164 ].

In addition to regulating glucose utilization and fatty acid β-oxidation in cancer, fasting or FMDs can also accelerate the conversion of energy metabolism mechanisms in cancer cells from aerobic glycolysis to mitochondrial OXPHOS for maintaining the growth of cancer cells in the nutrition-deprivation environment [ 152 ]. Subsequently, mitochondrial OXPHOS promotes ROS accumulation and decreases glutathione synthesis primarily derived by glycolysis and the pentose phosphate pathway, which leads to reduced ROS-mediated DNA damage. Strategies inhibiting glycolysis and glutaminolysis and promoting OXPHOS in order to delay tumor growth and overcome drug resistance are under investigation [ 152 ]. Of note, fasting or FMDs seem to promote metastasis, since several types of aggressive and metastatic cancer cells tend to be dependent on high-lactate production from high glycolytic activity [ 165 ].

Fasting or FMDs can trigger other alterations besides the metabolism changes that induce DSS in cancer cells. For example, fasting upregulated equilibrative nucleoside transporter 1 (ENT1) expression (gemcitabine transporter) to improve the anticancer activity of gemcitabine against pancreatic cancer [ 166 ]. In breast cancer and melanoma cells, fasting could induce SUMO modification of REV1 (a p53-binding protein and DNA polymerase) by the SUMO2 and/or SUMO3-dependent ways, consequently relieving the suppressive effect of REV1 on p53, which inhibited cancer cells by transcriptionally promoting expression of the pro-apoptotic genes [ 151 ]. In addition, a fasting-mimicking diet enhances the effect of the anti-estrogens tamoxifen and fulvestrant by reducing circulating IGF1 through EGR1 and PTEN-mediated inhibition of AKT/mTOR signaling [ 159 ]. In leukemia, a previous study reported that fasting could slow the progression of acute lymphoblastic leukemia (ALL) but not acute myeloid leukemia (AML) by activating the protein PR/SET domain 1 (PRDM1)-mediated leptin receptor and downstream signaling [ 167 ]. Furthermore, transcription factors PAX5 and IKZF1, commonly identified with more than 80% mutations in pre-B cell ALL, were indicated as tumor suppressors by exhibiting a persistent restriction on glucose uptake and energy supply [ 168 ]. Accordingly, energy crisis and cell death were observed in PAX5 and IKZF1 reconstituted pre-B-ALL cells, indicating a potential for developing the clinical application of fasting or FMDs in ALL [ 168 ].

Taken together, these observations demonstrate that although dysregulation of eating–fasting cycles have been identified as a key determinant for cancer development, fasting or FMDs can not only increase the sensitivity of cancer therapies but also reduce the side effects from chemotherapy, indicating a promising strategy for the prevention and treatment of cancer.

The interplay between activity–rest cycles and cancer

Based on epidemiological analyses, physical activity is associated with decreased risk of multiple cancers, including colorectal, breast, and prostate cancer [ 169 – 173 ]. Preclinical studies have also indicated that exercise has potential for cancer prevention (Fig. 4 ). Exercise training, such as treadmill running, voluntary wheel running, and swimming has been found to inhibit tumor initiation and progression in chemical, genetic or transplantable-triggered tumor mouse models [ 174 – 177 ]. However, exercise training has been shown to display different effects against a variety of cancers with different genetic backgrounds. For example, in the p53-deficient MMTV- Wnt mouse model bearing breast cancer, exercise training seemed to be ineffective against this cancer [ 178 ]. Nevertheless, strengthening physical exercise is still suggested for combating cancer regardless of cancer diagnosis. Notably, physical activity-driven antitumor effects can potentially be attributed to several mechanisms, which have different effects on different kinds of cancers. Fig. 4 The interplay between activity–rest cycles and cancer. a activity–rest cycles regulate immune function for tumor suppression. Exercise has been found to promote immune cell infiltration by epinephrine-driven NK cells circulation, resulting in a marked inhibition of cancer. Moreover, exercise also enhances naïve T cell populations and mitigates detrimental effects on T cells, leading to more efficient generation of immunological memory. b activity–rest cycles regulate the crosstalk between muscle and tumor. The crosstalk between muscle and tumor depends on skeletal muscle-secreted myokines. Exercise-induced myokines, including OSM, irisin, and SPARC, may play a role in cancer prevention and therapy. In addition, exercise-induced myokines can also induce the secretion of immune regulatory cytokines, including IL-6, IL-7, and IL-15, which indirectly regulate immune cell function. c , activity–rest cycles regulate tumor microenvironment. Exercise-mediated promotion of pro-angiogenic cytokines (such as VEGF) induces vascular remodeling to increase density and perfusion and reduce hypoxia in the tumor microenvironment. Furthermore, exercise was involved in the regulation of the Hippo signaling pathway, in which exercise-driven epinephrine markedly inhibited tumor formation by inducing Yap and Taz phosphorylation and subsequent degradation. NK cells: natural killer cells; OSM: oncostatin M; SPARC: secreted protein acidic and rich in cysteine; VEGF: vascular endothelial growth factor

Activity–rest cycles modulate immune functions

Exercise can modulate the circulation of immune cells by a mechanism mediated by adrenergic signaling and blood flow-induced shear stress, facilitating immune surveillance by eradicating identified malignant cells [ 179 ]. Indeed, an increasing number of studies have found exercise-induced immune cell mobilization as a common phenomenon independent of age, gender, or tumor type [ 180 , 181 ]. A study focusing on patients with breast cancer convincingly demonstrated that NK cell mobilization in breast cancer survivors during exercise was comparable to that in age-matched healthy people [ 182 ]. However, a recent randomized controlled trial suggested that exercise displayed no significant impact on resting NK cell function and circulating myokines in women with high-risk breast cancer [ 183 ], indicating a potentially ambiguous role of exercise in regulating NK cell function for cancer immunotherapy.

In terms of preclinical studies, transplantable or genetic animal cancer models are usually used to investigate the association between exercise and cancer [ 184 , 185 ]. For example, exercise was found to activate the immune system to suppress tumor progression in a genetic mouse model of mammary cancer following exercise training [ 186 ]. In addition, exercise-mediated immune system activation, such as NK cells and cytotoxic T cells infiltration, was also revealed in genetic tumor models, suggesting that additional immunological response was induced in the exercise-induced effect besides the initial immune response to the inoculated tumor cells [ 180 , 187 ]. In a wheel-running mouse model, exercise was revealed to promote immune cell infiltration by epinephrine-driven NK cells circulation, resulting in a marked inhibition of cancer growth [ 185 ]. Exercise also enhances naïve T cell populations and mitigates detrimental effects on T cells, leading to more efficient generation of immunological memory [ 188 , 189 ].

Increased body temperature is a major outcome of exercise, promoting the function and stimulus of immune cells [ 190 ]. A well-known observation is that hyperthermia can expand the diameter of intratumor blood vessels, therefore enhancing NK cells infiltration into the tumor and inhibiting cancer cell growth [ 191 ]. Furthermore, hyperthermia accelerates cytotoxic T cell recruitment into the tumor microenvironment by IL-6 trans-signaling-mediated tumor vasculature remodeling [ 184 ]. In fact, hyperthermia has been applied to clinical treatment for certain cancers, although the therapy temperature is generally higher than if exercise training-induced [ 192 – 194 ].

In summary, exercise could therefore be considered for cancer prevention or therapy due to its potential to promote an anticancer immunological response. However, exercise-mediated modulation of the immune system is complex, and the detailed mechanisms need to be further investigated [ 195 – 197 ].

Activity–rest cycles regulate the crosstalk between muscle and tumor

The crosstalk between muscle and tumor depends on skeletal muscle-secreted myokines produced during muscle contractions [ 198 – 201 ]. Recently, with the emergence of omics-based strategies, new exercise-induced myokines are gradually being identified in the muscle secretome [ 202 – 206 ]. Although the evidence, that exercise-driven myokines may play a role in cancer prevention or therapy, is still limited, several preclinical studies have indicated muscle-derived Oncostatin M (OSM) and Irisin may be effective against prostate and breast cancer [ 183 , 207 – 210 ]. In addition, the myokine secreted protein acidic and rich in cysteine (SPARC) produced by exercise training has been identified as an anticancer factor, as evidenced by decreased tumorigenesis in trained mice bearing colon cancer [ 211 – 213 ]. Notably, myokines are divided into distinct classes, with the potential to modulate the proliferation and differentiation of cancer cells by either directly inducing cell growth or antagonizing certain ligands [ 208 , 214 – 216 ]. Some myokines (like irisin) have been demonstrated to be modulators involved in the common cancer-related pathways, such as TGF-β or Wnt signaling [ 217 – 219 ].

Exercise-induced myokines can also induce the secretion of immune regulatory cytokines, including IL-6, IL-7, and IL-15, which indirectly regulate immune cell function [ 220 – 223 ]. For humans, IL-6 levels are controlled by exercise in a time and intensity-dependent way and are also related to the amount of muscle mass engaged in the exercise [ 224 – 226 ]. However, the importance of IL-6 produced during exercise in immune responses remains less well understood. A recent study indicated that exercise-mediated IL-6 seemed to improve immune cell infiltration. Anti-IL-6 antibody-mediated blockage of IL-6 signaling partially reversed the efficacy of exercise on inhibition of cancer cell proliferation [ 185 ]. Notably, direct IL-6 administration could not mimic exercise-related anticancer effects, implying that the role of IL-6 required a prior exercise-induced activation and recruitment of immune cells.

Activity–rest cycles regulate tumor microenvironment

Vascular remodeling attributed to abundant pro-angiogenic cytokines, such as VEGF (vascular endothelial growth factor) in the tumor microenvironment, is possibly the most well-known benefit of exercise on oncology indicated from pre-clinical investigations [ 227 – 230 ]. Numerous studies have revealed that vessel density and perfusion in tumors are involved in exercise-mediated VEGF production [ 231 – 233 ]. Furthermore, during exercise, endothelial cell recruitment is mediated by platelet derived growth factor receptor-beta (PDGFRβ) derived from platelets for tumor angiogenesis, dramatically reducing tumor hypoxia by upregulation of micro-vessel density and perfusion [ 232 , 234 , 235 ]. Hypoxia usually stimulates several stress response pathways to induce changes in the tumor microenvironment, especially immune microenvironment remodeling, therefore promoting tumor development [ 236 – 238 ]. For example, cytokines IL-4 and IL-10 triggered by hypoxia can induce differentiation of tumor-associated macrophages (TAMs) into an immunosuppressive M2 phenotype [ 239 , 240 ]. In addition, the hypoxic environment stimulates dendritic cells to induce the expression of indoleamine 2,3-dioxygenase (IDO), which performs an immunomodulatory role in T cell suppression [ 241 – 243 ]. A previous study also found reduction of CD8 + tumor-infiltrating lymphocytes (TILs) presenting in tumor hypoxic regions [ 244 , 245 ]. A hypoxic microenvironment has also been indicated to contribute to both dendritic cells-mediated inactivation of TILs and abnormal expression of PD-L1, resulting in immunotherapy resistance [ 246 – 249 ]. Interestingly, hyperoxia (60% oxygen) produced more than three-fold tumor infiltration CD8 + TILs compared to the control mice [ 244 ]. This finding provides the potential clinical implications of oxygen content regulation as every 10% increase in CD8 + TILs results in a 19% decrease in patient mortality [ 250 ]. However, sequestering chronic tumor patients in a 60% oxygen environment is not practical. Exercise, representing an available alternative, can reduce hypoxia in tumors, thus sensitizing cancer cells to immunotherapy by further increasing immune cell infiltration and reducing IDO-mediated immunosuppression.

Hippo signaling is one of the most important pathways for tumor initiation and development [ 251 , 252 ]. This pathway involves the growth and differentiation of tumor cells, and regulation of several signaling pathways related to the formation of the tumor microenvironment (including extracellular matrix remodeling) [ 253 , 254 ]. Recently, a study has reported that exercise was involved in the regulation of the Hippo signaling pathway [ 255 ]. Mechanically, exercise-driven epinephrine markedly inhibited tumor formation by inducing Yap and Taz phosphorylation and subsequent degradation [ 255 ]. In line with this, serum samples from breast cancer patients who were scheduled to participate in exercise training were able to show a 50% decrease in breast cancer metastasis in an experimental tumor model, attributed to exercise-induced catecholamine release [ 255 ].

Additional mechanisms are currently being investigated in exercise-mediated reduction of cancer progression. Secretion of several systemic factors (such as catecholamines, myokines), upregulation of blood flow-related shear stress, sympathetic activation, as well as increased body temperature, display immediate stress on tumor metabolism and homeostasis during exercise training [ 256 ]. If people are undertaking long-term training, the effects mentioned above will result in steady intratumor changes, such as strong immunogenicity, metabolism adaptation, and improved blood perfusion, which should help mitigate tumor development [ 257 , 258 ].

Potential application of clock-associated therapy in cancer management

The molecular understanding of circadian rhythms has raised new therapeutic frontiers for cancer which could put the circadian clock in an indispensable treatment role. Therefore, pharmacological modulation of the circadian clock and/or treating cancer in the clock may hold potential as new therapeutic options for better cancer management (Fig. 5 ). Fig. 5 Clock-based therapy in cancer management. a directly pharmacological targeting circadian clock for cancer therapy. Targeting the components of circadian clock has attracted much attention as a therapeutic approach to treat cancer. There are several pharmacologic agents targeting the components of circadian clock, including REV-ERBα/β, RORα/β/γ, CRY1/2, Casein Kinase family, and FBXL3. b , the effect of modulating circadian rhythms on conventional cancer therapy. Modulating the sleep–wake, eating–fasting, and activity–rest cycles can benefit the effect of chemotherapy, radiotherapy, and immunotherapy

Pharmacological targeting core components of the circadian clock for cancer therapy

Targeting the components of circadian clock has attracted much attention as a novel therapeutic approach to treat chronic diseases, such as chronic inflammatory diseases, metabolic syndrome, and cancer [ 259 , 260 ]. Theoretically, there exist two drug approaches for targeting the circadian clock: either by directly modulating the core circadian genes, or targeting their regulators. However, as BMAL1 and CLOCK are transcriptional factors, it is notoriously challenging to directly target these circadian core genes [ 261 , 262 ]. Hence, pharmacologic agents targeting proteins responsible for phosphorylation or degradation of clock components which negatively regulate BMAL1 and CLOCK have been developed as agonists or antagonists to disrupt the circadian network.

REV-ERBs

REV-ERBα/β are nuclear hormone receptors that can directly bind to the promoter of BMAL1 and CLOCK and thus negatively regulate their transcription [ 263 – 265 ]. The aberrant expression of REV-ERBs has been found in many cancer types in which they mainly regulate plasma glucose level, lipid, and energetic metabolism [ 266 ]. GSK4112, a small molecule molecular probe also known as SR6452, was the first synthetic agonist of REV-ERB obtained from a fluorescence resonance energy transfer biochemical screen, with an EC50 of 2.3 μM for inhibiting the transcriptional activity of Bmal1 [ 267 , 268 ]. However, the unsatisfactory pharmacokinetic profile and specificity of GSK4112 limited its use as a chemical tool in vivo, which drove the development of pyrrole derivatives SR9009 and SR9011 [ 269 , 270 ]. These two different agonists of REV-ERBs have been reported to display anticancer activity against different tumor types, including leukemia, brain, colon, breast, and melanoma, while exhibiting no obvious side effect on normal cells or tissues [ 271 – 274 ]. Further studies found that autophagy and de novo lipogenesis were identified as the key events in evoking the apoptotic response in malignant cells treated with SR9009 and SR9011 [ 274 ]. In addition, SR9011 and SR9009 also reduced glioblastoma stem cell (GSC) proliferation and were lethal to chemoresistant small-cell lung cancer (SCLC) cells by repressing the expression of the tricarboxylic acid (TCA) cycle enzymes [ 275 ] and suppression of autophagy [ 273 ], respectively. Other chemical agonists for REV-ERBα, including GSK2945, GSK0999, GSK5072, and GSK2667 have also been developed but their effects on cancer need further investigation [ 276 ].

RORs

Unlike REV-ERBs, RORs (including RORα, RORβ, and RORγ) can constitutively induce the transcription of Bmal1 through the ligand-independent recruitment of transcriptional co-activators [ 266 , 277 ]. There is evidence showing that RORγ was upregulated in metastatic castrate-resistant prostate cancer and promoted the expression of the androgen receptor, thus raising the possibility of targeting RORγ for cancer treatment [ 278 – 282 ]. Notably, the ROR-γ-selective antagonists XY018 and SR2211 block the growth of prostate cancer cells with androgen receptor expression and restore sensitivity to enzalutamide treatment (a commonly used androgen inhibitor for prostate cancer), in which induction of apoptosis and decreased expression of key proliferation and survival proteins were identified as key events [ 278 ]. Moreover, RORγ was found to show important regulatory functions in pancreatic cancer stem cells, and pharmacological targeting of RORγ by SR2211 inhibits the tumor growth and prolongs survival in several in vivo pancreatic cancer models [ 283 , 284 ]. In contrast, RORγ agonists can modulate multiple signaling pathways to enhance the antitumor immunity against leukemia, colon and breast cancer [ 285 – 288 ]. For example, LYC-54143 and LYC-53772 are two potent RORγ agonists which display cytotoxic activity by promoting cytokines/chemokines (i.e., IL-17A and GM-CSF) production and increasing co-stimulatory receptor expression (like CD226 and CD137) [ 288 ]. Based on this finding, another RORγ agonist, LYC-55716 (cintirorgon), is currently under Phase I clinical trial for treating patients with metastatic cancer alone [ 289 ] or in combination with pembrolizumab (clinical trial NCT03396497 ). Unlike RORγ, RORα was found to be downregulated in several cancer types, including breast, ovarian, and prostate cancer [ 290 – 293 ]. Treatment of RORα agonist SR1078 results in p53 stabilization and triggers apoptosis in human HepG2 cancer cells [ 294 , 295 ]. Another study found that pevonedistat (MLN4924), a small molecule AMP mimetic, could stabilize RORα by inhibiting its ubiquitination and consequent degradation, which in turn attenuated cell proliferation of osteosarcoma, chondrosarcoma, and leukemia by inducing cell cycle arrest and apoptosis [ 296 – 299 ]. MLN4924 has been evaluated in 40 clinical trials related to cancer [ 300 ].

CRY1/2

Distinct from REV-ERBs, CRY1 and CRY2 are important for inhibiting clock-controlled gene transcription by directly interacting with BMAL1/CLOCK complexes [ 301 – 304 ]. KL001 was the first compound found to directly bind to and stabilize CRY by preventing FBXL3-mediated ubiquitin-dependent degradation [ 305 ]. A recent study has demonstrated that KL001 treatment decreased OLIG2 and SOX2 expression and inhibited GSC proliferation with reduced toxicity in normal brain cells [ 275 , 306 ]. Interestingly, in vitro observations demonstrate that pharmacological targeting CRY by KS15 reduces proliferation of human breast cancer MCF-7 cells and increases the sensitivity of MCF-7 cells to treatment with doxorubicin and tamoxifen, but has no obvious cytotoxic effects on normal breast epithelial cells (MCF-10A) [ 307 ]. These contradictory findings indicate that the function of CRY in cancer treatment is context-dependent and that further research is needed to investigate its precise role.

Casein kinase (CK) family

The casein kinase 1 enzymes (CK1) are a family of serine/threonine kinases in which CK1δ and CK1ε phosphorylate PERs and CRYs and prime them for FBXL21 and β-TRCP mediated degradation [ 308 – 311 ]. The upregulation of CK1δ and CK1ε was observed in several cancer types, including melanoma, leukemia, pancreas, breast, and ovarian cancer, which highlights their potential as drug targets for anticancer therapy [ 312 – 315 ]. Indeed, breast cancer cells overexpressing CK1δ are sensitive to CK1δ/CK1ε inhibition caused by SR-3029 both in vitro and in vivo, while normal breast epithelial cells (MCF-10A) with low amounts of CK1δ are less sensitive to SR-3029 treatment [ 314 , 316 ]. Another inhibitor, BTX-A51, was found to induce apoptosis in AML progenitor cells in vitro and suppress growth in vivo in both genetical-engineered AML mouse models and in patient-derived xenograft mouse models [ 317 ]. BTX-A51 is currently in Phase I clinical trials for the treatment of patients with relapsed or refractory AML (clinical trial NCT04243785 ). Similarly, CK2 (casein kinase II) has also been found to regulate cell growth and proliferation of several cancers [ 318 ]. For example, CK2α was upregulated in CRC cells and conferred resistance to 5-FU treatment by inhibiting ER stress-induced apoptosis, and treatment with a CK2α inhibitor may exert a synergistic effect with 5-FU against drug-resistant cancer cells [ 319 ]. Targeting CK2 with a pan-CK2 inhibitor, BMS-699, resulted in disruption of myeloid cell differentiation and increased efficacy of immunotherapy in mice with lung, colon and breast carcinoma and lymphoma [ 320 ]. Moreover, some potent CK2 inhibitors, such as CX-4945 (silmitasertib) and GO289, have been developed which inhibit the proliferation of several human tumors [ 321 – 323 ]. CX-4945 was the first CK2 inhibitor that entered into clinical trials for the treatment of human tumors [ 324 , 325 ].

