Plants as a Source of Anticancer Agents: From Bench to Bedside.

1. Introduction

Cancer is a chronic disease and one of the main causes of death around the world. The global cancer burden is extensively rising, and it is considered as the second cause of death after cardiovascular disease. In 2020, 19.3 million new cancer cases were estimated, with 10.0 million cancer deaths worldwide and 250 million disability-adjusted life years because of cancer [ 1 , 2 ]. Regardless of the new developments in cancer therapy and revolutionary advances in genomics and molecular biology, multidrug resistance and drug side effects are still the vital cause of cancer treatment failure [ 3 ]. Since plants are a rich source of natural compounds that are characterized by their therapeutic effects, studying these compounds is thought to be a promising line for research on cancer [ 4 ]. In this context, phytochemicals, secondary metabolites extracted from plants, have diverse applications, including antidiabetic, anti-inflammatory, cardiovascular protective, antioxidant, and anticancer effects [ 5 ]. In particular, these phytochemicals can be classified into different groups such as flavonoids, alkaloids, phytosterols, terpenoids, sulfides, polyphenols, and others, which have been considered an important reservoir for novel anticancer agents [ 6 , 7 , 8 , 9 ]. Hence, plant secondary metabolites are recognized with many properties such as tumor growth inhibition, apoptosis induction, immune modulation, and angiogenesis suppression [ 4 , 10 ]. As well, several epidemiological studies have reported the role of phytochemicals and their derived analogues in modulating tumor cell-activating proteins, enzymes, and signaling pathways, stimulating DNA repair mechanisms, and conquering free radicals production [ 4 , 11 , 12 ]. They also interact with many intracellular pathways that regulate cell growth, such as the STAT3, PI3K/Akt/NF-κB signaling pathway, mTOR, and the Bcl-2/Bax mitochondrial pathway [ 9 , 13 ].

In this review, we have tried to choose the most effective and well-known phytochemicals that display a distinctive anticancer activity. As well, we described these phytochemicals thoroughly, starting with their chemical structure and ending with their antitumor activity.

2. Cancer Hallmarks as Targets for Natural Products

Cancer hallmarks are biological capabilities that are acquired during neoplastic transformation and help in organizing the complexity of cancer development. Many natural products exert their anticancer effect through targeting one or multiple cancer hallmarks, which are briefly discussed below.

2.1. Genomic Instability

Genomic instability is a property of many tumor cells that can be triggered by different mechanisms such as telomerase destruction, centrosome amplification, epigenetic modifications, and DNA impairment [ 14 ]. In a normal cell cycle, the integrity of the genome is controlled by specific checkpoints and any abnormality in function of these checkpoints can lead to development of tumorigenesis [ 15 , 16 ]. These checkpoints are regulated by different oncogenes and tumor suppressor genes; nevertheless, cancer cells can modify the functions of these genes resulting in stimulation of uncontrolled cell growth [ 16 ].

2.2. Sustained Proliferative Signaling

Modulating the expression of growth-promoting signals is a prominent feature of cancer cells in order to maintain their uncontrolled cell division and proliferation [ 17 ]. The essential targets to inhibit sustained proliferation in cancer include the following signaling pathways: hypoxia-inducible factor-1 (HIF-1), NF-κBs, PI3K/AKT, insulin-like growth factor receptor (IGF-1R), cyclin-dependent kinase (CDKs), and estrogen receptor signaling [ 18 ].

2.3. Evasion of Anti-Growth Signaling

The evasion of antigrowth signals is another strategy implemented by cancer cells to preserve proliferation. Blocking tumor suppressor genes that regulat the antigrowth signals, as well as mutations in these genes, have been detected in cancer cells [ 16 ]. In addition, the most identified mutated tumor suppressor genes is p53 followed by ataxia-telangiectasia mutated (ATM), cyclin-dependent kinase inhibitor 2A (CDKN2A), phosphatase and tensin homolog (PTEN), adenomatous polyposis coli (APC), breast cancer gene 1 and 2 (BRCA1 and BRCA2), retinoblastoma (RB), and Wilms tumor (WT1) [ 18 ].