To sum up, several agonists or antagonists targeting the core components of circadian rhythm have been developed and show promising anticancer effect in various cancer types. However, few compounds are entering clinic trials to enable the evaluation of the true efficacy in patients, and the dependence of these anticancer effects on clock modulation still needs further investigation (Table 1 ). Table 1 Summary of cancer types and their associations with disrupted rhythms Cancer types Disrupted rhythms Promotion/inhibition References Breast cancer/prostate cancer Shiftwork-induced disruption of sleep–wake cycles Promotion [ 49 – 52 ] Excessive calories-induced disruption of eating–fasting cycles Promotion [ 53 , 54 ] Fasting-induced disruption of eating–fasting cycles Inhibition [ 140 ] [ 151 ] Exercise-induced disruption of activity–rest cycles Inhibition [ 183 , 207 – 210 ] Colorectal cancer Short-term fasting-induced disruption of eating–fasting cycles Inhibition [ 149 – 151 ] Maintenance of activity–rest cycles Inhibition [ 55 , 56 ] Per2 mutation-induced disruption of circadian clock Promotion [ 57 ] Lung cancer Per2 mutation-induced disruption of circadian clock Promotion [ 23 ] Fasting-induced disruption of eating–fasting cycles Inhibition [ 383 ] Exercise-induced disruption of activity–rest cycles Inhibition [ 412 ] Liver cancer Per1/2 mutation or Bmal1 deletion-induced disruption of circadian clock Promotion [ 60 ] Acute lymphoblastic leukemia Fasting-induced disruption of eating–fasting cycles Inhibition [ 167 ] T cell lymphomas Cry1/2 or Rorc deletion-induced disruption of circadian clock Promotion [ 60 , 61 ] Glioma Fasting-induced disruption of eating–fasting cycles Inhibition [ 141 ] Pancreatic cancer Fasting-induced disruption of eating–fasting cycles Inhibition [ 166 ] Exercise-induced disruption of activity–rest cycles Inhibition [ 426 ]

Administrating drugs in clock: chronotherapy in cancer treatment

Chronotherapy has been defined as a strategy that utilizes the natural rhythms and cycles of physiological and biochemical processes to treat a disorder [ 326 – 328 ]. This type of therapy for cancer patients, aiming to reduce side effects and improve efficacy during cancer treatment, has been applied in the clinic even before more detailed mechanisms of the core circadian clock were known [ 329 – 332 ]. Subsequently, once the biological functions of circadian rhythms were revealed showing that drug PK, PD, and safety are highly depend on 24-h rhythm, the rationale for chronotherapy was supported [ 333 – 335 ]. Indeed, a suitable dosing time during the cycle can not only contribute to beneficial effects but also avoid adverse ones, especially for anticancer agents whose use may be limited due to their side effects on healthy host tissues [ 336 – 338 ]. For example, in cancer patients treated with constant-rate i.v. infusion of 5-fluorouracil (5-FU) for 5 days, the maximum plasma concentration (Cmax), and the best-tolerated time were found to be at 4:00 a.m [ 339 , 340 ]. Recent reports have indicated circadian characteristics of inhibitors targeting the estrogen receptor and tyrosine kinases in both treated mice and patients, as evidenced by observed daily pharmacokinetic variations [ 341 – 344 ]. In addition, several Phase I to Phase III clinical trials have confirmed the efficacy of chrono-modulated treatment in various tumors [ 345 , 346 ].

Importantly, chronotherapy potentially improves the survival rate and life quality of cancer patients by minimizing anticancer agents-driven cytotoxicity [ 347 – 349 ]. Mechanically, numerous anticancer drugs have consistently been demonstrated to display increased cytotoxicity to cells at specific phases of cell division, suggesting that optimization of dosing time for treatment by predicting circadian rhythms-related medicinal properties may translate into desired clinical outcomes [ 333 , 338 ]. In a randomized trial, cancer patients with a sinusoidal chronotherapy schedule showed better tolerability and efficacy to drugs than with a constant-rate infusion [ 350 ]. Another study on 186 metastatic colorectal cancer patients in a randomized multicenter phase III trial also reported that oxaliplatin, 5-FU, and chronoFLO delivered by chrono-modulated infusion reduced ~ fivefold the rate of severe mucosal toxicity and ~ 50% functional impairment from peripheral sensitive neuropathy compared with constant drug delivery (14% vs. 76% and 16% vs. 31%, respectively) [ 329 ]. Furthermore, timed administration of irinotecan was performed in 31 cancer patients and demonstrated that chrono-mediated infusion of irinotecan from 2:00 a.m. to 8:00 a.m. induced less severe diarrhea and interpatient variability compared with the conventional 30-min infusion in the morning [ 351 ]. A very recent clinical study evaluated the effect of immunotherapy time-of-day infusion on the overall survival of patients with advanced melanoma. These results suggested that adaptive immune responses are less robust when infused in the evening than in the daytime [ 352 , 353 ].

The application of a chronotherapeutic strategy for cancer treatment has stimulated developments in bioengineering, such as non-implantable multichannel time-programmable pumps for chrono-modulated drug delivery [ 354 – 356 ]. For example, in North America and the European Union, the IntelliJect™ device with four 30-mL reservoirs has been approved for treating cancer patients resulting in increased safety and efficacy of anticancer agents, based on chrono-mediated combination drug delivery of 5-FU, oxaliplatin, and leucovorin [ 328 , 336 , 357 , 358 ]. The liver is a well-known rhythmic organ. However, liver having tumor metastases shows no marked circadian regulation. When anticancer drugs were infused in a chrono-modulated way directly into the hepatic artery of patients with liver metastases beneficial effects were observed [ 359 , 360 ]. Indeed, this strategy has been confirmed as a safe and effective therapy by an international trial [ 361 ]. This study demonstrated that an automatic multichannel programmable pump, Mélodie®, could be used for treating colorectal cancer liver metastases by directly delivering anticancer agents (5-FU, oxaliplatin, irinotecan, and systemic cetuximab) into the hepatic artery, contributing to improvements in both toxic tolerability and drug effects [ 359 , 361 ].

The emerging field of nanocarrier-mediated drug delivery on chronotherapy is now attracting increasing attention as it has been shown to increase cancer curability without added side effects and risks for the patients, as well as having potential cost savings [ 362 – 364 ]. An increasing body of data is showing that chronotherapy combined with nanotechnology offers important advantages for effective drug delivery, contributing to more efficient and safer cancer therapy [ 356 , 365 – 367 ]. Recently, the synergistic anticancer effects of chrono-modulated delivery of paclitaxel (PTX)-loaded polymeric nanoparticles (PTX-NPs) were investigated on a human lung cancer-derived mouse xenograft model to identify the best time for drug delivery [ 368 – 370 ]. PTX in nanocarriers was initially rapidly released but subsequently turned into sustained release, showing a better anticancer effect than PTX single treatment [ 368 ]. Furthermore, the efficacy of PTX-NPs displayed a time-dependent effect and peaked at 15 h after light onset. Mechanically, PTX-NPs combined chronotherapy was verified to be associated with decreased Ki-67-mediated proliferation and CD31-mediated micro-vessel density, thereby resulting in inhibition of lung cancer by inducing cell apoptosis [ 368 ]. In addition to the above findings, a growing number of novel chrono-pharmaceutical delivery technologies are underway development and study. These strategies, by utilizing bedside or ambulatory pumps, facilitate more proficient cancer treatment by precisely delivering antitumor drugs in a circadian time-dependent manner.

In summary, chronotherapy is showing benefits not only for improving therapeutic efficiency but also for minimalizing the side effects of cancer treatment. However, the real application of chronotherapy in cancer treatment is still in its infancy, and more clinical trails are required to expand the clinical applications of chronotherapy in cancer treatment.

Fasting in cancer prevention and treatment

The fasting-feeding pattern is an important time cue that can also determine the robustness of daily circadian rhythms [ 371 – 374 ]. Although maintaining a robust fasting-feeding pattern is correlated with prevention of tumorigenesis, disruption of this circadian rhythm, either by time/calorie-restricted feeding or intermittent/periodic fasting, may benefit the outcome of cancer treatment [ 375 , 376 ]. For example, chronic calorie restriction (CR) and periodic fasting is attracting increasing attention for potential application to clinical cancer prevention and therapy based on long-lasting epidemiological studies and preclinical reports [ 159 , 377 – 381 ]. A diet that mimics the effects of fasting (FMD) has been developed and used in a pilot clinical study, aiming to maintain the cancer-preventive effects from CR or fasting while reducing adverse effects [ 162 , 382 ].

To date, four feasibility studies regarding cancer patients undergoing chemotherapy treated with fasting have been published [ 383 – 386 ]. In one of these studies, 10 patients with various cancers, such as lung, breast, esophageal, prostate, uterus, and ovarian cancer, volunteered to fast for 140 h before chemotherapy or for 56 h following chemotherapy. The results indicated that fasting induced no obvious adverse effects except for hunger and lightheadedness. Notably, 6 fasting patients showed a marked decrease in gastrointestinal, fatigue, and weakness events following chemotherapy. Furthermore, fasting did not compromise the anticancer effects from chemotherapy in those patients, as evidenced by no distinct difference of tumor volume or malignant markers compared to patients without fasting [ 383 ]. In line with this, 13 HER2-negative breast cancer patients were scheduled for treatment with fasting (only water supply) for 24 h or with standard nutrition regimens before and after the treatment with neo-adjuvant taxotere, adriamycin, and cyclophosphamide chemotherapy. Good tolerance was displayed to the short-term fasting, while a significant reduction of the erythrocyte and thrombocyte counts was shown at 7 days after chemotherapy [ 384 ]. Interestingly, non-fasted patients showed the upregulated expression of γ-H2AX (which indicates the levels of DNA damage) in leukocytes in 30 min after chemotherapy rather than the fasted patients [ 384 ]. Another interesting study evaluated the influence of fasting time with cancer patients. In this study, 20 patients primarily diagnosed with breast or ovarian cancer were randomized to treatment with 24- or 48-h fasting before platinum-derived chemotherapy or another 24-h fasting after platinum-derived chemotherapy (total 72-h fasting) [ 385 ]. During the fasting, three or more out of six patients in each cohort needed to consume less than 200 kcal per day. Fasting-related toxicities were only relatively minor, including dizziness, fatigue, and headache with some evidence of neutropenia in the 48- and 72-h cohorts [ 385 ]. Recently, a randomized clinical trial on 34 patients with ovarian or breast cancer was conducted to assess the effects of an FMD on life quality and side effects of chemotherapy [ 386 ]. In this study, a 36 ~ 48-h limited intake of 400 kcal per day was required before the treatment of chemotherapy. Subsequently, the same calorie limitation was performed for a further 24 h following chemotherapy [ 386 ]. From these data we can conclude that FMD does not lead to serious side effects per se, while improving chemotherapy-induced adverse reaction, like fatigue.

Therefore, fasting, either periodic or short-term, is attracting increasing attention for clinical cancer prevention and therapy and indeed displays visible effect on cancer treatment in some clinic trails, suggesting a potential adjuvant therapy for cancer in the future.

Exercise benefits cancer therapy

Timing exercise has long been utilized as a Zeitgeber for regulating circadian clock of some major body systems, such as skeletal muscle and the blood vessels [ 387 – 391 ]. Maintaining this clock might be an efficacious strategy for preventing and combating metabolic disease, including obesity, diabetes, cardiovascular disease, and cancer [ 392 – 394 ].

Accumulating literature has shown that exercise training can not only relieve treatment side effects but may also hold the potential to increase the potency and efficacy of cancer therapies [ 256 , 395 – 397 ]. Emerging evidence from pre-clinical studies has indicated that exercise regulates intratumoral vascular perfusion, systemic inflammation, sex hormone levels, and immune cell function during cancer treatment, implying that exercise may be not only healthy but also therapeutic [ 398 – 400 ].

The first line of treatment for most solid tumors is surgery, and radical tumor resection is usually considered as the most efficient therapeutic strategy, especially if the tumor is detected before it has metastasized [ 401 ]. Exercise training has been proved to be beneficial for the management of operable tumors at several distinct time points along the surgical treatment period, including the preoperative period, short-term immediately after surgery, and longer-term follow up [ 402 – 405 ] and is becoming increasingly popular. For example, in patients with early-stage lung cancer, preoperative exercise was found to improve walking endurance, peak exercise capacity, dyspnea and postoperative pulmonary complications, which are associated with the time of intensive care admissions, hospital stays, and hospital readmissions, as well as mortality in these patients [ 406 ]. Indeed, data from systematic review and meta-analysis have demonstrated that lung cancer patients undergoing an exercise regime had a lower risk of postoperative pulmonary complication, fewer days of intercostal catheter use, and a shorter length of hospitalization when compared with non-exercise patients [ 407 – 409 ]. In addition, exercise training immediately after cancer surgery is also beneficial to the outcome of cancer patients. Studies have been conducted to evaluate the effectiveness of an early onset exercise program on shoulder mobility, physical performance, and postoperative complications of breast cancer patients and found that shoulder-arm mobility of surgical breast cancer patients demonstrated significant improvement compared with the control group [ 410 , 411 ]. Moreover, longer-term exercise following surgery has been established as a feasible, safe, and effective method of decreasing postoperative side effects and improving life quality in lung cancer patients [ 412 ]. Nevertheless, the mechanisms behind the effects of exercise on surgical outcomes are still poorly understood, and further studies are needed to clarify the potential of exercise training for better cancer management in the perioperative period.

Radiotherapy is a cornerstone for cancer management, the effectiveness of which is dependent on sufficient delivery of oxygen to the tumor sites to generate enough ROS for eliminating cancer cells [ 413 , 414 ]. Exercise training is a promising adjunct therapy for cancer patients receiving radiotherapy, mainly by affecting blood circulation and oxygen delivery to the tumor location [ 415 ]. Several randomized controlled trials have reported that exercise training could mitigate fatigue in cancer patients receiving radiotherapy and generate longer-term improvements and additional benefits for quality of life [ 416 , 417 ], as well as reducing the severity of rectal toxicity during radiotherapy of prostate cancer [ 418 ]. Moreover, evidence from a preclinical mouse model of prostate cancer also demonstrated that exercise can improve radiotherapy efficiency by increasing natural killer cell infiltration and activity, resulting in increased tumor cell apoptosis [ 419 ]. However, very few clinical studies have been conducted to investigate the effect of either acute or prolonged exercise training on radiotherapy treatment response, thus delaying the application of exercise training in clinical cancer treatment.

Likewise, the efficacies of chemotherapy and immunotherapy are partially dependent on adequate intratumoral blood perfusion which can be enhanced by appropriate exercise training to assist in delivery of drugs or immune cells to the tumor sites [ 420 ]. Several preclinical studies using mouse models have found that soft aerobic exercise promotes tumor vascular function to enhance drug delivery to breast, prostate, and pancreatic tumors, thus increasing chemotherapy efficacy [ 421 – 425 ]. Moreover, exercise has been demonstrated to remodel the tumor vasculature in a PDX mouse model, which improves tumor regression and inhibits the recurrence of pancreatic ductal adenocarcinoma (PDAC) under gemcitabine treatment [ 426 ]. A previous study found that NK cell infiltration was significantly increased in tumors in wheel-running treated mice. Mechanistic analyses demonstrated that the growth suppression of tumors was attributed to an epinephrine-IL6-dependent mobilization and activation of NK cells [ 185 ]. Another recent study found that the combination of anti-PD-1 and exercise increased the percentage of CD8 + T cells and enhanced antitumor immune responses in mice with EO771 breast tumors [ 249 ]. However, much remains to be understood about the efficiency of exercise on immunotherapy in clinical cancer management.

Overall, the above findings indicate the potential therapeutic role of exercise training in cancer treatment. Nevertheless, current insights into the mechanistic effects of exercise on cancer therapy mainly stem from pre-clinical studies. Additional studies, especially a further understanding of the mechanisms involved and how they are controlled together with targeted clinical trials, are essential for a deeper understanding of the synergistic effects of exercise and conventional anticancer therapies.

Conclusions and perspectives

As discussed above, circadian control of biological processes is involved in almost all aspects of daily life, and tightly regulates multiple human behaviors, including sleep–wake, eating–fasting and activity–rest cycles. Chronic disruption of these biorhythms induced by external environmental or physiological changes may contribute to a wide range of human diseases, including sleep disorders, psychiatric and neurodegenerative diseases, cardiovascular disease, and especially cancers [ 11 , 326 , 427 – 430 ]. Indeed, several epidemiologic and animal studies have demonstrated the important role of the circadian clock in tumorigenesis and progression [ 427 ]. Although gene expression, cell division, and DNA repair are modulated by the clock, the concept that clock genes are general tumor suppressors remains unproven [ 326 ]. Moreover, tumor development will clearly cause clock disruptions, such as sleep deprivation and insufficient food intake, affecting bodily functions. This Janus effect is therefore attracting considerable interest worldwide for developing novel therapeutic strategies by modulating circadian rhythms. Table 2 summarizes the clinical studies related to clock-associated cancer therapy. Table 2 Summary of clinical studies in relation to circadian-modulated cancer therapy Treatments/drugs (targets) Study design Cancer type Main findings Ref LYC-55716 (RORγ agonist) Phase 1 clinical trials treating patients with LYC-55716 alone or in combination with pembrolizumab Relapsed metastatic cancer (NSCLC, gastroesophageal, renal cell, urothelial, and ovarian) Confirmed its safety and tolerability and choice of 450 mg BID dose for a phase 2a study [ 289 ] MLN4924 (RORα stabilization) A phase 1b study of MLN4924 plus docetaxel, gemcitabine, or combination of carboplatin and paclitaxel Solid tumors MLN4924 with docetaxel or with carboplatin plus paclitaxel was tolerable without cumulative toxicity [ 435 ] Phase 1, dose escalation study of MLN4924 in adult patients Lymphoma and multiple myeloma The population pharmacokinetic of MLN4924 was profiled [ 436 ] BTX-A51 (CKIα inhibitor) Phase 1a study to evaluate the safety, toxicity, pharmacokinetics and preliminary efficacy Relapsed or refractory acute myeloid leukemia Ongoing / Chrono-modulated capecitabine Phase 2 study to evaluate the feasibility and tolerability of capecitabine according to a specific time schedule Locally advanced primary rectal cancer Chrono-modulated capecitabine combined with adjuvant radiation therapy is tolerated and feasible [ 345 ] Chronotherapy with oxaliplatin, fluorouracil, and folinic acid Phase 3 study to test chrono-modulated infusion of oxaliplatin, fluorouracil, and folinic acid compared with a constant-rate infusion method Metastatic colorectal cancer Chronotherapy was significantly less toxic and more effective than constant-rate infusion [ 329 ] Chrono-modulated infusion of 5-fluorouracil and 5-fluorodeoxyuridine Randomized phase II trial comparing flat versus chrono-modulated infusion Hepatic metastases from colorectal cancer Supporting the use of chronotherapy in treating colorectal cancer liver metastases with combined arterial and venous fluoropyrimidine chemotherapy [ 437 ] Chrono-modulated infusion of 5-fluorouracil and mitomycin-C Phase 3 study of mitomycin-C with protracted venous infusion or circadian-timed infusion of 5-fluorouracil Advanced colorectal carcinoma Dose intensification of 5-FU using a circadian-timed infusion did not lead to improved response or survival [ 438 ] Vinorelbine combined with chrono-modulated 5-fluorouracil Phase 1 trial to study the optimal circadian time of vinorelbine combined with 5- fluorouracil Metastatic breast cancer Future optimal time-finding trials should have tolerability and/or activity as the primary endpoint in place of a particular toxicity [ 439 ] 4'-O-tetrahydropyranyl doxorubicin and cisplatin Randomized phase 2 trial to evaluate the circadian timing and dose-intensity Advanced ovarian cancer Dosing doxorubicin in the early morning and cisplatin in the late afternoon could decrease toxicities [ 434 ] Sunitinib Phase 2 study of sunitinib administered in a continuous once-daily dosing regimen Metastatic renal cell carcinoma Administration of 37.5 mg sunitinib on a continuous once-daily dosing regimen has a manageable safety profile [ 440 ] Chrono-modulated infusion of oxaliplatin in combination with capecitabine A randomized phase 2/3 trial to compare short-time and chrono-modulated infusion of oxaliplatin in combination with capecitabine Advanced colorectal cancer Infusion of 30-min oxaliplatin is safe and does not increase the severity of chronic neuropathy [ 441 ] Cisplatin-based chronotherapy A randomized controlled study to evaluate the superiority of cisplatin-based chronotherapy and pharmacokinetics for cisplatin Advanced non-small cell lung cancer Cisplatin-based chronotherapy has advantage in relieving side effects of chemotherapy [ 442 ] Chronotherapy of interleukin-2 A phase 1/2 study to evaluate the safety of IL-2 chronotherapy and determine the maximum tolerated dose Metastatic renal cell carcinoma IL-2 chronotherapy is safe, moderately toxic and active in metastatic RCC [ 443 ] Chrono-modulated capecitabine treatment A phase 1 study to evaluate the pharmacology of continuous chrono-modulated capecitabine treatment Advanced solid tumors Chrono-modulated treatment with capecitabine can lead to improved tolerability and efficacy [ 444 ] Cetuximab and circadian chrono-modulated chemotherapy A clinical trial to study safety, efficacy and improved secondary surgical resectability of combinational treatment Metastatic colorectal cancer Cetuximab combined with chronotherapy shows safe and effective therapeutic control of metastases [ 445 ] Chrono-modulated treatment of oxaliplatin, 5-fluorouracil and sodium folinate A clinical trial to evaluate non-hematological toxicity and patient characteristics treated with chrono-modulated chemotherapy Metastatic gastrointestinal cancer The chrono-modulated regimen with oxaliplatin, 5-FU and sodium folinate displays a manageable toxicity which depends on the patient characteristics [ 446 ]

There are, however, some concerns that need to be addressed before the successful application of combining conventional treatment with targeting of the circadian clock for clinical cancer management. Firstly, targeting one of the clock components may prove no more effective than combinational therapeutic strategies using two or more targeted drugs. Secondly, the circadian clock can coordinate disparate cellular pathways. This may result in unwanted side effects or even opposite outcomes during treatment. Therefore, determining the appropriate dosage to successfully target circadian rhythm to obtain transient repression rather than chronic treatment may be required to avoid detrimental effects. Most importantly, the preclinical efficacy of manipulating circadian rhythms needs to be extended to larger study cohorts [ 327 , 431 ], as results from a previous study with a small sample size claiming a substantial effect of chronotherapy on ovarian cancer were not reproduced in subsequent larger studies [ 432 – 434 ].