2.4. Resistance to Apoptosis

Cancer cells can promote the overexpression of anti-apoptotic proteins eventually suppressing the normal programmed cell death [ 17 ]. Moreover, cancer cells can limit or bypass apoptosis via many pathways such as altering the function of p53 tumor suppressor gene, increasing the expression of antiapoptotic regulators (Bcl-2 and Bcl-xL), promoting survival signals (Igf1/2), reducing the levels of proapoptotic factors (Bax, Bim, Puma), and suppressing the signals of the extrinsic ligand-induced death pathway [ 17 ].

2.5. Replicative Immortality

Cancer cells are recognized for their limitless replicative potential, which mediates tumor progression and invasion. Telomerase is a specialized reverse transcriptase that extends the ends of shortening chromosomes in dividing cells [ 16 , 19 ]; hence, activation of this enzyme is the key to maintain continuous cell division in many types of cancer [ 17 ]. In addition, replicative immortality can be modulated by suppressing many targets including telomerase, mTOR, CDK4/6, CDK 1,2,5,9, Akt, and PI3K [ 18 ].

2.6. Dysregulated Metabolism

Altering energy metabolism has been confirmed to be a cancer-associated trait, which involves the stimulation of many oncogenes and mutated suppressor genes [ 17 ]. In order to increase glucose uptake and lactate production, several glycolytic enzymes are activated, including hexokinase 2 (HK2), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), and pyruvate kinase isoform M2 (PKM2) [ 16 ]. In addition, overexpression of other metabolic regulators such as hypoxia-inducible factor 1 (HIF-1) and Myc oncogene was observed in cancer cells [ 20 , 21 ].

2.7. Tumor-Promoting Inflammation

A specific association between chronic inflammation and cancer development has been observed [ 22 , 23 ]. Furthermore, several factors have been identified for their crucial role in stimulating cancer-related inflammation, including cytokines (interleukins, TNF-α, TGF-β, and granulocyte macrophage colony-stimulating factor), chemokines, and transcription factors (NF-kB, STAT3, HIF-1-α) [ 22 ].

2.8. Angiogenesis

During the malignancy stage, an “angiogenic switch” is triggered in tumor cells, which involves stimulation of angiogenic factors that mediate vascularization (blood vessels formation) [ 24 ]. These new growing blood vessels would supply the dividing cancer cells with oxygen and nutrients, which are essential to sustain cell proliferation [ 24 ]. This angiogenesis process is regulated by many transmembrane proteins and pathways, including vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), Tie-angiopoietin pathways, platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and hepatocyte growth factor (HGF) [ 24 , 25 ].

2.9. Tissue Invasion and Metastasis

Cancer metastasis is a multi-step process that starts with local invasion of cancer cells into the surrounding tissues. The next step is intravasation into the nearby vessels, extravasation to distant tissues and organs, and finally adaptation to a new microenvironment during which micro-metastases will progress into a secondary tumor [ 17 ]. Tumor cell metastasis is known to be initiated by the disruption of cell–cell adhesion, which is comprised of tight junctions, adherens junctions, gap junctions, desmosomes, and hemidesmosomes [ 26 ].

2.10. Immune Evasion

Cancer cells apply different strategies to evade immune surveillance. These include modulating immune checkpoint pathways and recruiting immunosuppressive cells (e.g. regulatory T cells and myeloid-derived suppressor cells). Additional mechanisms involve impairing some elements of the immune system (e.g. suppressing infiltrating CTLs and NK cells by overexpression of TGF-β or other immunosuppressive factors) [ 17 ]. Figure 1 summarizes the cancer hallmarks with the main regulating markers.

3. Anticancer Drug Discovery

For decades, plants have been well known for their clinical usefulness as anticancer agents using diverse mechanisms of action [ 27 , 28 ]. Mostly, this is due to their abundant quantity of secondary metabolites, which possess significant pharmacological and biological activities including antitumor activity [ 29 ]. About 50% of antitumor drugs originate from natural products. These drugs could be isolated from plants or semi-synthetic compounds [ 30 ]. Such examples of antitumor drugs of clinical importance nowadays are taxanes (e.g. Taxol), vinblastine, vincristine, and the podophyllotoxin analogs that all originate from higher plants [ 31 ]. Firstly, in the 1950s, Robert Noble and Charles Beer of Canada discovered vincristine and vinblastine vinca alkaloids, which were isolated from the leaves of Catharanthus roseus (Madagascar periwinkle) [ 32 ]. In addition, taxane-derived drugs are isolated from the Taxus genus. Paclitaxel, which is commercially identified as Taxol ® , was firstly obtained in 1971 from Taxus brevifolia (Pacific yew). In the 1980s, another taxane semi-synthetic drug was isolated from Taxus baccata (European yew) known as docetaxel (Taxotere ® ) [ 33 ]. Recently, podophyllotoxin analogs have been of great interest in chemical modification, especially the semi-synthetic antitumor drugs teniposide and etoposide [ 34 ]. Podophyllotoxin was first obtained by Podwyssotzki in 1880 from the North American mayapple Podophyllum peltatum L. Moreover, this phytochemical has been collected from Podophyllum emodi ( Indian podophyllum ) [ 35 ]. Etoposide was synthesized for the first time in 1966 and was approved by the U.S. Food and Drug Administration (FDA) for cancer therapy in 1983 [ 36 ].

4. Chemoprevention Mechanisms of Plant-Derived Products

Cancer chemoprevention is a comprehensive term that defines the contribution of exterior agents to suppress cancer development. Many plants play a vital role in the chemoprevention process depending on various mechanisms [ 37 ]. Recently, researchers have paid attention to natural products as chemopreventive agents due to their low toxicity, availability, and affordable production cost [ 38 ]. In this review, we will cover the mechanisms of chemoprevention of the already-included natural products. Starting with curcumin, it has been found that it exerted a chemoprevention activity on ovarian cancer. This activity is carried out by inhibiting the NF-κB signaling pathway [ 39 ]. Needless to say, the inhibition of NF-κB is crucial in cancer treatment and prevention [ 40 ]. In addition, curcumin and its analog and metabolite have an antimetastatic activity by decreasing Hsp70 and toll-like receptor (TLR4). Moreover, it induces apoptosis via increasing caspase-9 and caspase-3 [ 41 ]. Resveratrol stimulates mitogen-activated protein (MAP) kinase phosphatase-1 (MKP-1) [ 42 ] and nuclear factor erythroid 2-related factor 2(Nrf2) [ 43 ]. Moreover, resveratrol suppresses NLRP3 inflammasome and cyclooxygenase (COX) [ 44 , 45 , 46 ]. Moreover, quercetin is widely known as an antioxidant and cell protective agent. It could scavenge reactive oxygen species (ROS) and decrease the risk of cancer development and DNA damage as well [ 47 ]. Quercetin activates apoptosis through augmented translocation of Bax to the mitochondrial membrane, rearrangement of Bcl-2 proteins, stimulation of caspases, and blockage of the ERK and PI3K/Akt signals [ 47 , 48 , 49 , 50 ]. Furthermore, EGCG has been confirmed to possess a chemopreventive activity via the suppression of carcinogenesis processes such as initiation, progression, and promotion [ 51 ]. EGCG showed remarkable regulatory effects on several signaling pathways such as NF-κB, JAK/STAT, AP-1, MAPK, and PI3K/AK [ 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 ]. Interestingly, EGCG has the ability to control the activity of androgen receptors in prostate cancer as well as the estrogen receptors in mammary cancers [ 60 , 61 ]. In A549 and H1299 lung cancer cell lines, allicin has proven its antineoplastic activity by modification of PI3K/AKT signaling. This modulation leads to the suppression of cellular invasion, proliferation, and metastasis [ 62 , 63 ]. Bat-Chen et al. demonstrated that allicin mediates apoptosis via induction of Nrf2, increased levels of hypodiploid DNA content, enhanced Bax levels, and decreased B-cell non-Hodgkin lymphoma-2 levels (Bcl-2) in human colon cancer HCT-116 cells [ 64 ]. Thymoquinone inhibits cell proliferation via taking control over main cell cycle checkpoints and encouraging cell cycle arrest at G1/G2, G0/G1, or G2/M phases [ 65 ]. TQ therapy remarkably reduces angiogenesis. Thus, through the extracellular receptor kinases pathway and Akt, TQ modulates the signal of vascular endothelial growth factor (VEGF) [ 66 ]. It acts as an antioxidant as well and augments the levels of the antioxidant HO-1, Nrf2, and SOD proteins [ 67 ]. Emodin leads to apoptosis induction and epithelial to mesenchymal transition (EMT) inhibition in colon cancer [ 68 , 69 , 70 ]. This phytochemical inhibits endothelial cell proliferation via cell cycle arrest in the G2/M phase. Similarly, it inhibits VEGFR2 and MMPs signaling pathways. Moreover, emodin has been defined as an inhibitor of tyrosine kinase and phosphorylation of ERK 1/2 downregulator, contributing to its antiangiogenic effect [ 71 , 72 , 73 ]. Genistein inhibits hepatocellular carcinoma in rats by suppression of the PDGF/versican bidirectional axis, inhibiting both PKC and ERK1 as downstream controllers [ 74 ]. In ovarian cancer, it leads to serum malondialdehyde downregulation, which is a marker for the expression of Bcl-2 and NFκB and oxidative stress as well. On the other hand, it upregulates HO-1, Nrf2, and Bax expression in ovarian tissues [ 75 ]. Genistein causes PTK signaling blocking by inhibition of protein-tyrosine kinase (PTK) and thus suppresses the proliferation of tumor cells indirectly [ 76 ]. In esophageal carcinoma, parthenolide (PTL) has been found to suppress the NF-кB/AP-1/VEGF signaling pathway [ 77 ]. Moreover, PTL has been revealed to induce classic apoptosis, as well as alterations in the Bcl-2 family and rising reactive oxygen species (ROS) production intracellularly [ 78 ]. PTL exerts proapoptotic stimulation of p53, together with reduced glutathione reduction [ 79 ]. Luteolin led to pancreatic cancer inhibition in a BOP-induced hamster model. This was achieved by downregulation of the STAT3 dihydropyrimidine dehydrogenase (DPYD) pathway, which has a central importance in the development of pancreatic cancer [ 80 ]. Additionally, luteolin activates apoptosis, suppresses proliferation, and modifies MAP kinase and Akt/mTOR pathways in HeLa human cervical cancer cells [ 81 ].