In summary, circadian rhythms participate in diverse biological pathways. Their manipulation holds the promise for beneficial treatment of not only cancer, but also other serious diseases. Based on significant advances in this area, which was honored by the 2017 Nobel Prize for Physiology or Medicine awarded jointly to Jeffrey C. Hall, Michael Rosbash and Michael W. Young, we believe that it will have excellent clinical potential in the near future.

Abbreviations

Acute myeloid leukemia

Brain and muscle aryl hydrocarbon receptor nuclear translocator 1

Casein kinase Iε

Circadian locomotor output cycles kaput

Calorie restriction

Colorectal cancer

C-reactive protein

Diethylnitrosamine

Differential stress resistance

Differential stress sensitization

Equilibrative nucleoside transporter 1

Fasting-mimicking diets

Growth hormone

Glioblastoma stem cell

Histone deacetylases

International Agency for Research on Cancer

Indoleamine 2,3-dioxygenase

Interferon

Lymphokine-activated killer

Limited ingredient diet

Natural killer

Nitric oxide

Non-rapid eye movement

Oncostatin M

Pancreatic ductal adenocarcinoma

Platelet derived growth factor receptor-beta

Protein PR/SET domain 1

Prolactin

Rapid eyes movement

Subfamilies of nuclear hormone receptors

Reactive oxygen species

Small-cell lung cancer

Suprachiasmatic nucleus

Soluble intercellular adhesions molecule

Secreted protein acidic and rich in cysteine

Short-term fasting

Slow-wave sleep

Tumor-associated macrophages

Tricarboxylic acid

Tumor-infiltrating lymphocytes

Tyrosine kinase inhibitors

Toll-like receptor 4

Vascular endothelial growth factor

World Health Organization

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Li Zhou and Zhe Zhang contribute equally to this work

Acknowledgements

Not applicable.

Authors' contributions

YT, WZ, and CH designed this manuscript. LZ and ZZ drafted the manuscript and drew the figures. EN revised the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by grants from National Key Research and Development Program of China (2020YFA0509400, 2019YFC1709101), Guangdong Basic and Applied Basic Research Foundation (2019B030302012), 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYJC21004), National Natural Science Foundation of China (81821002, 82130082, 81790251, 82003098 and 82103168), the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-D-202003), and Sichuan Science and Technology Program (2019YFH0108, 22GJHZ0007).

Availability of data and materials

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors have read and approved the final manuscript.

Competing interests

The authors declared that they have no competing interests.

References

1. Patke A Young MW Axelrod S Molecular mechanisms and physiological importance of circadian rhythms Nat Rev Mol Cell Biol 2020 21 67 84 31768006 10.1038/s41580-019-0179-2

2. Roenneberg T Merrow M Circadian clocks—the fall and rise of physiology Nat Rev Mol Cell Biol 2005 6 965 971 16341082 10.1038/nrm1766

3. Winfree AT Acute temperature sensitivity of the circadian rhythm in Drosophila J Insect Physiol 1972 18 181 185

4. Zimmerman WF Pittendrigh CS Pavlidis T Temperature compensation of the circadian oscillation in Drosophila pseudoobscura and its entrainment by temperature cycles J Insect Physiol 1968 14 669 684 5655535 10.1016/0022-1910(68)90226-6

5. Dunlap JC Genetic and molecular analysis of circadian rhythms Annu Rev Genet 1996 30 579 601 8982466 10.1146/annurev.genet.30.1.579

6. Dunlap JC Loros JJ Liu Y Crosthwaite SK Eukaryotic circadian systems: cycles in common Genes Cells 1999 4 01 10 10.1046/j.1365-2443.1999.00239.x 10231388

7. Gekakis N Staknis D Nguyen HB Davis FC Wilsbacher LD King DP Takahashi JS Weitz CJ Role of the CLOCK protein in the mammalian circadian mechanism Science 1998 280 1564 1569 9616112 10.1126/science.280.5369.1564

8. Honma S Ikeda M Abe H Tanahashi Y Namihira M Honma K-I Nomura M Circadian oscillation ofBMAL1, a partner of a mammalian clock GeneClock, in rat suprachiasmatic nucleus Biochem Biophys Res Commun 1998 250 83 87 9735336 10.1006/bbrc.1998.9275

9. Liu C Weaver DR Strogatz SH Reppert SM Cellular construction of a circadian clock: period determination in the suprachiasmatic nuclei Cell 1997 91 855 860 9413994 10.1016/s0092-8674(00)80473-0

10. Reinke H Asher G Crosstalk between metabolism and circadian clocks Nat Rev Mol Cell Biol 2019 20 227 241 30635659 10.1038/s41580-018-0096-9

11. Musiek ES Holtzman DM Mechanisms linking circadian clocks, sleep, and neurodegeneration Science 2016 354 1004 1008 27885006 10.1126/science.aah4968 PMC5219881

12. Richards J Gumz ML Advances in understanding the peripheral circadian clocks FASEB J 2012 26 3602 3613 22661008 10.1096/fj.12-203554 PMC3425819

13. Durgan DJ Young ME The cardiomyocyte circadian clock: emerging roles in health and disease Circ Res 2010 106 647 658 20203314 10.1161/CIRCRESAHA.109.209957 PMC3223121

14. Hanahan D Weinberg RA Hallmarks of cancer: the next generation Cell 2011 144 646 674 21376230 10.1016/j.cell.2011.02.013

15. Hanahan D Weinberg RA The hallmarks of cancer Cell 2000 100 57 70 10647931 10.1016/s0092-8674(00)81683-9

16. Straif K Baan R Grosse Y Secretan B El Ghissassi F Bouvard V Altieri A Benbrahim-Tallaa L Cogliano V Group WIAfRoCMW Carcinogenicity of shift-work, painting, and fire-fighting 2007 Elsevier 10.1016/S1470-2045(07)70373-X 19271347

17. Stevens RG Hansen J Costa G Haus E Kauppinen T Aronson KJ Castaño-Vinyals G Davis S Frings-Dresen MH Fritschi L Considerations of circadian impact for defining ‘shift work’in cancer studies: IARC working group report Occup Environ Med 2011 68 154 162 20962033 10.1136/oem.2009.053512

18. Lin H-H Farkas ME Altered circadian rhythms and breast cancer: from the human to the molecular level Front Endocrinol (Lausanne) 2018 9 219 29780357 10.3389/fendo.2018.00219 PMC5945923

19. Wendeu-Foyet MG Menegaux F Circadian disruption and prostate cancer risk: an updated review of epidemiological evidences Cancer Epidemiol Biomark Prev 2017 26 985 991 10.1158/1055-9965.EPI-16-1030 28377415

20. Innominato PF Focan C Gorlia T Moreau T Garufi C Waterhouse J Giacchetti S Coudert B Iacobelli S Genet D Circadian rhythm in rest and activity: a biological correlate of quality of life and a predictor of survival in patients with metastatic colorectal cancer Cancer Res 2009 69 4700 4707 19470769 10.1158/0008-5472.CAN-08-4747 PMC2690615

21. Bishehsari F Levi F Turek FW Keshavarzian A Circadian rhythms in GI health and diseases Gastroenterology 2016 151 e1 27480174 10.1053/j.gastro.2016.07.036 PMC5002365

22. Tahara Y Shibata S Circadian rhythms of liver physiology and disease: experimental and clinical evidence Nat Rev Gastroenterol Hepatol 2016 13 217 26907879 10.1038/nrgastro.2016.8

23. Papagiannakopoulos T Bauer MR Davidson SM Heimann M Subbaraj L Bhutkar A Bartlebaugh J Vander Heiden MG Jacks T Circadian rhythm disruption promotes lung tumorigenesis Cell Metab 2016 24 324 331 27476975 10.1016/j.cmet.2016.07.001 PMC5367626

24. Voigt RM Forsyth CB Green SJ Engen PA Keshavarzian A Circadian rhythm and the gut microbiome Int Rev Neurobiol 2016 131 193 205 27793218 10.1016/bs.irn.2016.07.002

25. Gery S Koeffler HP Circadian rhythms and cancer Cell Cycle 2010 9 1097 1103 20237421 10.4161/cc.9.6.11046 PMC5884684

26. Lévi F Circadian chronotherapy for human cancers Lancet Oncol 2001 2 307 315 11905786 10.1016/S1470-2045(00)00326-0

27. Kelleher FC Rao A Maguire A Circadian molecular clocks and cancer Cancer Lett 2014 342 9 18 24099911 10.1016/j.canlet.2013.09.040

28. Schibler U Sassone-Corsi P A web of circadian pacemakers Cell 2002 111 919 922 12507418 10.1016/s0092-8674(02)01225-4

29. Ozturk N Ozturk D Kavakli IH Okyar A Molecular aspects of circadian pharmacology and relevance for cancer chronotherapy Int J Mol Sci 2017 18 2168 10.3390/ijms18102168 PMC5666849 29039812

30. Rosenwasser AM Turek FW Neurobiology of circadian rhythm regulation Sleep Med Clin 2015 10 403 412 26568118 10.1016/j.jsmc.2015.08.003

31. Hastings MH Maywood ES Brancaccio M Generation of circadian rhythms in the suprachiasmatic nucleus Nat Rev Neurosci 2018 19 453 469 29934559 10.1038/s41583-018-0026-z

32. Shearman LP Sriram S Weaver DR Maywood ES Chaves I Zheng B Kume K Lee CC van der Horst GT Hastings MH Interacting molecular loops in the mammalian circadian clock Science 2000 288 1013 1019 10807566 10.1126/science.288.5468.1013

33. Haque SN Booreddy SR Welsh DK Effects of BMAL1 manipulation on the brain's master circadian clock and behavior Yale J Biol Med 2019 92 251 258 31249486 PMC6585533

34. Kondratov RV Shamanna RK Kondratova AA Gorbacheva VY Antoch MP Dual role of the CLOCK/BMAL1 circadian complex in transcriptional regulation FASEB J 2006 20 530 532 16507766 10.1096/fj.05-5321fje

35. Vielhaber EL Duricka D Ullman KS Virshup DM Nuclear export of mammalian PERIOD proteins J Biol Chem 2001 276 45921 45927 11591712 10.1074/jbc.M107726200 PMC1513547

36. Akashi M Okamoto A Tsuchiya Y Todo T Nishida E Node K A positive role for PERIOD in mammalian circadian gene expression Cell Rep 2014 7 1056 1064 24794436 10.1016/j.celrep.2014.03.072

37. Schmalen I Reischl S Wallach T Klemz R Grudziecki A Prabu JR Benda C Kramer A Wolf E Interaction of circadian clock proteins CRY1 and PER2 is modulated by zinc binding and disulfide bond formation Cell 2014 157 1203 1215 24855952 10.1016/j.cell.2014.03.057

38. Lee H Lee JW The roles of CKI in circadian rhythm Future Med Chem 2019 11 2621 2624 31556695 10.4155/fmc-2019-0179

39. Ukai-Tadenuma M Kasukawa T Ueda HR Proof-by-synthesis of the transcriptional logic of mammalian circadian clocks Nat Cell Biol 2008 10 1154 1163 18806789 10.1038/ncb1775

40. Duez H Staels B Rev-erb-alpha: an integrator of circadian rhythms and metabolism J Appl Physiol 1985 2009 107 1972 1980 10.1152/japplphysiol.00570.2009 PMC2966474 19696364

41. Ikeda R Tsuchiya Y Koike N Umemura Y Inokawa H Ono R Inoue M Sasawaki Y Grieten T Okubo N REV-ERBalpha and REV-ERBbeta function as key factors regulating Mammalian Circadian Output Sci Rep 2019 9 10171 31308426 10.1038/s41598-019-46656-0 PMC6629614

42. Jetten AM Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism Nucl Recept Signal 2009 7 e003 19381306 10.1621/nrs.07003 PMC2670432

43. Reszka E Przybek M Muurlink O Peplonska B Circadian gene variants and breast cancer Cancer Lett 2017 390 137 145 28109907 10.1016/j.canlet.2017.01.012

44. Morgan MN Dvuchbabny S Martinez CA Kerr B Cistulli PA Cook KM The cancer clock is (not) ticking: links between circadian rhythms and cancer Clocks Sleep 2019 1 435 458 33089179 10.3390/clockssleep1040034 PMC7445810

45. Chu LW Till C Yang B Tangen CM Goodman PJ Yu K Zhu Y Han S Hoque AM Ambrosone C Circadian genes and risk of prostate cancer in the prostate cancer prevention trial Mol Carcinog 2018 57 462 466 29318656 10.1002/mc.22770 PMC5940353

46. Arafa K Emara M Insights about circadian clock and molecular pathogenesis in gliomas Front Oncol 2020 10 199 32195174 10.3389/fonc.2020.00199 PMC7061216

47. Sulli G Lam MTY Panda S Interplay between circadian clock and cancer: new frontiers for cancer treatment Trends Cancer 2019 5 475 494 31421905 10.1016/j.trecan.2019.07.002 PMC7120250

48. Straif K Baan R Grosse Y Secretan B El Ghissassi F Bouvard V Altieri A Benbrahim-Tallaa L Cogliano V Carcinogenicity of shift-work, painting, and fire-fighting Lancet Oncol 2007 8 1065 1066 19271347 10.1016/S1470-2045(07)70373-X

49. Salamanca-Fernández E Rodríguez-Barranco M Guevara M Ardanaz E Olry de Labry Lima A Sánchez MJ Night-shift work and breast and prostate cancer risk: updating the evidence from epidemiological studies An Sist Sanit Navar 2018 41 211 226 30063040 10.23938/ASSN.0307

50. Gehlert S Clanton M On Behalf Of The Shift W Breast Cancer Strategic Advisory G Shift work and breast cancer Int J Environ Res Public Health 2020 17 9544 10.3390/ijerph17249544 PMC7767214 33419321

51. Hansen J Night shift work and risk of breast cancer Curr Environ Health Rep 2017 4 325 339 28770538 10.1007/s40572-017-0155-y

52. Travis RC Balkwill A Fensom GK Appleby PN Reeves GK Wang XS Roddam AW Gathani T Peto R Green J Night shift work and breast cancer incidence: three prospective studies and meta-analysis of published studies J Natl Cancer Inst 2016 108 djw169 27758828 10.1093/jnci/djw169 PMC5241898

53. Kogevinas M Espinosa A Castelló A Gómez-Acebo I Guevara M Martin V Amiano P Alguacil J Peiro R Moreno V Effect of mistimed eating patterns on breast and prostate cancer risk (MCC-Spain Study) Int J Cancer 2018 143 2380 2389 30016830 10.1002/ijc.31649 PMC6220994

54. Marinac CR Natarajan L Sears DD Gallo LC Hartman SJ Arredondo E Patterson RE Prolonged nightly fasting and breast cancer risk: findings from NHANES (2009–2010) Cancer Epidemiol Biomark Prev 2015 24 783 789 10.1158/1055-9965.EPI-14-1292 PMC4417458 25896523

55. Mormont MC Waterhouse J Bleuzen P Giacchetti S Jami A Bogdan A Lellouch J Misset JL Touitou Y Lévi F Marked 24-h rest/activity rhythms are associated with better quality of life, better response, and longer survival in patients with metastatic colorectal cancer and good performance status Clin Cancer Res 2000 6 3038 3045 10955782

56. Innominato PF Komarzynski S Palesh OG Dallmann R Bjarnason GA Giacchetti S Ulusakarya A Bouchahda M Haydar M Ballesta A Circadian rest-activity rhythm as an objective biomarker of patient-reported outcomes in patients with advanced cancer Cancer Med 2018 7 4396 4405 30088335 10.1002/cam4.1711 PMC6143939

57. Wood PA Yang X Taber A Oh EY Ansell C Ayers SE Al-Assaad Z Carnevale K Berger FG Peña MM Period 2 mutation accelerates ApcMin/+ tumorigenesis Mol Cancer Res 2008 6 1786 1793 19010825 10.1158/1541-7786.MCR-08-0196 PMC4136553

58. Fu L Pelicano H Liu J Huang P Lee C The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo Cell 2002 111 41 50 12372299 10.1016/s0092-8674(02)00961-3

59. Mteyrek A Filipski E Guettier C Okyar A Lévi F Clock gene Per2 as a controller of liver carcinogenesis Oncotarget 2016 7 85832 85847 27494874 10.18632/oncotarget.11037 PMC5349878

60. Lee S Donehower LA Herron AJ Moore DD Fu L Disrupting circadian homeostasis of sympathetic signaling promotes tumor development in mice PLoS ONE 2010 5 e10995 20539819 10.1371/journal.pone.0010995 PMC2881876

61. Ueda E Kurebayashi S Sakaue M Backlund M Koller B Jetten AM High incidence of T-cell lymphomas in mice deficient in the retinoid-related orphan receptor RORgamma Cancer Res 2002 62 901 909 11830550

62. Gu X Xing L Shi G Liu Z Wang X Qu Z Wu X Dong Z Gao X Liu G The circadian mutation PER2(S662G) is linked to cell cycle progression and tumorigenesis Cell Death Differ 2012 19 397 405 21818120 10.1038/cdd.2011.103 PMC3278723

63. Antoch MP Gorbacheva VY Vykhovanets O Toshkov IA Kondratov RV Kondratova AA Lee C Nikitin AY Disruption of the circadian clock due to the Clock mutation has discrete effects on aging and carcinogenesis Cell Cycle 2008 7 1197 1204 18418054 10.4161/cc.7.9.5886 PMC2744375