5. Plant-Derived Natural Products with Potential Anticancer Effects

5.1. Curcumin

Curcumin, also called diferuloylmethane, is the main natural polyphenol found in the rhizome of Curcuma longa (Family: Zingiberaceae) and in multiple other Curcuma species [ 39 ]. It is a yellow natural product, commonly known as turmeric, commonly used as a food spice and colorant [ 82 ]. The chemical structure of curcumin consists of two aromatic O-methoxy phenolic groups, β-dicarbonyl moiety and a seven-carbon linker containing two enone moieties. The IUPAC name for curcumin is (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) [ 83 , 84 ].

Curcumin has been traditionally used in Asian countries as a medical herb due to its multiple health benefits [ 85 ]. These include anti-inflammatory, antioxidant, antibacterial, antiviral, anti-diabetic, wound-healing ability, and potential anticancer and chemopreventive activity [ 85 , 86 ].

Curcumin has been shown to inhibit carcinogenesis in preclinical studies performed on various cell lines, including prostate, pancreatic, ovarian, oral epithelial leukemia, hepatic, breast, cervical, gastric, and colon cancer [ 87 ]. Several mechanisms have been suggested to explain the promising results of curcumin in cancer treatment. One of the major mechanisms of curcumin anticancer effects is its antioxidant properties, since it can increase serum concentration of antioxidants such as superoxide dismutase (SOD), glutathione peroxidase (GPx), and lipid peroxides. Moreover, curcumin also acts as a good scavenger for different forms of free radicals, such as reactive oxygen (ROS) and reactive nitrogen species (RNS), and inhibits ROS-generating enzymes such as lipoxygenase/cyclooxygenase and xanthine hydrogenase/oxidase [ 88 , 89 , 90 ]. In addition, curcumin can modulate several signaling pathways associated with cancer growth, such as suppression of angiogenesis and induction of apoptosis [ 91 ]. Moreover, Yang et al. reported that curcumin also induces apoptosis through the activation of the JNK/ERK/AP1 pathways in human acute monocytic leukemia THP-1 cells [ 92 ]. The anticancer effect of curcumin can also be exerted via downregulation of pyruvate kinase M2 (PKM2), hence decreasing lactate production and uptake of glucose in cancer cells [ 93 ].