64. Antoch MP Toshkov I Kuropatwinski KK Jackson M Deficiency in PER proteins has no effect on the rate of spontaneous and radiation-induced carcinogenesis Cell Cycle 2013 12 3673 3680 24091726 10.4161/cc.26614 PMC3903718

65. Janich P Pascual G Merlos-Suárez A Batlle E Ripperger J Albrecht U Cheng HY Obrietan K Di Croce L Benitah SA The circadian molecular clock creates epidermal stem cell heterogeneity Nature 2011 480 209 214 22080954 10.1038/nature10649

66. Puram RV Kowalczyk MS de Boer CG Schneider RK Miller PG McConkey M Tothova Z Tejero H Heckl D Järås M Core circadian clock genes regulate leukemia stem cells in AML Cell 2016 165 303 316 27058663 10.1016/j.cell.2016.03.015 PMC4826477

67. Disruption of core circadian clock genes reduces leukemia growth. Cancer Discov. 2016;6:569. 10.1158/2159-8290.CD-RW2016-074 27102075

68. Lee JH Gaddameedhi S Ozturk N Ye R Sancar A DNA damage-specific control of cell death by cryptochrome in p53-mutant ras-transformed cells Cancer Res 2013 73 785 791 23149912 10.1158/0008-5472.CAN-12-1994 PMC3548992

69. Chan AB Parico GCG Fribourgh JL Ibrahim LH Bollong MJ Partch CL Lamia KA CRY2 missense mutations suppress P53 and enhance cell growth Proc Natl Acad Sci USA 2021 118 4077 10.1073/pnas.2101416118 PMC8271769 34183418

70. Lange T Dimitrov S Born J Effects of sleep and circadian rhythm on the human immune system Ann N Y Acad Sci 2010 1193 48 59 20398008 10.1111/j.1749-6632.2009.05300.x

71. Petrovsky N Towards a unified model of neuroendocrine-immune interaction Immunol Cell Biol 2001 79 350 357 11488982 10.1046/j.1440-1711.2001.01029.x

72. Haus E Smolensky MH Biologic rhythms in the immune system Chronobiol Int 1999 16 581 622 10513884 10.3109/07420529908998730

73. Liu X Chen B Huang Z Duan R Li H Xie L Wang R Li Z Gao Y Zheng Y Effects of poor sleep on the immune cell landscape as assessed by single-cell analysis Commun Biol 2021 4 1325 34824394 10.1038/s42003-021-02859-8 PMC8617259

74. Brooks JF 2nd Behrendt CL Ruhn KA Lee S Raj P Takahashi JS Hooper LV The microbiota coordinates diurnal rhythms in innate immunity with the circadian clock Cell 2021 184 4154 67.e12 34324837 10.1016/j.cell.2021.07.001 PMC8967342

75. Dimitrov S Lange T Fehm HL Born J A regulatory role of prolactin, growth hormone, and corticosteroids for human T-cell production of cytokines Brain Behav Immun 2004 18 368 374 15157954 10.1016/j.bbi.2003.09.014

76. Dimitrov S Lange T Tieken S Fehm HL Born J Sleep associated regulation of T helper 1/T helper 2 cytokine balance in humans Brain Behav Immun 2004 18 341 348 15157951 10.1016/j.bbi.2003.08.004

77. Lange T Dimitrov S Fehm HL Westermann J Born J Shift of monocyte function toward cellular immunity during sleep Arch Intern Med 2006 166 1695 1700 16983046 10.1001/archinte.166.16.1695

78. Irwin M Mascovich A Gillin JC Willoughby R Pike J Smith TL Partial sleep deprivation reduces natural killer cell activity in humans Psychosom Med 1994 56 493 498 7871104 10.1097/00006842-199411000-00004

79. Irwin M McClintick J Costlow C Fortner M White J Gillin JC Partial night sleep deprivation reduces natural killer and cellular immune responses in humans FASEB J 1996 10 643 653 8621064 10.1096/fasebj.10.5.8621064

80. Schernhammer ES Laden F Speizer FE Willett WC Hunter DJ Kawachi I Fuchs CS Colditz GA Night-shift work and risk of colorectal cancer in the nurses' health study J Natl Cancer Inst 2003 95 825 828 12783938 10.1093/jnci/95.11.825

81. Schernhammer ES Razavi P Li TY Qureshi AA Han J Rotating night shifts and risk of skin cancer in the nurses' health study J Natl Cancer Inst 2011 103 602 606 21335547 10.1093/jnci/djr044 PMC3071354

82. Papantoniou K Devore EE Massa J Strohmaier S Vetter C Yang L Shi Y Giovannucci E Speizer F Schernhammer ES Rotating night shift work and colorectal cancer risk in the nurses' health studies Int J Cancer 2018 143 2709 2717 29978466 10.1002/ijc.31655 PMC6235706

83. Irwin MR Wang M Campomayor CO Collado-Hidalgo A Cole S Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation Arch Intern Med 2006 166 1756 1762 16983055 10.1001/archinte.166.16.1756

84. Irwin MR Wang M Ribeiro D Cho HJ Olmstead R Breen EC Martinez-Maza O Cole S Sleep loss activates cellular inflammatory signaling Biol Psychiatry 2008 64 538 540 18561896 10.1016/j.biopsych.2008.05.004 PMC2547406

85. Dimitrov S Lange T Benedict C Nowell MA Jones SA Scheller J Rose-John S Born J Sleep enhances IL-6 trans-signaling in humans FASEB J 2006 20 2174 2176 16912152 10.1096/fj.06-5754fje

86. van Leeuwen WM Lehto M Karisola P Lindholm H Luukkonen R Sallinen M Härmä M Porkka-Heiskanen T Alenius H Sleep restriction increases the risk of developing cardiovascular diseases by augmenting proinflammatory responses through IL-17 and CRP PLoS ONE 2009 4 e4589 19240794 10.1371/journal.pone.0004589 PMC2643002

87. Puttonen S Kivimäki M Elovainio M Pulkki-Råback L Hintsanen M Vahtera J Telama R Juonala M Viikari JS Raitakari OT Shift work in young adults and carotid artery intima-media thickness: The Cardiovascular Risk in Young Finns study Atherosclerosis 2009 205 608 613 19215924 10.1016/j.atherosclerosis.2009.01.016

88. Irwin MR Sleep and inflammation: partners in sickness and in health Nat Rev Immunol 2019 19 702 715 31289370 10.1038/s41577-019-0190-z

89. Vgontzas AN Papanicolaou DA Bixler EO Lotsikas A Zachman K Kales A Prolo P Wong ML Licinio J Gold PW Circadian interleukin-6 secretion and quantity and depth of sleep J Clin Endocrinol Metab 1999 84 2603 2607 10443646 10.1210/jcem.84.8.5894

90. Dimitrov S Besedovsky L Born J Lange T Differential acute effects of sleep on spontaneous and stimulated production of tumor necrosis factor in men Brain Behav Immun 2015 47 201 210 25500219 10.1016/j.bbi.2014.11.017

91. Redwine L Dang J Hall M Irwin M Disordered sleep, nocturnal cytokines, and immunity in alcoholics Psychosom Med 2003 65 75 85 12554818 10.1097/01.psy.0000038943.33335.d2

92. Redwine L Hauger RL Gillin JC Irwin M Effects of sleep and sleep deprivation on interleukin-6, growth hormone, cortisol, and melatonin levels in humans J Clin Endocrinol Metab 2000 85 3597 3603 11061508 10.1210/jcem.85.10.6871

93. Knutson KL Spiegel K Penev P Van Cauter E The metabolic consequences of sleep deprivation Sleep Med Rev 2007 11 163 178 17442599 10.1016/j.smrv.2007.01.002 PMC1991337

94. Mullington JM Haack M Toth M Serrador JM Meier-Ewert HK Cardiovascular, inflammatory, and metabolic consequences of sleep deprivation Prog Cardiovasc Dis 2009 51 294 302 19110131 10.1016/j.pcad.2008.10.003 PMC3403737

95. Aldabal L Bahammam AS Metabolic, endocrine, and immune consequences of sleep deprivation Open Respir Med J 2011 5 31 43 21754974 10.2174/1874306401105010031 PMC3132857

96. Kuhs H Farber D Tolle R Serum prolactin, growth hormone, total corticoids, thyroid hormones and thyrotropine during serial therapeutic sleep deprivation Biol Psychiatry 1996 39 857 864 9172706 10.1016/0006-3223(95)00240-5

97. Spiegel K Leproult R L'Hermite-Balériaux M Copinschi G Penev PD Van Cauter E Leptin levels are dependent on sleep duration: relationships with sympathovagal balance, carbohydrate regulation, cortisol, and thyrotropin J Clin Endocrinol Metab 2004 89 5762 5771 15531540 10.1210/jc.2004-1003

98. Morgan L Hampton S Gibbs M Arendt J Circadian aspects of postprandial metabolism Chronobiol Int 2003 20 795 808 14535354 10.1081/cbi-120024218

99. Knutsson A Hammar N Karlsson B Shift workers' mortality scrutinized Chronobiol Int 2004 21 1049 1053 15646249 10.1081/cbi-200035942

100. Tanaka K Sakata K Oishi M Morimoto H Nakada S Uetani M Nogawa K Suwazono Y Estimation of the benchmark duration of shiftwork associated with weight gain in male Japanese workers Chronobiol Int 2010 27 1895 1910 20969530 10.3109/07420528.2010.516045

101. Karlsson B Knutsson A Lindahl B Is there an association between shift work and having a metabolic syndrome? Results from a population based study of 27,485 people Occup Environ Med 2001 58 747 752 11600731 10.1136/oem.58.11.747 PMC1740071

102. van Amelsvoort LG Schouten EG Kok FJ Duration of shiftwork related to body mass index and waist to hip ratio Int J Obes Relat Metab Disord 1999 23 973 978 10490804 10.1038/sj.ijo.0801028

103. Yoshida J Eguchi E Nagaoka K Ito T Ogino K Association of night eating habits with metabolic syndrome and its components: a longitudinal study BMC Public Health 2018 18 1366 30537972 10.1186/s12889-018-6262-3 PMC6288903

104. Al-Aubaidy HA Jelinek HF Oxidative DNA damage and obesity in type 2 diabetes mellitus Eur J Endocrinol 2011 164 899 904 21436346 10.1530/EJE-11-0053

105. Ligibel J Obesity and breast cancer Oncology (Williston Park) 2011 25 994 1000 22106549

106. O'Connor MJ Targeting the DNA damage response in cancer Mol Cell 2015 60 547 560 26590714 10.1016/j.molcel.2015.10.040

107. Srinivas US Tan BWQ Vellayappan BA Jeyasekharan AD ROS and the DNA damage response in cancer Redox Biol 2019 25 101084 30612957 10.1016/j.redox.2018.101084 PMC6859528

108. Ribezzo F Shiloh Y Schumacher B Systemic DNA damage responses in aging and diseases Semin Cancer Biol 2016 37–38 26 35 26773346 10.1016/j.semcancer.2015.12.005 PMC4886830

109. Zisapel N New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation Br J Pharmacol 2018 175 3190 3199 29318587 10.1111/bph.14116 PMC6057895

110. Galano A Tan DX Reiter RJ Melatonin: a versatile protector against oxidative DNA damage Molecules 2018 23 530 10.3390/molecules23030530 PMC6017920 29495460

111. Majidinia M Sadeghpour A Mehrzadi S Reiter RJ Khatami N Yousefi B Melatonin: A pleiotropic molecule that modulates DNA damage response and repair pathways J Pineal Res 2017 63 e12416 10.1111/jpi.12416 28439991

112. Wei T Li C Heng Y Gao X Zhang G Wang H Zhao X Meng Z Zhang Y Hou H Association between night-shift work and level of melatonin: systematic review and meta-analysis Sleep Med 2020 75 502 509 33022488 10.1016/j.sleep.2020.09.018

113. Bhatti P Mirick DK Randolph TW Gong J Buchanan DT Zhang JJ Davis S Oxidative DNA damage during sleep periods among nightshift workers Occup Environ Med 2016 73 537 544 27307003 10.1136/oemed-2016-103629

114. Bhatti P Mirick DK Randolph TW Gong J Buchanan DT Zhang JJ Davis S Oxidative DNA damage during night shift work Occup Environ Med 2017 74 680 683 28652381 10.1136/oemed-2017-104414

115. Cheung V Yuen VM Wong GTC Choi SW The effect of sleep deprivation and disruption on DNA damage and health of doctors Anaesthesia 2019 74 434 440 30675716 10.1111/anae.14533

116. Koritala BSC Porter KI Arshad OA Gajula RP Mitchell HD Arman T Manjanatha MG Teeguarden J Van Dongen HPA McDermott JE Night shift schedule causes circadian dysregulation of DNA repair genes and elevated DNA damage in humans J Pineal Res 2021 70 e12726 33638890 10.1111/jpi.12726 PMC8011353

117. Ashok Kumar PV Dakup PP Sarkar S Modasia JB Motzner MS Gaddameedhi S It's about time: advances in understanding the circadian regulation of DNA damage and repair in carcinogenesis and cancer treatment outcomes Yale J Biol Med 2019 92 305 316 31249491 PMC6585512

118. Zada D Sela Y Matosevich N Monsonego A Lerer-Goldshtein T Nir Y Appelbaum L Parp1 promotes sleep, which enhances DNA repair in neurons Mol Cell 2021 81 4979 4993.e7 34798058 10.1016/j.molcel.2021.10.026 PMC8688325

119. Vaccaro A Kaplan Dor Y Nambara K Pollina EA Lin C Greenberg ME Rogulja D Sleep loss can cause death through accumulation of reactive oxygen species in the gut Cell 2020 181 1307 28.e15 32502393 10.1016/j.cell.2020.04.049

120. Neuzillet C Tijeras-Raballand A Cohen R Cros J Faivre S Raymond E de Gramont A Targeting the TGFβ pathway for cancer therapy Pharmacol Ther 2015 147 22 31 25444759 10.1016/j.pharmthera.2014.11.001

121. Opp MR Cytokines and sleep Sleep Med Rev 2005 9 355 364 16102986 10.1016/j.smrv.2005.01.002

122. Dantzer R O'Connor JC Freund GG Johnson RW Kelley KW From inflammation to sickness and depression: when the immune system subjugates the brain Nat Rev Neurosci 2008 9 46 56 18073775 10.1038/nrn2297 PMC2919277

123. Voronov E Shouval DS Krelin Y Cagnano E Benharroch D Iwakura Y Dinarello CA Apte RN IL-1 is required for tumor invasiveness and angiogenesis Proc Natl Acad Sci USA 2003 100 2645 2650 12598651 10.1073/pnas.0437939100 PMC151394

124. Liu X Nemeth DP McKim DB Zhu L DiSabato DJ Berdysz O Gorantla G Oliver B Witcher KG Wang Y Cell-type-specific interleukin 1 receptor 1 signaling in the brain regulates distinct neuroimmune activities Immunity 2019 50 317 33.e6 30683620 10.1016/j.immuni.2018.12.012 PMC6759085

125. Walker WH II Borniger JC Molecular mechanisms of cancer-induced sleep disruption Int J Mol Sci 2019 20 2780 10.3390/ijms20112780 PMC6600154 31174326

126. Imeri L Opp MR Krueger JM An IL-1 receptor and an IL-1 receptor antagonist attenuate muramyl dipeptide- and IL-1-induced sleep and fever Am J Physiol 1993 265 R907 R913 8238464 10.1152/ajpregu.1993.265.4.R907

127. Opp MR Krueger JM Anti-interleukin-1 beta reduces sleep and sleep rebound after sleep deprivation in rats Am J Physiol 1994 266 R688 R695 8160860 10.1152/ajpregu.1994.266.3.R688

128. Alam MN McGinty D Bashir T Kumar S Imeri L Opp MR Szymusiak R Interleukin-1beta modulates state-dependent discharge activity of preoptic area and basal forebrain neurons: role in sleep regulation Eur J Neurosci 2004 20 207 216 15245493 10.1111/j.1460-9568.2004.03469.x

129. Kapás L Shibata M Kimura M Krueger JM Inhibition of nitric oxide synthesis suppresses sleep in rabbits Am J Physiol 1994 266 R151 R157 8304536 10.1152/ajpregu.1994.266.1.R151

130. Takahashi S Kapás L Fang J Krueger JM Somnogenic relationships between tumor necrosis factor and interleukin-1 Am J Physiol 1999 276 R1132 R1140 10198395 10.1152/ajpregu.1999.276.4.R1132

131. Bauer J Hohagen F Ebert T Timmer J Ganter U Krieger S Lis S Postler E Voderholzer U Berger M Interleukin-6 serum levels in healthy persons correspond to the sleep-wake cycle Clin Investig 1994 72 315 8043981 10.1007/BF00180048

132. Späth-Schwalbe E Hansen K Schmidt F Schrezenmeier H Marshall L Burger K Fehm HL Born J Acute effects of recombinant human interleukin-6 on endocrine and central nervous sleep functions in healthy men J Clin Endocrinol Metab 1998 83 1573 1579 9589658 10.1210/jcem.83.5.4795

133. Opp M Obal F Jr Cady AB Johannsen L Krueger JM Interleukin-6 is pyrogenic but not somnogenic Physiol Behav 1989 45 1069 1072 2476835 10.1016/0031-9384(89)90239-4

134. Hogan D Morrow JD Smith EM Opp MR Interleukin-6 alters sleep of rats J Neuroimmunol 2003 137 59 66 12667648 10.1016/s0165-5728(03)00038-9

135. Bryant PA Trinder J Curtis N Sick and tired: does sleep have a vital role in the immune system? Nat Rev Immunol 2004 4 457 467 15173834 10.1038/nri1369

136. Irwin M Effects of sleep and sleep loss on immunity and cytokines Brain Behav Immun 2002 16 503 512 12401464 10.1016/s0889-1591(02)00003-x

137. Kerr J Anderson C Lippman SM Physical activity, sedentary behaviour, diet, and cancer: an update and emerging new evidence Lancet Oncol 2017 18 e457 e471 28759385 10.1016/S1470-2045(17)30411-4 PMC10441558

138. Kushi LH Doyle C McCullough M Rock CL Demark-Wahnefried W Bandera EV Gapstur S Patel AV Andrews K Gansler T American Cancer Society Guidelines on nutrition and physical activity for cancer prevention: reducing the risk of cancer with healthy food choices and physical activity CA Cancer J Clin 2012 62 30 67 22237782 10.3322/caac.20140

139. Calle EE Rodriguez C Walker-Thurmond K Thun MJ Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults N Engl J Med 2003 348 1625 1638 12711737 10.1056/NEJMoa021423

140. Lee C Raffaghello L Brandhorst S Safdie FM Bianchi G Martin-Montalvo A Pistoia V Wei M Hwang S Merlino A Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy Sci Transl Med. 2012 4 124ra27 22323820 10.1126/scitranslmed.3003293 PMC3608686

141. Raffaghello L Lee C Safdie FM Wei M Madia F Bianchi G Longo VD Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy Proc Natl Acad Sci USA 2008 105 8215 8220 18378900 10.1073/pnas.0708100105 PMC2448817

142. Jardé T Perrier S Vasson MP Caldefie-Chézet F Molecular mechanisms of leptin and adiponectin in breast cancer Eur J Cancer 2011 47 33 43 20889333 10.1016/j.ejca.2010.09.005

143. Pollak M The insulin and insulin-like growth factor receptor family in neoplasia: an update Nat Rev Cancer 2012 12 159 169 22337149 10.1038/nrc3215

144. Lee C Safdie FM Raffaghello L Wei M Madia F Parrella E Hwang D Cohen P Bianchi G Longo VD Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index Cancer Res 2010 70 1564 1572 20145127 10.1158/0008-5472.CAN-09-3228 PMC2836202

145. Cheng CW Adams GB Perin L Wei M Zhou X Lam BS Da Sacco S Mirisola M Quinn DI Dorff TB Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression Cell Stem Cell 2014 14 810 823 24905167 10.1016/j.stem.2014.04.014 PMC4102383

146. Pietrocola F Pol J Vacchelli E Rao S Enot DP Baracco EE Levesque S Castoldi F Jacquelot N Yamazaki T Caloric restriction mimetics enhance anticancer immunosurveillance Cancer Cell 2016 30 147 160 27411589 10.1016/j.ccell.2016.05.016 PMC5715805

147. Di Biase S Lee C Brandhorst S Manes B Buono R Cheng CW Cacciottolo M Martin-Montalvo A de Cabo R Wei M Fasting-mimicking diet reduces HO-1 to promote T cell-mediated tumor cytotoxicity Cancer Cell 2016 30 136 146 27411588 10.1016/j.ccell.2016.06.005 PMC5388544

148. Newman JC Verdin E Ketone bodies as signaling metabolites Trends Endocrinol Metab 2014 25 42 52 24140022 10.1016/j.tem.2013.09.002 PMC4176946

149. Di Biase S Shim HS Kim KH Vinciguerra M Rappa F Wei M Brandhorst S Cappello F Mirzaei H Lee C Fasting regulates EGR1 and protects from glucose- and dexamethasone-dependent sensitization to chemotherapy PLoS Biol 2017 15 e2001951 28358805 10.1371/journal.pbio.2001951 PMC5373519

150. Safdie F Brandhorst S Wei M Wang W Lee C Hwang S Conti PS Chen TC Longo VD Fasting enhances the response of glioma to chemo- and radiotherapy PLoS ONE 2012 7 e44603 22984531 10.1371/journal.pone.0044603 PMC3439413

151. Shim HS Wei M Brandhorst S Longo VD Starvation promotes REV1 SUMOylation and p53-dependent sensitization of melanoma and breast cancer cells Cancer Res 2015 75 1056 1067 25614517 10.1158/0008-5472.CAN-14-2249 PMC4359966

152. Bianchi G Martella R Ravera S Marini C Capitanio S Orengo A Emionite L Lavarello C Amaro A Petretto A Fasting induces anti-Warburg effect that increases respiration but reduces ATP-synthesis to promote apoptosis in colon cancer models Oncotarget 2015 6 11806 11819 25909219 10.18632/oncotarget.3688 PMC4494906

153. Di Biase S Longo VD Fasting-induced differential stress sensitization in cancer treatment Mol Cell Oncol. 2016 3 e1117701 27314084 10.1080/23723556.2015.1117701 PMC4909408

154. Tinkum KL Stemler KM White LS Loza AJ Jeter-Jones S Michalski BM Kuzmicki C Pless R Stappenbeck TS Piwnica-Worms D Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival Proc Natl Acad Sci U S A 2015 112 E7148 E7154 26644583 10.1073/pnas.1509249112 PMC4697381

155. de Groot S Pijl H van der Hoeven JJM Kroep JR Effects of short-term fasting on cancer treatment J Exp Clin Cancer Res 2019 38 209 31113478 10.1186/s13046-019-1189-9 PMC6530042

156. Schumacher B Garinis GA Hoeijmakers JH Age to survive: DNA damage and aging Trends Genet 2008 24 77 85 18192065 10.1016/j.tig.2007.11.004

157. Yakar S Liu JL Stannard B Butler A Accili D Sauer B LeRoith D Normal growth and development in the absence of hepatic insulin-like growth factor I Proc Natl Acad Sci U S A 1999 96 7324 7329 10377413 10.1073/pnas.96.13.7324 PMC22084

158. Antunes F Erustes AG Costa AJ Nascimento AC Bincoletto C Ureshino RP Pereira GJS Smaili SS Autophagy and intermittent fasting: the connection for cancer therapy? Clinics (Sao Paulo) 2018 73 e814s 30540126 10.6061/clinics/2018/e814s PMC6257056

159. Caffa I Spagnolo V Vernieri C Valdemarin F Becherini P Wei M Brandhorst S Zucal C Driehuis E Ferrando L Fasting-mimicking diet and hormone therapy induce breast cancer regression Nature 2020 583 620 624 32669709 10.1038/s41586-020-2502-7 PMC7881940

160. Kanarek N Petrova B Sabatini DM Dietary modifications for enhanced cancer therapy Nature 2020 579 507 517 32214253 10.1038/s41586-020-2124-0

161. Cathcart P Craddock C Stebbing J Fasting: starving cancer Lancet Oncol 2017 18 431 28368246 10.1016/S1470-2045(17)30196-1

162. Brandhorst S Choi IY Wei M Cheng CW Sedrakyan S Navarrete G Dubeau L Yap LP Park R Vinciguerra M A Periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan Cell Metab 2015 22 86 99 26094889 10.1016/j.cmet.2015.05.012 PMC4509734

163. Lo Re O Panebianco C Porto S Cervi C Rappa F Di Biase S Caraglia M Pazienza V Vinciguerra M Fasting inhibits hepatic stellate cells activation and potentiates anti-cancer activity of Sorafenib in hepatocellular cancer cells J Cell Physiol 2018 233 1202 1212 28471474 10.1002/jcp.25987

164. Shi Y Felley-Bosco E Marti TM Orlowski K Pruschy M Stahel RA Starvation-induced activation of ATM/Chk2/p53 signaling sensitizes cancer cells to cisplatin BMC Cancer 2012 12 571 23211021 10.1186/1471-2407-12-571 PMC3527202

165. Strickaert A Saiselet M Dom G De Deken X Dumont JE Feron O Sonveaux P Maenhaut C Cancer heterogeneity is not compatible with one unique cancer cell metabolic map Oncogene 2017 36 2637 2642 27797377 10.1038/onc.2016.411 PMC5442421

166. D'Aronzo M Vinciguerra M Mazza T Panebianco C Saracino C Pereira SP Graziano P Pazienza V Fasting cycles potentiate the efficacy of gemcitabine treatment in in vitro and in vivo pancreatic cancer models Oncotarget 2015 6 18545 18557 26176887 10.18632/oncotarget.4186 PMC4621909

167. Lu Z Xie J Wu G Shen J Collins R Chen W Kang X Luo M Zou Y Huang LJ Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation Nat Med 2017 23 79 90 27941793 10.1038/nm.4252 PMC6956990

168. Chan LN Chen Z Braas D Lee JW Xiao G Geng H Cosgun KN Hurtz C Shojaee S Cazzaniga V Metabolic gatekeeper function of B-lymphoid transcription factors Nature 2017 542 479 483 28192788 10.1038/nature21076 PMC5621518

169. Moore SC Lee IM Weiderpass E Campbell PT Sampson JN Kitahara CM Keadle SK Arem H Berrington de Gonzalez A Hartge P Association of leisure-time physical activity with risk of 26 types of cancer in 1.44 million adults JAMA Intern Med 2016 176 816 825 27183032 10.1001/jamainternmed.2016.1548 PMC5812009

170. Kenfield SA Stampfer MJ Giovannucci E Chan JM Physical activity and survival after prostate cancer diagnosis in the health professionals follow-up study J Clin Oncol 2011 29 726 732 21205749 10.1200/JCO.2010.31.5226 PMC3056656

171. Van Blarigan EL Meyerhardt JA Role of physical activity and diet after colorectal cancer diagnosis J Clin Oncol 2015 33 1825 1834 25918293 10.1200/JCO.2014.59.7799 PMC4438267

172. Van Blarigan EL Fuchs CS Niedzwiecki D Zhang S Saltz LB Mayer RJ Mowat RB Whittom R Hantel A Benson A Association of survival with adherence to the American Cancer Society nutrition and physical activity guidelines for cancer survivors after colon cancer diagnosis: the CALGB 89803/alliance trial JAMA Oncol 2018 4 783 790 29710284 10.1001/jamaoncol.2018.0126 PMC6145685

173. Cannioto RA Hutson A Dighe S McCann W McCann SE Zirpoli GR Barlow W Kelly KM DeNysschen CA Hershman DL Physical activity before, during, and after chemotherapy for high-risk breast cancer: relationships with survival J Natl Cancer Inst 2021 113 54 63 32239145 10.1093/jnci/djaa046 PMC7781460

174. Ashcraft KA Peace RM Betof AS Dewhirst MW Jones LW Efficacy and mechanisms of aerobic exercise on cancer initiation, progression, and metastasis: a critical systematic review of in vivo preclinical data Cancer Res 2016 76 4032 4050 27381680 10.1158/0008-5472.CAN-16-0887 PMC5378389

175. Koelwyn GJ Quail DF Zhang X White RM Jones LW Exercise-dependent regulation of the tumour microenvironment Nat Rev Cancer 2017 17 620 632 28943640 10.1038/nrc.2017.78

176. Arfianti A Pok S Barn V Haigh WG Yeh MM Ioannou GN Teoh NC Farrell GC Exercise retards hepatocarcinogenesis in obese mice independently of weight control J Hepatol 2020 73 140 148 32302728 10.1016/j.jhep.2020.02.006

177. Pedersen L Christensen JF Hojman P Effects of exercise on tumor physiology and metabolism Cancer J 2015 21 111 116 25815851 10.1097/PPO.0000000000000096

178. Colbert LH Westerlind KC Perkins SN Haines DC Berrigan D Donehower LA Fuchs-Young R Hursting SD Exercise effects on tumorigenesis in a p53-deficient mouse model of breast cancer Med Sci Sports Exerc 2009 41 1597 1605 19568200 10.1249/MSS.0b013e31819f1f05 PMC3040490

179. Gustafson MP Wheatley-Guy CM Rosenthal AC Gastineau DA Katsanis E Johnson BD Simpson RJ Exercise and the immune system: taking steps to improve responses to cancer immunotherapy J Immunother Cancer 2021 9 e001872 34215686 10.1136/jitc-2020-001872 PMC8256759

180. Idorn M Hojman P Exercise-dependent regulation of NK cells in cancer protection Trends Mol Med 2016 22 565 577 27262760 10.1016/j.molmed.2016.05.007

181. Song M Chan AT The potential role of exercise and nutrition in harnessing the immune system to improve colorectal cancer survival Gastroenterology 2018 155 596 600 30076837 10.1053/j.gastro.2018.07.038 PMC6571501

182. Evans ES Hackney AC McMurray RG Randell SH Muss HB Deal AM Battaglini CL Impact of acute intermittent exercise on natural killer cells in breast cancer survivors Integr Cancer Ther 2015 14 436 445 25873292 10.1177/1534735415580681

183. Coletta AM Agha NH Baker FL Niemiro GM Mylabathula PL Brewster AM Bevers TB Fuentes-Mattei E Basen-Engquist K Gilchrist SC The impact of high-intensity interval exercise training on NK-cell function and circulating myokines for breast cancer prevention among women at high risk for breast cancer Breast Cancer Res Treat 2021 187 407 416 33555464 10.1007/s10549-021-06111-z PMC8189992

184. Fisher DT Chen Q Skitzki JJ Muhitch JB Zhou L Appenheimer MM Vardam TD Weis EL Passanese J Wang WC IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells J Clin Invest 2011 121 3846 3859 21926464 10.1172/JCI44952 PMC3195455

185. Pedersen L Idorn M Olofsson GH Lauenborg B Nookaew I Hansen RH Johannesen HH Becker JC Pedersen KS Dethlefsen C Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution Cell Metab 2016 23 554 562 26895752 10.1016/j.cmet.2016.01.011

186. Rundqvist H Velica P Barbieri L Gameiro PA Bargiela D Gojkovic M Mijwel S Reitzner SM Wulliman D Ahlstedt E Cytotoxic T-cells mediate exercise-induced reductions in tumor growth Elife 2020 9 e59996 33095157 10.7554/eLife.59996 PMC7584454

187. Gross E Sunwoo JB Bui JD Cancer immunosurveillance and immunoediting by natural killer cells Cancer J 2013 19 483 489 24270347 10.1097/PPO.0000000000000005

188. Bartlett DB Duggal NA Moderate physical activity associated with a higher naive/memory T-cell ratio in healthy old individuals: potential role of IL15 Age Ageing 2020 49 368 373 32221610 10.1093/ageing/afaa035

189. Duggal NA Pollock RD Lazarus NR Harridge S Lord JM Major features of immunesenescence, including reduced thymic output, are ameliorated by high levels of physical activity in adulthood Aging Cell 2018 17 e12750 10.1111/acel.12750 PMC5847865 29517845

190. Evans SS Repasky EA Fisher DT Fever and the thermal regulation of immunity: the immune system feels the heat Nat Rev Immunol 2015 15 335 349 25976513 10.1038/nri3843 PMC4786079

191. Hurwitz MD Hyperthermia and immunotherapy: clinical opportunities Int J Hyperthermia 2019 36 4 9 31795827 10.1080/02656736.2019.1653499

192. Mahmood J Shukla HD Soman S Samanta S Singh P Kamlapurkar S Saeed A Amin NP Vujaskovic Z Immunotherapy, radiotherapy, and hyperthermia: a combined therapeutic approach in pancreatic cancer treatment Cancers (Basel). 2018 10 469 10.3390/cancers10120469 PMC6316720 30486519

193. Chang M Hou Z Wang M Li C Lin J Recent advances in hyperthermia therapy-based synergistic immunotherapy Adv Mater 2021 33 e2004788 33289219 10.1002/adma.202004788

194. Toraya-Brown S Fiering S Local tumour hyperthermia as immunotherapy for metastatic cancer Int J Hyperthermia 2014 30 531 539 25430985 10.3109/02656736.2014.968640 PMC4558619

195. Wang J Liu S Li G Xiao J Exercise regulates the immune system Adv Exp Med Biol 2020 1228 395 408 32342473 10.1007/978-981-15-1792-1_27

196. Scheffer DDL Latini A Exercise-induced immune system response: Anti-inflammatory status on peripheral and central organs Biochim Biophys Acta Mol Basis Dis 2020 1866 165823 32360589 10.1016/j.bbadis.2020.165823 PMC7188661

197. Ticinesi A Lauretani F Tana C Nouvenne A Ridolo E Meschi T Exercise and immune system as modulators of intestinal microbiome: implications for the gut-muscle axis hypothesis Exerc Immunol Rev 2019 25 84 95 30753131

198. Pedersen BK Febbraio MA Muscles, exercise and obesity: skeletal muscle as a secretory organ Nat Rev Endocrinol 2012 8 457 465 22473333 10.1038/nrendo.2012.49

199. Hoffmann C Weigert C Skeletal muscle as an endocrine organ: the role of myokines in exercise adaptations Cold Spring Harb Perspect Med 2017 7 a029793 28389517 10.1101/cshperspect.a029793 PMC5666622

200. Ruiz-Casado A Martin-Ruiz A Perez LM Provencio M Fiuza-Luces C Lucia A Exercise and the Hallmarks of Cancer Trends Cancer 2017 3 423 441 28718417 10.1016/j.trecan.2017.04.007

201. Miao Y Hu B Wang Q Yang Q Zhou S Myokines related to leukocyte recruitment are down-regulated in osteosarcoma Int J Med Sci 2018 15 859 866 30008597 10.7150/ijms.24928 PMC6036099

202. Whitham M Febbraio MA The ever-expanding myokinome: discovery challenges and therapeutic implications Nat Rev Drug Discov 2016 15 719 729 27616294 10.1038/nrd.2016.153

203. Catoire M Mensink M Kalkhoven E Schrauwen P Kersten S Identification of human exercise-induced myokines using secretome analysis Physiol Genomics 2014 46 256 267 24520153 10.1152/physiolgenomics.00174.2013

204. Weigert C Lehmann R Hartwig S Lehr S The secretome of the working human skeletal muscle—a promising opportunity to combat the metabolic disaster? Proteomics Clin Appl 2014 8 5 18 24376246 10.1002/prca.201300094

205. Catoire M Kersten S The search for exercise factors in humans FASEB J 2015 29 1615 1628 25593123 10.1096/fj.14-263699

206. Pourteymour S Eckardt K Holen T Langleite T Lee S Jensen J Birkeland KI Drevon CA Hjorth M Global mRNA sequencing of human skeletal muscle: search for novel exercise-regulated myokines Mol Metab 2017 6 352 365 28377874 10.1016/j.molmet.2017.01.007 PMC5369209

207. Rocha-Rodrigues S Matos A Afonso J Mendes-Ferreira M Abade E Teixeira E Silva B Murawska-Cialowicz E Oliveira MJ Ribeiro R Skeletal muscle-adipose tissue-tumor axis: molecular mechanisms linking exercise training in prostate cancer Int J Mol Sci 2021 22 4469 33922898 10.3390/ijms22094469 PMC8123194

208. Kim JS Galvao DA Newton RU Gray E Taaffe DR Exercise-induced myokines and their effect on prostate cancer Nat Rev Urol 2021 18 519 542 34158658 10.1038/s41585-021-00476-y

209. Gannon NP Vaughan RA Garcia-Smith R Bisoffi M Trujillo KA Effects of the exercise-inducible myokine irisin on malignant and non-malignant breast epithelial cell behavior in vitro Int J Cancer 2015 136 E197 202 25124080 10.1002/ijc.29142

210. Kim JS Wilson RL Taaffe DR Galvao DA Gray E Newton RU Myokine expression and tumor-suppressive effect of serum following 12 weeks of exercise in prostate cancer patients on ADT Med Sci Sports Exerc 2021 54 197 205 10.1249/MSS.0000000000002783 PMC8754092 34559721

211. Aoi W Naito Y Takagi T Tanimura Y Takanami Y Kawai Y Sakuma K Hang LP Mizushima K Hirai Y A novel myokine, secreted protein acidic and rich in cysteine (SPARC), suppresses colon tumorigenesis via regular exercise Gut 2013 62 882 889 22851666 10.1136/gutjnl-2011-300776

212. Liu YP Hsiao M Exercise-induced SPARC prevents tumorigenesis of colon cancer Gut 2013 62 810 811 23086830 10.1136/gutjnl-2012-303235

213. Matsuo K Sato K Suemoto K Miyamoto-Mikami E Fuku N Higashida K Tsuji K Xu Y Liu X Iemitsu M A mechanism underlying preventive effect of high-intensity training on colon cancer Med Sci Sports Exerc 2017 49 1805 1816 28463901 10.1249/MSS.0000000000001312

214. Severinsen MCK Pedersen BK Muscle-organ crosstalk: the emerging roles of myokines Endocr Rev 2020 41 594 609 10.1210/endrev/bnaa016 PMC7288608 32393961

215. Kim JS Galvao DA Newton RU Gray E Taaffe DR Publisher correction: exercise-induced myokines and their effect on prostate cancer Nat Rev Urol 2021 19 64 10.1038/s41585-021-00501-0 34230660

216. Severinsen MCK Pedersen BK Corrigendum to: Muscle-organ crosstalk: the emerging roles of myokines Endocr Rev 2021 42 97 99 33045039 10.1210/endrev/bnaa024 PMC7846083

217. Li X Liu Y Liu Q Wang S Ma Y Jin Q Recombinant human irisin regulated collagen II, matrix metalloproteinase-13 and the Wnt/beta-catenin and NF-kappaB signaling pathways in interleukin-1beta-induced human SW1353 cells Exp Ther Med 2020 19 2879 2886 32256772 10.3892/etm.2020.8562 PMC7086223

218. Chen X Sun K Zhao S Geng T Fan X Sun S Zheng M Jin Q Irisin promotes osteogenic differentiation of bone marrow mesenchymal stem cells by activating autophagy via the Wnt//beta-catenin signal pathway Cytokine 2020 136 155292 32950809 10.1016/j.cyto.2020.155292

219. Dong HN Park SY Le CT Choi DH Cho EH Irisin regulates the functions of hepatic stellate cells Endocrinol Metab (Seoul) 2020 35 647 655 32981307 10.3803/EnM.2020.658 PMC7520590

220. Bay ML Pedersen BK Muscle-organ crosstalk: focus on immunometabolism Front Physiol 2020 11 567881 33013484 10.3389/fphys.2020.567881 PMC7509178

221. Roy P Chowdhury S Roy HK Exercise-induced myokines as emerging therapeutic agents in colorectal cancer prevention and treatment Future Oncol 2018 14 309 312 29318900 10.2217/fon-2017-0555

222. Khan SU Ghafoor S Myokines: discovery challenges and therapeutic impediments J Pak Med Assoc 2019 69 1014 1017 31983736

223. Leal LG Lopes MA Batista ML Jr Physical exercise-induced myokines and muscle-adipose tissue crosstalk: a review of current knowledge and the implications for health and metabolic diseases Front Physiol 2018 9 1307 30319436 10.3389/fphys.2018.01307 PMC6166321

224. Hennigar SR McClung JP Pasiakos SM Nutritional interventions and the IL-6 response to exercise FASEB J 2017 31 3719 3728 28507168 10.1096/fj.201700080R

225. Pedersen BK Febbraio MA Muscle as an endocrine organ: focus on muscle-derived interleukin-6 Physiol Rev 2008 88 1379 1406 18923185 10.1152/physrev.90100.2007