Curcumin can also induce cell cycle arrest at the G2/M phase, probably by decreasing the expression of CDC2 and CDC25, and increasing P21 expression [ 94 ]. This result was observed in hematological cancers [ 95 ]. In addition, curcumin has affected the cellular development in non-small cell lung cancer and stimulated G0/G1 phase arrest via MTA1 (metastasis-associated protein 1)-mediated deactivation of the Wnt/β-catenin pathway [ 96 ]. Additionally, several studies suggest that curcumin exerts its anticancer properties by targeting different microRNA (miRNA) expressions, such as miR-181b, miR-203, miR-9, miR-19, miR-21, miR203, miR-9, and miR-208 [ 97 ]. Needless to say, miRNA plays a crucial role in various physiological conditions, including differentiation, growth, angiogenesis, and apoptosis. Hence, dysregulation of these molecules can upregulate and downregulate several cellular and molecular targets leading to the progression of cancer [ 98 ]. On the other hand, the synergistic role of curcumin in combination with other chemotherapeutic agents has been reported, an effect that leads to the enhanced effectiveness and decreased toxic effects of these drugs [ 99 ]. In another study, Zhang et al. reported that pre-treatment with curcumin followed by 5-fluorouracil increased the susceptibility of the colon cancer cells [ 100 ]. Likewise, Guorgui et al. have shown that a combination of curcumin and doxorubicin demonstrates a stronger additive effect by causing a 79% reduction in the proliferation of Hodgkin lymphoma (L-540) cells [ 101 ]. Similar synergistic activity of curcumin with docetaxel [ 102 ], cisplatin [ 103 , 104 ], and doxorubicin [ 105 ] has been also reported.

Interestingly, curcumin has been shown to reverse the multidrug resistance of cancerous cells [ 106 ]. Xiao-qing et al. have shown that curcumin can reverse the multidrug resistance of the human gastric carcinoma SGC7901/VCR cell line, thus increasing the sensitivity to vincristine by decreasing both the function and expression of P-gp, resulting in high intracellular drug concentration [ 107 ]. Recently, similar findings regarding the potential of curcumin to reverse the multidrug resistance towards doxorubicin in colon cancer treatment have been also reported [ 108 ].

On the other hand, curcumin displays no toxicity effect on normal cells [ 109 ]. A phase I human trial with 25 patients taking up to 8000 mg of curcumin per day for three months discovered no harm from curcumin [ 109 ]. Five further human trials utilizing 1125–2500 mg of curcumin per day revealed it to be safe [ 109 ].

5.2. Resveratrol

Resveratrol is a polyphenolic compound produced by plants in response to environmental stress and can be found in at least 72 plant species, such as mulberries, peanuts, cranberries, blueberries, and grapes [ 110 ]. Resveratrol is a natural stilbene containing two aromatic rings linked together by a methylene double bond to form 3,4′,5-trihydroxystilbene. It exists in both cis- and trans- isoforms. The trans form is more stable and potent than the cis form [ 111 ]. Studies have reported that resveratrol exhibits many wide ranges of activities, including antioxidant [ 112 ], anti-inflammatory [ 113 ], cardiovascular protective [ 114 ], anti-aging [ 115 ], and anticancer properties [ 116 ].

Recently, several studies have focused on the anticancer properties of resveratrol, which revealed a high ability to target multiple pathways involved in cancer initiation, promotion, and progression [ 46 , 117 ]. First of all, the antioxidant effects of resveratrol contribute significantly to the health benefits of this phytochemical, since it can act as a scavenger of a number of free radicals. In addition, resveratrol increases the expression of various antioxidant enzymes, such as SOD, catalase (CAT), glutathione reductase (GS-R), (GPx), and glutathione S-transferase (GST). Thus, resveratrol, through these two antioxidant effects, protects cells from oxidative damage [ 118 ]. Conversely, as chemotherapeutics, resveratrol in combination with As2O3 can enhance apoptosis-inducing oxidative stress via induction of ROS [ 119 ].

A second possible anticancer mechanism of resveratrol is related to kinases, which play a critical role in cell growth and proliferation and are typically over-expressed in many tumors. Resveratrol specifically targets many kinases, including EGF, extracellular-signal-regulated kinases (ERK), and VEGF, thus decreasing their expression and resulting in antigrowth signaling activity [ 120 ].