226. Pedersen BK Febbraio M Muscle-derived interleukin-6—a possible link between skeletal muscle, adipose tissue, liver, and brain Brain Behav Immun 2005 19 371 376 15935612 10.1016/j.bbi.2005.04.008

227. Tsai MS Kuo ML Chang CC Wu YT The effects of exercise training on levels of vascular endothelial growth factor in tumor-bearing mice Cancer Biomark 2013 13 307 313 24440969 10.3233/CBM-130359 PMC12928301

228. Vital TM Stein AM de Melo Coelho FG Arantes FJ Teodorov E Santos-Galduroz RF Physical exercise and vascular endothelial growth factor (VEGF) in elderly: a systematic review Arch Gerontol Geriatr 2014 59 234 239 24856646 10.1016/j.archger.2014.04.011

229. Shalamzari SA Agha-Alinejad H Alizadeh S Shahbazi S Khatib ZK Kazemi A Saei MA Minayi N The effect of exercise training on the level of tissue IL-6 and vascular endothelial growth factor in breast cancer bearing mice Iran J Basic Med Sci 2014 17 231 258 24904714 PMC4046231

230. Buss LA Dachs GU Effects of exercise on the tumour microenvironment Adv Exp Med Biol 2020 1225 31 51 32030646 10.1007/978-3-030-35727-6_3

231. Buss LA Ang AD Hock B Robinson BA Currie MJ Dachs GU Effect of post-implant exercise on tumour growth rate, perfusion and hypoxia in mice PLoS ONE 2020 15 e0229290 32187204 10.1371/journal.pone.0229290 PMC7080225

232. Betof AS Lascola CD Weitzel D Landon C Scarbrough PM Devi GR Palmer G Jones LW Dewhirst MW Modulation of murine breast tumor vascularity, hypoxia and chemotherapeutic response by exercise J Natl Cancer Inst 2015 107 div040 10.1093/jnci/djv040 PMC4822524 25780062

233. Goel S Wong AH Jain RK Vascular normalization as a therapeutic strategy for malignant and nonmalignant disease Cold Spring Harb Perspect Med 2012 2 a006486 22393532 10.1101/cshperspect.a006486 PMC3282493

234. Buss LA Dachs GU Voluntary exercise slows breast tumor establishment and reduces tumor hypoxia in ApoE(-/-) mice J Appl Physiol 1985 2018 124 938 949 10.1152/japplphysiol.00738.2017 29357514

235. Lin B Song X Yang D Bai D Yao Y Lu N Anlotinib inhibits angiogenesis via suppressing the activation of VEGFR2, PDGFRbeta and FGFR1 Gene 2018 654 77 86 29454091 10.1016/j.gene.2018.02.026

236. Jones LW Antonelli J Masko EM Broadwater G Lascola CD Fels D Dewhirst MW Dyck JR Nagendran J Flores CT Exercise modulation of the host-tumor interaction in an orthotopic model of murine prostate cancer J Appl Physiol 1985 2012 113 263 272 10.1152/japplphysiol.01575.2011 PMC3404704 22604887

237. Jones LW Viglianti BL Tashjian JA Kothadia SM Keir ST Freedland SJ Potter MQ Moon EJ Schroeder T Herndon JE 2nd Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer J Appl Physiol 1985 2010 108 343 348 10.1152/japplphysiol.00424.2009 PMC2822670 19959769

238. Patel DI Abuchowski K Bedolla R Rivas P Musi N Reddick R Kumar AP Nexrutine and exercise similarly prevent high grade prostate tumors in transgenic mouse model PLoS ONE 2019 14 e0226187 31856170 10.1371/journal.pone.0226187 PMC6922346

239. Murdoch C Giannoudis A Lewis CE Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues Blood 2004 104 2224 2234 15231578 10.1182/blood-2004-03-1109

240. Murdoch C Lewis CE Macrophage migration and gene expression in response to tumor hypoxia Int J Cancer 2005 117 701 708 16106399 10.1002/ijc.21422

241. Uyttenhove C Pilotte L Theate I Stroobant V Colau D Parmentier N Boon T Van den Eynde BJ Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase Nat Med 2003 9 1269 1274 14502282 10.1038/nm934

242. Wainwright DA Balyasnikova IV Chang AL Ahmed AU Moon KS Auffinger B Tobias AL Han Y Lesniak MS IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival Clin Cancer Res 2012 18 6110 6121 22932670 10.1158/1078-0432.CCR-12-2130 PMC3500434

243. Kiyozumi Y Baba Y Okadome K Yagi T Ishimoto T Iwatsuki M Miyamoto Y Yoshida N Watanabe M Komohara Y IDO1 expression is associated with immune tolerance and poor prognosis in patients with surgically resected esophageal cancer Ann Surg 2019 269 1101 1108 31082908 10.1097/SLA.0000000000002754

244. Hatfield SM Kjaergaard J Lukashev D Schreiber TH Belikoff B Abbott R Sethumadhavan S Philbrook P Ko K Cannici R Immunological mechanisms of the antitumor effects of supplemental oxygenation Sci Transl Med. 2015 7 277ra30 25739764 10.1126/scitranslmed.aaa1260 PMC4641038

245. Leone RD Horton MR Powell JD Something in the air: hyperoxic conditioning of the tumor microenvironment for enhanced immunotherapy Cancer Cell 2015 27 435 436 25873169 10.1016/j.ccell.2015.03.014 PMC4696011

246. Barsoum IB Smallwood CA Siemens DR Graham CH A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells Cancer Res 2014 74 665 674 24336068 10.1158/0008-5472.CAN-13-0992

247. Barsoum IB Hamilton TK Li X Cotechini T Miles EA Siemens DR Graham CH Hypoxia induces escape from innate immunity in cancer cells via increased expression of ADAM10: role of nitric oxide Cancer Res 2011 71 7433 7441 22006996 10.1158/0008-5472.CAN-11-2104

248. Ruf M Moch H Schraml P PD-L1 expression is regulated by hypoxia inducible factor in clear cell renal cell carcinoma Int J Cancer 2016 139 396 403 26945902 10.1002/ijc.30077

249. Buss LA Williams T Hock B Ang AD Robinson BA Currie MJ Dachs GU Effects of exercise and anti-PD-1 on the tumour microenvironment Immunol Lett 2021 239 60 71 34480981 10.1016/j.imlet.2021.08.005

250. Ashcraft KA Warner AB Jones LW Dewhirst MW Exercise as adjunct therapy in cancer Semin Radiat Oncol 2019 29 16 24 30573180 10.1016/j.semradonc.2018.10.001 PMC6656408

251. Dey A Varelas X Guan KL Targeting the Hippo pathway in cancer, fibrosis, wound healing and regenerative medicine Nat Rev Drug Discov 2020 19 480 494 32555376 10.1038/s41573-020-0070-z PMC7880238

252. Moya IM Halder G Hippo-YAP/TAZ signalling in organ regeneration and regenerative medicine Nat Rev Mol Cell Biol 2019 20 211 226 30546055 10.1038/s41580-018-0086-y

253. Zanconato F Cordenonsi M Piccolo S YAP/TAZ at the roots of cancer Cancer Cell 2016 29 783 803 27300434 10.1016/j.ccell.2016.05.005 PMC6186419

254. Totaro A Panciera T Piccolo S YAP/TAZ upstream signals and downstream responses Nat Cell Biol 2018 20 888 899 30050119 10.1038/s41556-018-0142-z PMC6186418

255. Dethlefsen C Hansen LS Lillelund C Andersen C Gehl J Christensen JF Pedersen BK Hojman P Exercise-induced catecholamines activate the hippo tumor suppressor pathway to reduce risks of breast cancer development Cancer Res 2017 77 4894 4904 28887324 10.1158/0008-5472.CAN-16-3125

256. Hojman P Gehl J Christensen JF Pedersen BK Molecular mechanisms linking exercise to cancer prevention and treatment Cell Metab 2018 27 10 21 29056514 10.1016/j.cmet.2017.09.015

257. Hojman P Exercise protects from cancer through regulation of immune function and inflammation Biochem Soc Trans 2017 45 905 911 28673937 10.1042/BST20160466

258. Bigley AB Spielmann G LaVoy EC Simpson RJ Can exercise-related improvements in immunity influence cancer prevention and prognosis in the elderly? Maturitas 2013 76 51 56 23870832 10.1016/j.maturitas.2013.06.010

259. Roenneberg T Merrow M The circadian clock and human health Curr Biol 2016 26 R432 R443 27218855 10.1016/j.cub.2016.04.011

260. Rijo-Ferreira F Takahashi JS Genomics of circadian rhythms in health and disease Genome Med 2019 11 82 31847894 10.1186/s13073-019-0704-0 PMC6916512

261. Trott AJ Menet JS Regulation of circadian clock transcriptional output by CLOCK:BMAL1 PLoS Genet 2018 14 e1007156 29300726 10.1371/journal.pgen.1007156 PMC5771620

262. Takahashi JS Transcriptional architecture of the mammalian circadian clock Nat Rev Genet 2017 18 164 179 27990019 10.1038/nrg.2016.150 PMC5501165

263. Cho H Zhao X Hatori M Yu RT Barish GD Lam MT Chong LW DiTacchio L Atkins AR Glass CK Regulation of circadian behaviour and metabolism by REV-ERB-alpha and REV-ERB-beta Nature 2012 485 123 127 22460952 10.1038/nature11048 PMC3367514

264. Solt LA Wang Y Banerjee S Hughes T Kojetin DJ Lundasen T Shin Y Liu J Cameron MD Noel R Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists Nature 2012 485 62 68 22460951 10.1038/nature11030 PMC3343186

265. Uriz-Huarte A Date A Ang H Ali S Brady HJM Fuchter MJ The transcriptional repressor REV-ERB as a novel target for disease Bioorg Med Chem Lett 2020 30 127395 32738989 10.1016/j.bmcl.2020.127395

266. Kojetin DJ Burris TP REV-ERB and ROR nuclear receptors as drug targets Nat Rev Drug Discov 2014 13 197 216 24577401 10.1038/nrd4100 PMC4865262

267. Grant D Yin L Collins JL Parks DJ Orband-Miller LA Wisely GB Joshi S Lazar MA Willson TM Zuercher WJ GSK4112, a small molecule chemical probe for the cell biology of the nuclear heme receptor Rev-erbalpha ACS Chem Biol 2010 5 925 932 20677822 10.1021/cb100141y

268. Chen H Chu G Zhao L Yamauchi N Shigeyoshi Y Hashimoto S Hattori MA Rev-erbalpha regulates circadian rhythms and StAR expression in rat granulosa cells as identified by the agonist GSK4112 Biochem Biophys Res Commun 2012 420 374 379 22425774 10.1016/j.bbrc.2012.02.164

269. Geldof L Deventer K Roels K Tudela E Van Eeno P In vitro metabolic studies of REV-ERB Agonists SR9009 and SR9011 Int J Mol Sci 2016 17 1676 10.3390/ijms17101676 PMC5085709 27706103

270. Mazzarino M Rizzato N Stacchini C de la Torre X Botre F A further insight into the metabolic profile of the nuclear receptor Rev-erb agonist, SR9009 Drug Test Anal 2018 10 1670 1681 30395700 10.1002/dta.2538

271. Wagner PM Monjes NM Guido ME Chemotherapeutic effect of SR9009, a REV-ERB agonist, on the human glioblastoma T98G cells ASN Neuro 2019 11 1759091419892713 31825658 10.1177/1759091419892713 PMC6909277

272. Wang Y Kojetin D Burris TP Anti-proliferative actions of a synthetic REV-ERBalpha/beta agonist in breast cancer cells Biochem Pharmacol 2015 96 315 322 26074263 10.1016/j.bcp.2015.06.010 PMC4526361

273. Shen W Zhang W Ye W Wang H Zhang Q Shen J Hong Q Li X Wen G Wei T SR9009 induces a REV-ERB dependent anti-small-cell lung cancer effect through inhibition of autophagy Theranostics 2020 10 4466 4480 32292508 10.7150/thno.42478 PMC7150483

274. Sulli G Rommel A Wang X Kolar MJ Puca F Saghatelian A Plikus MV Verma IM Panda S Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence Nature 2018 553 351 355 29320480 10.1038/nature25170 PMC5924733

275. Dong Z Zhang G Qu M Gimple RC Wu Q Qiu Z Prager BC Wang X Kim LJY Morton AR Targeting glioblastoma stem cells through disruption of the circadian clock Cancer Discov 2019 9 1556 1573 31455674 10.1158/2159-8290.CD-19-0215 PMC6983300

276. Trump RP Bresciani S Cooper AW Tellam JP Wojno J Blaikley J Orband-Miller LA Kashatus JA Boudjelal M Dawson HC Optimized chemical probes for REV-ERBalpha J Med Chem 2013 56 4729 4737 23656296 10.1021/jm400458q PMC4347663

277. Guillaumond F Dardente H Giguere V Cermakian N Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors J Biol Rhythms 2005 20 391 403 16267379 10.1177/0748730405277232

278. Wang J Zou JX Xue X Cai D Zhang Y Duan Z Xiang Q Yang JC Louie MC Borowsky AD ROR-gamma drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer Nat Med 2016 22 488 496 27019329 10.1038/nm.4070 PMC5030109

279. Wang J Zou JX Xue X Cai D Zhang Y Duan Z Xiang Q Yang JC Louie MC Borowsky AD Corrigendum: ROR-gamma drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer Nat Med 2016 22 692 27270780 10.1038/nm0616-692b

280. Stone L Prostate cancer: ROR-gamma drives androgen receptor expression Nat Rev Urol 2016 13 237 27071453 10.1038/nrurol.2016.71

281. Zheng J Wang J Wang Q Zou H Wang H Zhang Z Chen J Wang Q Wang P Zhao Y Targeting castration-resistant prostate cancer with a novel RORgamma antagonist elaiophylin Acta Pharm Sin B 2020 10 2313 2322 33354503 10.1016/j.apsb.2020.07.001 PMC7745055

282. Gao M Guo L Wang H Huang J Han F Xiang S Wang J Orphan nuclear receptor RORgamma confers doxorubicin resistance in prostate cancer Cell Biol Int 2020 44 2170 2176 32584473 10.1002/cbin.11411

283. Lytle NK Ferguson LP Rajbhandari N Gilroy K Fox RG Deshpande A Schurch CM Hamilton M Robertson N Lin W A multiscale map of the stem cell state in pancreatic adenocarcinoma Cell 2019 177 572 86.e22 30955884 10.1016/j.cell.2019.03.010 PMC6711371

284. Yao W Maitra A Hear pancreatic cancer stem cells ROR Cell 2019 177 516 518 31002791 10.1016/j.cell.2019.04.002

285. Jetten AM Cook DN (Inverse) Agonists of retinoic acid-related orphan receptor gamma: regulation of immune responses, inflammation, and autoimmune disease Annu Rev Pharmacol Toxicol 2020 60 371 390 31386594 10.1146/annurev-pharmtox-010919-023711 PMC6952538

286. Liu X Zawidzka EM Li H Lesch CA Dunbar J Bousley D Zou W Hu X Carter LL RORgamma agonists enhance the sustained antitumor activity through intrinsic Tc17 cytotoxicity and Tc1 recruitment Cancer Immunol Res 2019 7 1054 1063 31064778 10.1158/2326-6066.CIR-18-0714

287. Chang MR Dharmarajan V Doebelin C Garcia-Ordonez RD Novick SJ Kuruvilla DS Kamenecka TM Griffin PR Synthetic RORgammat agonists enhance protective immunity ACS Chem Biol 2016 11 1012 1018 26785144 10.1021/acschembio.5b00899 PMC5178133

288. Hu X Liu X Moisan J Wang Y Lesch CA Spooner C Morgan RW Zawidzka EM Mertz D Bousley D Synthetic RORgamma agonists regulate multiple pathways to enhance antitumor immunity Oncoimmunology. 2016 5 e1254854 28123897 10.1080/2162402X.2016.1254854 PMC5215247

289. Mahalingam D Wang JS Hamilton EP Sarantopoulos J Nemunaitis J Weems G Carter L Hu X Schreeder M Wilkins HJ Phase 1 open-label, multicenter study of first-in-class RORgamma agonist LYC-55716 (cintirorgon): safety, tolerability, and preliminary evidence of antitumor activity Clin Cancer Res 2019 25 3508 3516 30819679 10.1158/1078-0432.CCR-18-3185

290. Zhu Y McAvoy S Kuhn R Smith DI RORA, a large common fragile site gene, is involved in cellular stress response Oncogene 2006 25 2901 2908 16462772 10.1038/sj.onc.1209314

291. Mao W Xiong G Wu Y Wang C St Clair D Li JD Xu R RORalpha suppresses cancer-associated inflammation by repressing respiratory complex I-dependent ROS generation Int J Mol Sci 2021 22 10665 34639006 10.3390/ijms221910665 PMC8509002

292. Park SC Park IG Kim H Lee JM N-terminal domain mediated regulation of RORalpha1 inhibits invasive growth in prostate cancer Int J Mol Sci 2019 20 1684 10.3390/ijms20071684 PMC6479703 30987323

293. Wang Z Xiong F Wang X Qi Y Yu H Zhu Y Zhu H Nuclear receptor retinoid-related orphan receptor alpha promotes apoptosis but is reduced in human gastric cancer Oncotarget 2017 8 11105 11113 28052040 10.18632/oncotarget.14364 PMC5355250

294. Wang Y Solt LA Kojetin DJ Burris TP Regulation of p53 stability and apoptosis by a ROR agonist PLoS ONE 2012 7 e34921 22509368 10.1371/journal.pone.0034921 PMC3324542

295. Wang Y Kumar N Nuhant P Cameron MD Istrate MA Roush WR Griffin PR Burris TP Identification of SR1078, a synthetic agonist for the orphan nuclear receptors RORalpha and RORgamma ACS Chem Biol 2010 5 1029 1034 20735016 10.1021/cb100223d PMC3003750

296. Zhang S Zhang J Deng Z Liu H Mao W Jiang F Xia Z Li JD Circadian clock components RORalpha and Bmal1 mediate the anti-proliferative effect of MLN4924 in osteosarcoma cells Oncotarget 2016 7 66087 66099 27602774 10.18632/oncotarget.11807 PMC5323217

297. Zhang Y Shi CC Zhang HP Li GQ Li SS MLN4924 suppresses neddylation and induces cell cycle arrest, senescence, and apoptosis in human osteosarcoma Oncotarget 2016 7 45263 45274 27223074 10.18632/oncotarget.9481 PMC5216721

298. Wu MH Lee CY Huang TJ Huang KY Tang CH Liu SH Kuo KL Kuan FC Lin WC Shi CS MLN4924, a protein neddylation inhibitor, suppresses the growth of human chondrosarcoma through inhibiting cell proliferation and inducing endoplasmic reticulum stress-related apoptosis Int J Mol Sci 2018 20 72 10.3390/ijms20010072 PMC6337205 30586948

299. Han K Wang Q Cao H Qiu G Cao J Li X Wang J Shen B Zhang J The NEDD8-activating enzyme inhibitor MLN4924 induces G2 arrest and apoptosis in T-cell acute lymphoblastic leukemia Oncotarget 2016 7 23812 23824 26993774 10.18632/oncotarget.8068 PMC5029665

300. Rahman S Wittine K Sedic M Markova-Car EP Small molecules targeting biological clock; a novel prospective for anti-cancer drugs Molecules 2020 25 4937 10.3390/molecules25214937 PMC7663518 33114496

301. Cao X Yang Y Selby CP Liu Z Sancar A Molecular mechanism of the repressive phase of the mammalian circadian clock Proc Natl Acad Sci U S A 2021 118 e2021174118 33443219 10.1073/pnas.2021174118 PMC7812753

302. Ye R Selby CP Chiou YY Ozkan-Dagliyan I Gaddameedhi S Sancar A Dual modes of CLOCK:BMAL1 inhibition mediated by cryptochrome and period proteins in the mammalian circadian clock Genes Dev 2014 28 1989 1998 25228643 10.1101/gad.249417.114 PMC4173159

303. Chiou YY Yang Y Rashid N Ye R Selby CP Sancar A Mammalian period represses and de-represses transcription by displacing CLOCK-BMAL1 from promoters in a Cryptochrome-dependent manner Proc Natl Acad Sci U S A 2016 113 E6072 E6079 27688755 10.1073/pnas.1612917113 PMC5068302