A third suggested mechanism for the anticancer activity of resveratrol is related to its anti-inflammatory activity, since several types of cancer are, to some extent, promoted by a certain degree of systemic, low-grade chronic inflammation [ 121 ]. Ren et al. have reported that resveratrol suppresses the inflammatory biomarker tumor necrosis factor α (TNF-α-)-induced signaling in a dose-dependent manner, both via nuclear factor kappa-B (NFκB) activation and transcriptional activity of p65 [ 122 ]. Furthermore, in colon cancer, resveratrol actually encouraged cell cycle arrest at the G1 phase. That was achieved by lowering cyclin E1 and cyclin D1 and increasing p53 in a dose-dependent manner [ 123 ]. In addition, resveratrol treatment resulted in increasing p27 and p21 gene expression levels, as well as lowering cyclin B gene expression [ 124 ]. Moreover, substantial evidence has demonstrated that resveratrol can induce apoptosis in a wide variety of cancer cells, although the underlying mechanism differs greatly among different cancer cell types [ 46 ]. Li et al. suggested that resveratrol induces apoptosis through activating caspase-3 and caspase-9, upregulating Bcl-2-associated X protein, and inducing expression of p53 [ 125 ]. On the other hand, in ovarian cancer cells, resveratrol has been shown to inhibit proliferation and induce apoptosis via inhibiting glycolysis and targeting the AMPK/mTOR signaling pathway [ 126 ]. Moreover, resveratrol can inhibit metastasis by targeting different pathways. In pancreatic cancer cells, resveratrol suppresses the metastatic potential in vitro by modulating EMT-related factors via the PI3K/Akt/NF-κB signaling pathway [ 127 ]. Likewise, resveratrol has been shown to inhibit the invasiveness and metastasis of prostate cancer cells by downregulating glioma-associated oncogene homolog 1, which is a transcription factor in the Hedgehog signaling pathway [ 128 ]. Recent studies suggested that the antitumor effects of resveratrol can also be mediated through enhancing antitumor immunity and reversing the immunosuppressive tumor microenvironment, which is established via stimulating cytokines/chemokines secretion and expression of several other immune-related genes [ 129 ]. These mechanisms were supported by the findings of Lee et al. which demonstrated that resveratrol increases the expression of activating receptors on natural killer (NK) cells, an effect which could facilitate NK-cell-mediated killing of cancer cells [ 130 ]. In closing, it remains to be said that, like many other phytochemicals, resveratrol shows a synergistic inhibitory effect on the proliferation of various cancer cells and increases their chemosensitivity to many chemotherapeutic agents, such as temozolomide, cisplatin, doxorubicin, 5-fluorouracil, gemcitabine, docetaxel, and paclitaxel [ 131 ].

Lastly, despite the high cytotoxicity of resveratrol toward tumor cells, it appears to be well tolerated with no significant harm recorded against normal cells [ 132 ]. These findings are significant in the context of human efficacy investigations, and they lend support to the use of resveratrol as a pharmacological agent in human medicine [ 132 ].

5.3. Quercetin

Quercetin is a natural lipophilic product and one of the most plentiful flavonoids. Flavonoids are known for their low molecular weight and phenolic structure that mainly exists in the seeds, bark, leaves, and flowers of plants [ 133 ]. Flavonoids are categorized into six classes and quercetin falls under the subclass of flavonols.

Quercetin’s name comes from the Latin quercetum , meaning oak forest, after the oak genus Quercus , and its IUPAC name is 3,3′,4′,5,7-pentahydroxyflavanone (or) 3,3′,4′,5,7-pentahydroxy-2-phenylchromen-4-one, with the molecular formula C15H10O7. Quercetin has three rings with five hydroxyl groups attached at positions 3, 5, 7, 3′, and 4′ that play a major role in its biological activity and formation of derivatives. The main groups of derivatives are glycosides, ethers, and less frequently sulfate and prenyl substituents [ 134 ]. Quercetin naturally is an aglycone, missing a glycosyl group, so glycosidic derivatives are achieved by replacing the hydroxyl group (mainly at position 3 and less frequently at position 7) with a sugar-like glucose, rhamnose, or rutinose, resulting in increased water solubility, absorption, and in vivo effects compared to quercetin aglycone [ 135 , 136 , 137 ]. On the other hand, ether derivatives are achieved by forming an ether bond between any hydroxyl group and an alcohol, mainly methanol [ 138 ]. Quercetin is found in many foods such as capers, apples, berries, brassica vegetables, grapes, pepper, asparagus, onions, broccoli, shallots, cherries, tea, and tomatoes. Quercetin is also well observed in medicinal plants, such as Ginkgo biloba , Hypericum perforatum , and Sambucus Canadensis [ 139 , 140 , 141 ].