304. Parico GCG Perez I Fribourgh JL Hernandez BN Lee HW Partch CL The human CRY1 tail controls circadian timing by regulating its association with CLOCK:BMAL1 Proc Natl Acad Sci U S A 2020 117 27971 27979 33106415 10.1073/pnas.1920653117 PMC7668087

305. Hirota T Lee JW St John PC Sawa M Iwaisako K Noguchi T Pongsawakul PY Sonntag T Welsh DK Brenner DA Identification of small molecule activators of cryptochrome Science 2012 337 1094 1097 22798407 10.1126/science.1223710 PMC3589997

306. Solanas G Benitah SA Alterations to the circadian clock make brain tumours vulnerable Nature 2019 574 337 338 31611687 10.1038/d41586-019-03042-0

307. Chun SK Chung S Kim HD Lee JH Jang J Kim J Kim D Son GH Oh YJ Suh YG A synthetic cryptochrome inhibitor induces anti-proliferative effects and increases chemosensitivity in human breast cancer cells Biochem Biophys Res Commun 2015 467 441 446 26407844 10.1016/j.bbrc.2015.09.103

308. Eide EJ Woolf MF Kang H Woolf P Hurst W Camacho F Vielhaber EL Giovanni A Virshup DM Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation Mol Cell Biol 2005 25 2795 2807 15767683 10.1128/MCB.25.7.2795-2807.2005 PMC1061645

309. Isojima Y Nakajima M Ukai H Fujishima H Yamada RG Masumoto KH Kiuchi R Ishida M Ukai-Tadenuma M Minami Y CKIepsilon/delta-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock Proc Natl Acad Sci U S A 2009 106 15744 15749 19805222 10.1073/pnas.0908733106 PMC2736905

310. Yang Y Xu T Zhang Y Qin X Molecular basis for the regulation of the circadian clock kinases CK1delta and CK1epsilon Cell Signal 2017 31 58 65 28057520 10.1016/j.cellsig.2016.12.010

311. Guo G Wang K Hu SS Tian T Liu P Mori T Chen P Johnson CH Qin X Autokinase activity of casein kinase 1 delta/epsilon governs the period of mammalian circadian rhythms J Biol Rhythms 2019 34 482 496 31392916 10.1177/0748730419865406 PMC7007343

312. Janovska P Normant E Miskin H Bryja V Targeting casein kinase 1 (CK1) in hematological cancers Int J Mol Sci 2020 21 9026 10.3390/ijms21239026 PMC7730698 33261128

313. Sinnberg T Wang J Sauer B Schittek B Casein kinase 1alpha has a non-redundant and dominant role within the CK1 family in melanoma progression BMC Cancer 2016 16 594 27488834 10.1186/s12885-016-2643-0 PMC4973074

314. Rosenberg LH Lafitte M Quereda V Grant W Chen W Bibian M Noguchi Y Fallahi M Yang C Chang JC Therapeutic targeting of casein kinase 1delta in breast cancer Sci Transl Med. 2015 7 318ra202 26676609 10.1126/scitranslmed.aac8773 PMC4809734

315. Shen C Nayak A Melendez RA Wynn DT Jackson J Lee E Ahmed Y Robbins DJ Casein kinase 1alpha as a regulator of Wnt-driven cancer Int J Mol Sci 2020 21 5940 10.3390/ijms21165940 PMC7460588 32824859

316. Bibian M Rahaim RJ Choi JY Noguchi Y Schurer S Chen W Nakanishi S Licht K Rosenberg LH Li L Development of highly selective casein kinase 1delta/1epsilon (CK1delta/epsilon) inhibitors with potent antiproliferative properties Bioorg Med Chem Lett 2013 23 4374 4380 23787102 10.1016/j.bmcl.2013.05.075 PMC3783656

317. Minzel W Venkatachalam A Fink A Hung E Brachya G Burstain I Shaham M Rivlin A Omer I Zinger A Small molecules co-targeting CKIalpha and the transcriptional kinases CDK7/9 control AML in preclinical models Cell 2018 175 171 185 30146162 10.1016/j.cell.2018.07.045 PMC6701634

318. Hanif IM Hanif IM Shazib MA Ahmad KA Pervaiz S Casein kinase II: an attractive target for anti-cancer drug design Int J Biochem Cell Biol 2010 42 1602 1605 20558317 10.1016/j.biocel.2010.06.010

319. Kim HJ Han YS Lee JH Lee SH Casein Kinase 2alpha Enhances 5-fluorouracil resistance in colorectal cancer cells by inhibiting endoplasmic reticulum stress Anticancer Res 2020 40 1419 1426 32132038 10.21873/anticanres.14083

320. Hashimoto A Gao C Mastio J Kossenkov A Abrams SI Purandare AV Desilva H Wee S Hunt J Jure-Kunkel M Inhibition of casein kinase 2 disrupts differentiation of myeloid cells in cancer and enhances the efficacy of immunotherapy in mice Cancer Res 2018 78 5644 5655 30139814 10.1158/0008-5472.CAN-18-1229 PMC6168407

321. Kim HM Jeong I Kim HJ Kang SK Kwon WS Kim TS Park KH Jung M Soong J Lin SC Casein kinase 2 inhibitor, CX-4945, as a potential targeted anticancer agent in gastric cancer Anticancer Res 2018 38 6171 6180 30396934 10.21873/anticanres.12970

322. Oshima T Niwa Y Kuwata K Srivastava A Hyoda T Tsuchiya Y Kumagai M Tsuyuguchi M Tamaru T Sugiyama A Cell-based screen identifies a new potent and highly selective CK2 inhibitor for modulation of circadian rhythms and cancer cell growth Sci Adv 2019 5 eaau9060 30746467 10.1126/sciadv.aau9060 PMC6357737

323. Siddiqui-Jain A Drygin D Streiner N Chua P Pierre F O'Brien SE Bliesath J Omori M Huser N Ho C CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy Cancer Res 2010 70 10288 10298 21159648 10.1158/0008-5472.CAN-10-1893

324. D'Amore C Borgo C Sarno S Salvi M Role of CK2 inhibitor CX-4945 in anti-cancer combination therapy—potential clinical relevance Cell Oncol (Dordr) 2020 43 1003 1016 33052585 10.1007/s13402-020-00566-w PMC7717057

325. Pierre F Chua PC O'Brien SE Siddiqui-Jain A Bourbon P Haddach M Michaux J Nagasawa J Schwaebe MK Stefan E Pre-clinical characterization of CX-4945, a potent and selective small molecule inhibitor of CK2 for the treatment of cancer Mol Cell Biochem 2011 356 37 43 21755459 10.1007/s11010-011-0956-5

326. Sancar A Van Gelder RN Clocks, cancer, and chronochemotherapy Science 2021 371 eabb0738 33384351 10.1126/science.abb0738

327. Yang Y Lindsey-Boltz LA Vaughn CM Selby CP Cao X Liu Z Hsu DS Sancar A Circadian clock, carcinogenesis, chronochemotherapy connections J Biol Chem 2021 297 101068 34375638 10.1016/j.jbc.2021.101068 PMC8403766

328. Ballesta A Innominato PF Dallmann R Rand DA Levi FA Systems chronotherapeutics Pharmacol Rev 2017 69 161 199 28351863 10.1124/pr.116.013441 PMC5394920

329. Levi F Zidani R Misset JL Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer Int Organ Cancer Chronother Lancet 1997 350 681 686 10.1016/s0140-6736(97)03358-8 9291901

330. Sandor V Chronotherapy with 5-fluorouracil, oxaliplatin, and folinic acid in colorectal cancer Lancet 1997 350 1325 1326 9357429 10.1016/S0140-6736(05)62486-5

331. Efficace F Innominato PF Bjarnason G Coens C Humblet Y Tumolo S Genet D Tampellini M Bottomley A Garufi C Validation of patient's self-reported social functioning as an independent prognostic factor for survival in metastatic colorectal cancer patients: results of an international study by the Chronotherapy Group of the European Organisation for Research and Treatment of Cancer J Clin Oncol 2008 26 2020 2026 18421055 10.1200/JCO.2007.12.3117

332. Giacchetti S Bjarnason G Garufi C Genet D Iacobelli S Tampellini M Smaaland R Focan C Coudert B Humblet Y Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer: the European Organisation for Research and Treatment of Cancer Chronotherapy Group J Clin Oncol 2006 24 3562 3569 16877722 10.1200/JCO.2006.06.1440

333. Dong D Yang D Lin L Wang S Wu B Circadian rhythm in pharmacokinetics and its relevance to chronotherapy Biochem Pharmacol 2020 178 114045 32446886 10.1016/j.bcp.2020.114045

334. Hill RJW Innominato PF Levi F Ballesta A Optimizing circadian drug infusion schedules towards personalized cancer chronotherapy PLoS Comput Biol 2020 16 e1007218 31986133 10.1371/journal.pcbi.1007218 PMC7004559

335. Bicker J Alves G Falcao A Fortuna A Timing in drug absorption and disposition: the past, present, and future of chronopharmacokinetics Br J Pharmacol 2020 177 2215 2239 32056195 10.1111/bph.15017 PMC7174881

336. Levi F Okyar A Dulong S Innominato PF Clairambault J Circadian timing in cancer treatments Annu Rev Pharmacol Toxicol 2010 50 377 421 20055686 10.1146/annurev.pharmtox.48.113006.094626

337. Innominato PF Roche VP Palesh OG Ulusakarya A Spiegel D Levi FA The circadian timing system in clinical oncology Ann Med 2014 46 191 207 24915535 10.3109/07853890.2014.916990

338. Dallmann R Okyar A Levi F Dosing-time makes the poison: circadian regulation and pharmacotherapy Trends Mol Med 2016 22 430 445 27066876 10.1016/j.molmed.2016.03.004

339. Levi F Schibler U Circadian rhythms: mechanisms and therapeutic implications Annu Rev Pharmacol Toxicol 2007 47 593 628 17209800 10.1146/annurev.pharmtox.47.120505.105208

340. Altinok A Levi F Goldbeter A Identifying mechanisms of chronotolerance and chronoefficacy for the anticancer drugs 5-fluorouracil and oxaliplatin by computational modeling Eur J Pharm Sci 2009 36 20 38 19041394 10.1016/j.ejps.2008.10.024

341. Binkhorst L Kloth JSL de Wit AS de Bruijn P Lam MH Chaves I Burger H van Alphen RJ Hamberg P van Schaik RHN Circadian variation in tamoxifen pharmacokinetics in mice and breast cancer patients Breast Cancer Res Treat 2015 152 119 128 26050156 10.1007/s10549-015-3452-x PMC4469299

342. Kloth JS Binkhorst L de Wit AS de Bruijn P Hamberg P Lam MH Burger H Chaves I Wiemer EA van der Horst GT Relationship between sunitinib pharmacokinetics and administration time: preclinical and clinical evidence Clin Pharmacokinet 2015 54 851 858 25647628 10.1007/s40262-015-0239-5 PMC4513224

343. Lankheet NA Kloth JS Gadellaa-van Hooijdonk CG Cirkel GA Mathijssen RH Lolkema MP Schellens JH Voest EE Sleijfer S de Jonge MJ Pharmacokinetically guided sunitinib dosing: a feasibility study in patients with advanced solid tumours Br J Cancer 2014 110 2441 2449 24736581 10.1038/bjc.2014.194 PMC4021528

344. Liu J Wang CY Ji SG Xu X Wang PP Zhang B Zhao LY Liu L Lin PP Liu LK chronopharmacokinetics of erlotinib and circadian rhythms of related metabolic enzymes in Lewis tumor-bearing mice Eur J Drug Metab Pharmacokinet 2016 41 627 635 26189006 10.1007/s13318-015-0284-3

345. Bajetta E Pietrantonio F Buzzoni R Ferrario E Valvo F Mariani L Dotti KF Biondani P Formisano B Gevorgyan A Chronomodulated capecitabine and adjuvant radiation in intermediate-risk to high-risk rectal cancer: a phase II study Am J Clin Oncol 2014 37 545 549 23428953 10.1097/COC.0b013e31827ecd1d

346. Akgun Z Saglam S Yucel S Gural Z Balik E Cipe G Yildiz S Kilickap S Okyar A Kaytan-Saglam E Neoadjuvant chronomodulated capecitabine with radiotherapy in rectal cancer: a phase II brunch regimen study Cancer Chemother Pharmacol 2014 74 751 756 25102935 10.1007/s00280-014-2558-x

347. Bernard S Cajavec Bernard B Levi F Herzel H Tumor growth rate determines the timing of optimal chronomodulated treatment schedules PLoS Comput Biol 2010 6 e1000712 20333244 10.1371/journal.pcbi.1000712 PMC2841621

348. Hesse J Martinelli J Aboumanify O Ballesta A Relogio A A mathematical model of the circadian clock and drug pharmacology to optimize irinotecan administration timing in colorectal cancer Comput Struct Biotechnol J 2021 19 5170 5183 34630937 10.1016/j.csbj.2021.08.051 PMC8477139

349. Dulong S Ballesta A Okyar A Levi F Identification of circadian determinants of cancer chronotherapy through in vitro chronopharmacology and mathematical modeling Mol Cancer Ther 2015 14 2154 2164 26141947 10.1158/1535-7163.MCT-15-0129

350. Ortiz-Tudela E Iurisci I Beau J Karaboue A Moreau T Rol MA Madrid JA Levi F Innominato PF The circadian rest-activity rhythm, a potential safety pharmacology endpoint of cancer chemotherapy Int J Cancer 2014 134 2717 2725 24510611 10.1002/ijc.28587

351. Innominato PF Karaboue A Focan C Chollet P Giacchetti S Bouchahda M Ulusakarya A Torsello A Adam R Levi FA Efficacy and safety of chronomodulated irinotecan, oxaliplatin, 5-fluorouracil and leucovorin combination as first- or second-line treatment against metastatic colorectal cancer: results from the International EORTC 05011 Trial Int J Cancer 2020 148 2512 2521 10.1002/ijc.33422 PMC8048520 33270911

352. Qian DC Kleber T Brammer B Xu KM Switchenko JM Janopaul-Naylor JR Zhong J Yushak ML Harvey RD Paulos CM Effect of immunotherapy time-of-day infusion on overall survival among patients with advanced melanoma in the USA (MEMOIR): a propensity score-matched analysis of a single-centre, longitudinal study Lancet Oncol 2021 22 1777 1786 34780711 10.1016/S1470-2045(21)00546-5

353. Levi F Daytime versus evening infusions of immune checkpoint inhibitors Lancet Oncol 2021 22 1648 1650 34780710 10.1016/S1470-2045(21)00607-0

354. Khan Z Pillay V Choonara YE du Toit LC Drug delivery technologies for chronotherapeutic applications Pharm Dev Technol 2009 14 602 612 19883249 10.3109/10837450902922736

355. Levi F Okyar A Circadian clocks and drug delivery systems: impact and opportunities in chronotherapeutics Expert Opin Drug Deliv 2011 8 1535 1541 22097903 10.1517/17425247.2011.618184

356. Sunil SA Srikanth MV Rao NS Uhumwangho MU Latha K Murthy KV Chronotherapeutic drug delivery systems: an approach to circadian rhythms diseases Curr Drug Deliv 2011 8 622 633 21831038 10.2174/156720111797635559

357. Popov I Jelic S Radosavljevic D Nikolic-Tomasevic A [Chronotherapy with high dose carboplatin, 5-fluorouracil and leucovorin in advanced colorectal carcinoma] Srp Arh Celok Lek 1998 126 355 361 9863407

358. Focan C Denis B Kreutz F Focan-Henrard D Levi F Ambulatory chronotherapy with 5-fluorouracil, folinic acid, and carboplatin for advanced non-small cell lung cancer. A phase II feasibility trial J Infus Chemother 1995 5 148 152 8528976

359. Levi FA Boige V Hebbar M Smith D Lepere C Focan C Karaboue A Guimbaud R Carvalho C Tumolo S Conversion to resection of liver metastases from colorectal cancer with hepatic artery infusion of combined chemotherapy and systemic cetuximab in multicenter trial OPTILIV Ann Oncol 2016 27 267 274 26578731 10.1093/annonc/mdv548

360. Bouchahda M Adam R Giacchetti S Castaing D Brezault-Bonnet C Hauteville D Innominato PF Focan C Machover D Levi F Rescue chemotherapy using multidrug chronomodulated hepatic arterial infusion for patients with heavily pretreated metastatic colorectal cancer Cancer 2009 115 4990 4999 19637365 10.1002/cncr.24549

361. Levi F Karaboue A Etienne-Grimaldi MC Paintaud G Focan C Innominato P Bouchahda M Milano G Chatelut E Pharmacokinetics of irinotecan, oxaliplatin and 5-fluorouracil during hepatic artery chronomodulated infusion: a translational European OPTILIV Study Clin Pharmacokinet 2017 56 165 177 27393140 10.1007/s40262-016-0431-2

362. Youan BB Chronopharmaceutical drug delivery systems: Hurdles, hype or hope? Adv Drug Deliv Rev 2010 62 898 903 20438781 10.1016/j.addr.2010.04.010 PMC3065827

363. Ohdo S Chrono-drug-delivery focused on biological clock: intra- and inter-individual variability of molecular clock Adv Drug Deliv Rev 2010 62 857 858 20553776 10.1016/j.addr.2010.05.007

364. Zhang Z Qin S Chen Y Zhou L Yang M Tang Y Zuo J Zhang J Mizokami A Nice EC Inhibition of NPC1L1 disrupts adaptive responses of drug-tolerant persister cells to chemotherapy EMBO Mol Med 2022 14 e14903 35023619 10.15252/emmm.202114903 PMC8819355

365. Patil SS Shahiwala A Patented pulsatile drug delivery technologies for chronotherapy Expert Opin Ther Pat 2014 24 845 856 24810112 10.1517/13543776.2014.916281

366. Dumpa NR Sarabu S Bandari S Zhang F Repka MA Chronotherapeutic drug delivery of ketoprofen and ibuprofen for improved treatment of early morning stiffness in arthritis using hot-melt extrusion technology AAPS PharmSciTech 2018 19 2700 2709 29968041 10.1208/s12249-018-1095-z PMC6067978

367. Maqbool I Akhtar M Ahmad R Sadaquat H Noreen S Batool A Khan SU Novel multiparticulate pH triggered delayed release chronotherapeutic drug delivery of celecoxib-beta-cyclodextrin inclusion complexes by using Box–Behnken design Eur J Pharm Sci 2020 146 105254 32023488 10.1016/j.ejps.2020.105254

368. Hu J Fu S Peng Q Han Y Xie J Zan N Chen Y Fan J Paclitaxel-loaded polymeric nanoparticles combined with chronomodulated chemotherapy on lung cancer: in vitro and in vivo evaluation Int J Pharm 2017 516 313 322 27884713 10.1016/j.ijpharm.2016.11.047

369. Hu J Fu S Peng Q Han Y Xie J Zan N Chen Y Fan J Corrigendum to "Paclitaxel-loaded polymeric nanoparticles combined with chronomodulated chemotherapy on lung cancer: in vitro and in vivo evaluation" [Int. J. Pharmaceut. 516 (2017) 313-322] Int J Pharm 2020 573 118878 27884713 10.1016/j.ijpharm.2016.11.047

370. Zhao X Fan J Wu P Wei C Chen Q Ming Z Yan J Yang L Chronic chemotherapy with paclitaxel nanoparticles induced apoptosis in lung cancer in vitro and in vivo Int J Nanomed 2019 14 1299 1309 10.2147/IJN.S188049 PMC6391150 30863062

371. Potter GD Cade JE Grant PJ Hardie LJ Nutrition and the circadian system Br J Nutr 2016 116 434 442 27221157 10.1017/S0007114516002117 PMC4930144

372. Longo VD Panda S Fasting, circadian rhythms, and time-restricted feeding in healthy lifespan Cell Metab 2016 23 1048 1059 27304506 10.1016/j.cmet.2016.06.001 PMC5388543

373. Manoogian ENC Panda S Circadian rhythms, time-restricted feeding, and healthy aging Ageing Res Rev 2017 39 59 67 28017879 10.1016/j.arr.2016.12.006 PMC5814245

374. Parr EB Heilbronn LK Hawley JA A time to eat and a time to exercise Exerc Sport Sci Rev 2020 48 4 10 31688298 10.1249/JES.0000000000000207 PMC6948807

375. Nencioni A Caffa I Cortellino S Longo VD Fasting and cancer: molecular mechanisms and clinical application Nat Rev Cancer 2018 18 707 719 30327499 10.1038/s41568-018-0061-0 PMC6938162

376. Chaix A Manoogian ENC Melkani GC Panda S Time-restricted eating to prevent and manage chronic metabolic diseases Annu Rev Nutr 2019 39 291 315 31180809 10.1146/annurev-nutr-082018-124320 PMC6703924

377. O'Flanagan CH Smith LA McDonell SB Hursting SD When less may be more: calorie restriction and response to cancer therapy BMC Med 2017 15 106 28539118 10.1186/s12916-017-0873-x PMC5442682

378. Brandhorst S Longo VD Fasting and caloric restriction in cancer prevention and treatment Recent Results Cancer Res 2016 207 241 266 27557543 10.1007/978-3-319-42118-6_12 PMC7476366

379. Castejon M Plaza A Martinez-Romero J Fernandez-Marcos PJ Cabo R Diaz-Ruiz A Energy restriction and colorectal cancer: a call for additional research Nutrients 2020 12 114 10.3390/nu12010114 PMC7019819 31906264

380. Zhang J Deng Y Khoo BL Fasting to enhance cancer treatment in models: the next steps J Biomed Sci 2020 27 58 32370764 10.1186/s12929-020-00651-0 PMC7201989

381. Sadeghian M Rahmani S Khalesi S Hejazi E A review of fasting effects on the response of cancer to chemotherapy Clin Nutr 2021 40 1669 1681 33153820 10.1016/j.clnu.2020.10.037

382. Wei M Brandhorst S Shelehchi M Mirzaei H Cheng CW Budniak J Groshen S Mack WJ Guen E Di Biase S Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease Sci Transl Med. 2017 9 eaai8700 28202779 10.1126/scitranslmed.aai8700 PMC6816332

383. Safdie FM Dorff T Quinn D Fontana L Wei M Lee C Cohen P Longo VD Fasting and cancer treatment in humans: a case series report Aging (Albany N Y) 2009 1 988 1007 10.18632/aging.100114 PMC2815756 20157582

384. de Groot S Vreeswijk MP Welters MJ Gravesteijn G Boei JJ Jochems A Houtsma D Putter H van der Hoeven JJ Nortier JW The effects of short-term fasting on tolerance to (neo) adjuvant chemotherapy in HER2-negative breast cancer patients: a randomized pilot study BMC Cancer 2015 15 652 26438237 10.1186/s12885-015-1663-5 PMC4595051

385. Dorff TB Groshen S Garcia A Shah M Tsao-Wei D Pham H Cheng CW Brandhorst S Cohen P Wei M Safety and feasibility of fasting in combination with platinum-based chemotherapy BMC Cancer 2016 16 360 27282289 10.1186/s12885-016-2370-6 PMC4901417

386. Bauersfeld SP Kessler CS Wischnewsky M Jaensch A Steckhan N Stange R Kunz B Bruckner B Sehouli J Michalsen A The effects of short-term fasting on quality of life and tolerance to chemotherapy in patients with breast and ovarian cancer: a randomized cross-over pilot study BMC Cancer 2018 18 476 29699509 10.1186/s12885-018-4353-2 PMC5921787

387. Tahara Y Aoyama S Shibata S The mammalian circadian clock and its entrainment by stress and exercise J Physiol Sci 2017 67 1 10 27084533 10.1007/s12576-016-0450-7 PMC5138246

388. Sato S Basse AL Schonke M Chen S Samad M Altintas A Laker RC Dalbram E Barres R Baldi P Time of exercise specifies the impact on muscle metabolic pathways and systemic energy homeostasis Cell Metab 2019 30 92 110.e4 31006592 10.1016/j.cmet.2019.03.013

389. Choi Y Cho J No MH Heo JW Cho EJ Chang E Park DH Kang JH Kwak HB Re-setting the circadian clock using exercise against sarcopenia Int J Mol Sci 2020 21 3106 10.3390/ijms21093106 PMC7247148 32354038

390. Garcia-Ortiz L Recio-Rodriguez JI Martin-Cantera C Cabrejas-Sanchez A Gomez-Arranz A Gonzalez-Viejo N Iturregui-San Nicolas E Patino-Alonso MC Gomez-Marcos MA Group E Physical exercise, fitness and dietary pattern and their relationship with circadian blood pressure pattern, augmentation index and endothelial dysfunction biological markers: EVIDENT study protocol BMC Public Health 2010 10 233 20459634 10.1186/1471-2458-10-233 PMC2881095

391. Matteucci E Consani C Masoni MC Giampietro O Circadian blood pressure variability in type 1 diabetes subjects and their nondiabetic siblings—influence of erythrocyte electron transfer Cardiovasc Diabetol 2010 9 61 20920366 10.1186/1475-2840-9-61 PMC2959008

392. Chen HM Cheung DST Lin YY Wu YC Liu CY Lin KC Lin YJ Lin CC Relationships of exercise timing with sleep, fatigue and rest-activity rhythms of lung cancer patients in Taiwan: an exploratory study Eur J Cancer Care (Engl). 2020 29 e13233 32100388 10.1111/ecc.13233

393. Gabriel BM Zierath JR Circadian rhythms and exercise—re-setting the clock in metabolic disease Nat Rev Endocrinol 2019 15 197 206 30655625 10.1038/s41574-018-0150-x

394. Yamanaka Y Hashimoto S Takasu NN Tanahashi Y Nishide SY Honma S Honma K Morning and evening physical exercise differentially regulate the autonomic nervous system during nocturnal sleep in humans Am J Physiol Regul Integr Comp Physiol 2015 309 R1112 R1121 26333783 10.1152/ajpregu.00127.2015

395. Tong CKW Lau B Davis MK Exercise training for cancer survivors Curr Treat Options Oncol 2020 21 53 32462229 10.1007/s11864-020-00752-w

396. Cavalheri V Granger CL Exercise training as part of lung cancer therapy Respirology 2020 25 Suppl 2 80 87 32567236 10.1111/resp.13869

397. Cavalheri V Tahirah F Nonoyama M Jenkins S Hill K Exercise training undertaken by people within 12 months of lung resection for non-small cell lung cancer Cochrane Database Syst Rev 2013 6 CD009955 10.1002/14651858.CD009955.pub2 23904353

398. Idorn M Thor SP Exercise and cancer: from "Работает" to "therapeutic"? Cancer Immunol Immunother 2017 66 667 671 28324125 10.1007/s00262-017-1985-z PMC5406418

399. Holmen Olofsson G Jensen AWP Idorn M Thor Straten P Exercise oncology and immuno-oncology; a (future) dynamic duo Int J Mol Sci 2020 21 3816 10.3390/ijms21113816 PMC7312459 32471301

400. Saner NJ Lee MJ Kuang J Pitchford NW Roach GD Garnham A Genders AJ Stokes T Schroder EA Huo Z Exercise mitigates sleep-loss-induced changes in glucose tolerance, mitochondrial function, sarcoplasmic protein synthesis, and diurnal rhythms Mol Metab. 2021 43 101110 33137489 10.1016/j.molmet.2020.101110 PMC7704425

401. Wyld L Audisio RA Poston GJ The evolution of cancer surgery and future perspectives Nat Rev Clin Oncol 2015 12 115 124 25384943 10.1038/nrclinonc.2014.191

402. Wilson DJ Exercise for the patient after breast cancer surgery Semin Oncol Nurs 2017 33 98 105 28063632 10.1016/j.soncn.2016.11.010

403. Avancini A Sartori G Gkountakos A Casali M Trestini I Tregnago D Bria E Jones LW Milella M Lanza M Physical activity and exercise in lung cancer care: will promises be fulfilled? Oncologist 2020 25 e555 e569 32162811 10.1634/theoncologist.2019-0463 PMC7066706

404. Bourke L Smith D Steed L Hooper R Carter A Catto J Albertsen PC Tombal B Payne HA Rosario DJ Exercise for men with prostate cancer: a systematic review and meta-analysis Eur Urol 2016 69 693 703 26632144 10.1016/j.eururo.2015.10.047

405. Yang A Sokolof J Gulati A The effect of preoperative exercise on upper extremity recovery following breast cancer surgery: a systematic review Int J Rehabil Res 2018 41 189 196 29683834 10.1097/MRR.0000000000000288

406. Rosero ID Ramirez-Velez R Lucia A Martinez-Velilla N Santos-Lozano A Valenzuela PL Morilla I Izquierdo M Systematic review and meta-analysis of randomized, controlled trials on preoperative physical exercise interventions in patients with non-small-cell lung cancer Cancers (Basel). 2019 11 944 10.3390/cancers11070944 PMC6678369 31284372

407. Cavalheri V Granger C Preoperative exercise training for patients with non-small cell lung cancer Cochrane Database Syst Rev 2017 6 CD012020 28589547 10.1002/14651858.CD012020.pub2 PMC6481477

408. Ni HJ Pudasaini B Yuan XT Li HF Shi L Yuan P Exercise training for patients pre- and postsurgically treated for non-small cell lung cancer: a systematic review and meta-analysis Integr Cancer Ther 2017 16 63 73 27151583 10.1177/1534735416645180 PMC5736064

409. Cavalheri V Tahirah F Nonoyama M Jenkins S Hill K Exercise training for people following lung resection for non-small cell lung cancer—a Cochrane systematic review Cancer Treat Rev 2014 40 585 594 24268442 10.1016/j.ctrv.2013.11.001

410. Kilgour RD Jones DH Keyserlingk JR Effectiveness of a self-administered, home-based exercise rehabilitation program for women following a modified radical mastectomy and axillary node dissection: a preliminary study Breast Cancer Res Treat 2008 109 285 295 17624606 10.1007/s10549-007-9649-x

411. Scaffidi M Vulpiani MC Vetrano M Conforti F Marchetti MR Bonifacino A Marchetti P Saraceni VM Ferretti A Early rehabilitation reduces the onset of complications in the upper limb following breast cancer surgery Eur J Phys Rehabil Med 2012 48 601 611 22510674

412. Cavalheri V Burtin C Formico VR Nonoyama ML Jenkins S Spruit MA Hill K Exercise training undertaken by people within 12 months of lung resection for non-small cell lung cancer Cochrane Database Syst Rev 2019 6 CD009955 31204439 10.1002/14651858.CD009955.pub3 PMC6571512

413. Allen C Her S Jaffray DA Radiotherapy for cancer: present and future Adv Drug Deliv Rev 2017 109 1 2 28189183 10.1016/j.addr.2017.01.004

414. Citrin DE Recent developments in radiotherapy N Engl J Med 2017 377 1065 1075 28902591 10.1056/NEJMra1608986

415. Schumacher O Galvao DA Taaffe DR Chee R Spry N Newton RU Exercise modulation of tumour perfusion and hypoxia to improve radiotherapy response in prostate cancer Prostate Cancer Prostatic Dis 2021 24 1 14 32632128 10.1038/s41391-020-0245-z PMC8012204

416. Segal RJ Reid RD Courneya KS Sigal RJ Kenny GP Prud'Homme DG Malone SC Wells GA Scott CG Slovinec D'Angelo ME Randomized controlled trial of resistance or aerobic exercise in men receiving radiation therapy for prostate cancer J Clin Oncol 2009 27 344 351 19064985 10.1200/JCO.2007.15.4963

417. Lipsett A Barrett S Haruna F Mustian K O'Donovan A The impact of exercise during adjuvant radiotherapy for breast cancer on fatigue and quality of life: a systematic review and meta-analysis Breast 2017 32 144 155 28189100 10.1016/j.breast.2017.02.002

418. Kapur G Windsor PM McCowan C The effect of aerobic exercise on treatment-related acute toxicity in men receiving radical external beam radiotherapy for localised prostate cancer Eur J Cancer Care (Engl) 2010 19 643 647 20030701 10.1111/j.1365-2354.2009.01083.x

419. Dufresne S Gueritat J Chiavassa S Noblet C Assi M Rioux-Leclercq N Rannou-Bekono F Lefeuvre-Orfila L Paris F Rebillard A Exercise training improves radiotherapy efficiency in a murine model of prostate cancer FASEB J 2020 34 4984 4996 32043634 10.1096/fj.201901728R

420. Esteves M Monteiro MP Duarte JA Role of regular physical exercise in tumor vasculature: favorable modulator of tumor milieu Int J Sports Med 2021 42 389 406 33307553 10.1055/a-1308-3476

421. McCullough DJ Stabley JN Siemann DW Behnke BJ Modulation of blood flow, hypoxia, and vascular function in orthotopic prostate tumors during exercise J Natl Cancer Inst 2014 106 dju036 24627275 10.1093/jnci/dju036 PMC3982888

422. Schadler KL Thomas NJ Galie PA Bhang DH Roby KC Addai P Till JE Sturgeon K Zaslavsky A Chen CS Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy Oncotarget 2016 7 65429 65440 27589843 10.18632/oncotarget.11748 PMC5323166

423. Garcia E Becker VG McCullough DJ Stabley JN Gittemeier EM Opoku-Acheampong AB Sieman DW Behnke BJ Blood flow responses to mild-intensity exercise in ectopic vs. orthotopic prostate tumors; dependence upon host tissue hemodynamics and vascular reactivity J Appl Physiol 2016 121 15 24 27125846 10.1152/japplphysiol.00266.2016 PMC4967242

424. Jones LW Dewhirst MW Therapeutic properties of aerobic training after a cancer diagnosis: more than a one-trick pony? J Natl Cancer Inst 2014 106 dju042 24627274 10.1093/jnci/dju042 PMC3982890

425. Jones LW Eves ND Courneya KS Chiu BK Baracos VE Hanson J Johnson L Mackey JR Effects of exercise training on antitumor efficacy of doxorubicin in MDA-MB-231 breast cancer xenografts Clin Cancer Res 2005 11 6695 6698 16166449 10.1158/1078-0432.CCR-05-0844

426. Florez Bedoya CA Cardoso ACF Parker N Ngo-Huang A Petzel MQ Kim MP Fogelman D Romero SG Wang H Park M Exercise during preoperative therapy increases tumor vascularity in pancreatic tumor patients Sci Rep 2019 9 13966 31562341 10.1038/s41598-019-49582-3 PMC6765012

427. Ruan W Yuan X Eltzschig HK Circadian rhythm as a therapeutic target Nat Rev Drug Discov 2021 20 287 307 33589815 10.1038/s41573-020-00109-w PMC8525418

428. Crnko S Du Pre BC Sluijter JPG Van Laake LW Circadian rhythms and the molecular clock in cardiovascular biology and disease Nat Rev Cardiol 2019 16 437 447 30796369 10.1038/s41569-019-0167-4

429. Allada R Bass J Circadian Mechanisms in Medicine N Engl J Med 2021 384 550 561 33567194 10.1056/NEJMra1802337 PMC8108270

430. Koronowski KB Sassone-Corsi P Communicating clocks shape circadian homeostasis Science 2021 371 eabd0951 33574181 10.1126/science.abd0951 PMC8123919

431. Sancar A Lindsey-Boltz LA Gaddameedhi S Selby CP Ye R Chiou YY Kemp MG Hu J Lee JH Ozturk N Circadian clock, cancer, and chemotherapy Biochemistry 2015 54 110 123 25302769 10.1021/bi5007354 PMC4303322

432. Hrushesky WJ Circadian timing of cancer chemotherapy Science 1985 228 73 75 3883493 10.1126/science.3883493

433. Hrushesky WJ Bjarnason GA Circadian cancer therapy J Clin Oncol 1993 11 1403 1417 8315438 10.1200/JCO.1993.11.7.1403

434. Levi F Benavides M Chevelle C Le Saunier F Bailleul F Misset JL Regensberg C Vannetzel JM Reinberg A Mathe G Chemotherapy of advanced ovarian cancer with 4'-O-tetrahydropyranyl doxorubicin and cisplatin: a randomized phase II trial with an evaluation of circadian timing and dose-intensity J Clin Oncol 1990 8 705 714 2179481 10.1200/JCO.1990.8.4.705

435. Lockhart AC Bauer TM Aggarwal C Lee CB Harvey RD Cohen RB Sedarati F Nip TK Faessel H Dash AB Phase Ib study of pevonedistat, a NEDD8-activating enzyme inhibitor, in combination with docetaxel, carboplatin and paclitaxel, or gemcitabine, in patients with advanced solid tumors Invest New Drugs 2019 37 87 97 29781056 10.1007/s10637-018-0610-0 PMC6510847

436. Faessel HM Mould DR Zhou X Faller DV Sedarati F Venkatakrishnan K Population pharmacokinetics of pevonedistat alone or in combination with standard of care in patients with solid tumours or haematological malignancies Br J Clin Pharmacol 2019 85 2568 2579 31355467 10.1111/bcp.14078 PMC6848912

437. Focan C Levi F Kreutz F Focan-Henrard D Lobelle JP Adam R Dallemagne B Jehaes C Markiewicz S Weerts J Continuous delivery of venous 5-fluorouracil and arterial 5-fluorodeoxyuridine for hepatic metastases from colorectal cancer: feasibility and tolerance in a randomized phase II trial comparing flat versus chronomodulated infusion Anticancer Drugs 1999 10 385 392 10378673 10.1097/00001813-199904000-00006

438. Price TJ Ross PJ Hickish T Tait D Norman AR Ford HE Middleton G Sumpter K Hill M Oates J Phase III study of mitomycin-C with protracted venous infusion or circadian-timed infusion of 5-fluorouracil in advanced colorectal carcinoma Clin Colorectal Cancer 2004 3 235 242 15025796 10.3816/CCC.2004.n.004

439. Coudert B Focan C Genet D Giacchetti S Cvickovic F Zambelli A Fillet G Chollet P Amoroso D Van Der Auwera J A randomized multicenter study of optimal circadian time of vinorelbine combined with chronomodulated 5-fluorouracil in pretreated metastatic breast cancer patients: EORTC trial 05971 Chronobiol Int 2008 25 680 696 18780198 10.1080/07420520802384036

440. Escudier B Roigas J Gillessen S Harmenberg U Srinivas S Mulder SF Fountzilas G Peschel C Flodgren P Maneval EC Phase II study of sunitinib administered in a continuous once-daily dosing regimen in patients with cytokine-refractory metastatic renal cell carcinoma J Clin Oncol 2009 27 4068 4075 19652072 10.1200/JCO.2008.20.5476

441. Qvortrup C Jensen BV Fokstuen T Nielsen SE Keldsen N Glimelius B Bjerregaard B Mejer J Larsen FO Pfeiffer P A randomized study comparing short-time infusion of oxaliplatin in combination with capecitabine XELOX(30) and chronomodulated XELOX(30) as first-line therapy in patients with advanced colorectal cancer Ann Oncol 2010 21 87 91 19622596 10.1093/annonc/mdp272

442. Li J Chen R Ji M Zou SL Zhu LN Cisplatin-based chronotherapy for advanced non-small cell lung cancer patients: a randomized controlled study and its pharmacokinetics analysis Cancer Chemother Pharmacol 2015 76 651 655 26093951 10.1007/s00280-015-2804-x

443. Re GL Santeufemia DA Re FL Bortolus R Doretto P Marus W Buttazzi L Lenardon O Falda A Piazza R Interleukin-2 chronotherapy for metastatic renal cell carcinoma: Results of a phase I–II study Cytokine 2020 128 154984 31972343 10.1016/j.cyto.2019.154984

444. Roosendaal J Jacobs BAW Pluim D Rosing H de Vries N van Werkhoven E Nuijen B Beijnen JH Huitema ADR Schellens JHM Phase I pharmacological study of continuous chronomodulated capecitabine treatment Pharm Res 2020 37 89 32382808 10.1007/s11095-020-02828-6 PMC7205843

445. Levi F Karaboue A Gorden L Innominato PF Saffroy R Giacchetti S Hauteville D Guettier C Adam R Bouchahda M Cetuximab and circadian chronomodulated chemotherapy as salvage treatment for metastatic colorectal cancer (mCRC): safety, efficacy and improved secondary surgical resectability Cancer Chemother Pharmacol 2011 67 339 348 20401611 10.1007/s00280-010-1327-8

446. Farker K Merkel U Wedding U Hippius M Hoffken K Hoffmann A Chronomodulated chemotherapy with oxaliplatin, 5-FU and sodium folinate in metastatic gastrointestinal cancer patients: original analysis of non-hematological toxicity and patient characteristics in a pilot investigation Int J Clin Pharmacol Ther 2006 44 31 37 16425969 10.5414/cpp44031