Regarding its pharmacological effects, quercetin has been shown to exhibit antiviral, antibacterial, anti-inflammatory as well as anticarcinogenic effects [ 142 , 143 , 144 ]. The anticarcinogenic effects are mediated through several mechanisms, such as targeting free radicals, inducing apoptosis, regulating cell cycle, and targeting important key molecules in cancer development, in addition to a unique impact on certain types of cancer.

Quercetin’s antioxidant effects protect cells from the actions of ROS and RNS, which contribute to cancer development. In addition, quercetin contributes to the reduction of ROS-induced injury by increasing the expression of endogenous antioxidant enzymes [ 145 , 146 ].

A second mechanism that may play a role in the anticancer effects of quercetin is the induction of apoptosis by mitochondrial pathways, which involves stimulation of caspase-3 and caspase-9 followed by the release of cytochrome c (Cyt c) and cleavage of poly-ADP-ribose polymerase (PARP) [ 147 , 148 , 149 ]. Moreover, quercetin also stimulates the proapoptotic genes and inhibits the antiapoptotic genes prompting cell death through the intrinsic and extrinsic pathways of apoptosis [ 150 ]. Additionally, quercetin inhibits PI3K/AKT/mTOR and STAT3 pathways specifically in primary effusion lymphoma (PEL) cells, leading to downregulation in the expression of the pro-survival cellular proteins such as c-FLIP, cyclin D1, and c-Myc. Quercetin also reduces the release of IL-6 and IL-10 cytokines, leading to PEL cell death [ 151 ]. In parallel, Wang et al. reported that quercetin induces transcription factor EB-mediated lysosome activation and increases ferritin degradation, thus leading to ferroptosis and Bid-involved apoptosis, especially in p53-independent cancer cells [ 152 ]. Furthermore, quercetin may have a role in breast cancer therapy. Anti-proliferative effects of quercetin have been demonstrated in the MCF-7 cell line by various mechanisms, including reducing the phosphorylation of P38MAPK, a hallmark of cell proliferation, and influencing the G1 phase and causing apoptosis by suppressing cyclin D1, P21, and Twist expression [ 153 , 154 ]. In thyroid cancer, quercetin plays a role in upregulating Pro-NAG-1/GDF15 in differentiated thyroid cancer cells leading to apoptosis induction and cell cycle arrest [ 155 ].

Moreover, quercetin results in cell cycle arrest by its effect on numerous target proteins such as p21, p53, p27, cyclin D, cyclin B, and cyclin-dependent kinases. By preference, quercetin induces cell cycle arrest at the G2/M phase by inauguration of p21 and p73 and cyclin B inhibition, together at the translation and transcription levels [ 47 ]. Moreover, quercetin has been shown to inhibit an important key molecule, VEGF, which plays a significant role in the survival of endothelial cells and can cause tumor angiogenesis [ 156 , 157 ]. Similarly, Sharmila et al. revealed that quercetin supplementation also normalizes the following factors: insulin-like growth factor receptor 1 (IGFIR), AKT, androgen receptor (AR), and cell proliferation proteins, which are known to be increased in cancer. In osteosarcoma, Shenglong Li et al. indicated that quercetin assists in reducing the invasion, adhesion, proliferation, and migration rates of human metastatic osteosarcoma cells by inhibiting parathyroid hormone receptor 1 (PTHR1) activity [ 158 ]. In addition, quercetin can alter the depolarization of mitochondria and calcium cytoplasmic concentration [ 159 ], has a role in increasing the phosphorylation of c-Jun N-terminal kinase, ERK1/2, P38, and P90RSK proteins, and inhibits the phosphorylation of S6, AKT, and P70S6K proteins [ 159 ].

In regard to thyroid cancer, the anticancer activity of quercetin was demonstrated through downregulation of Hsp90 levels and reducing chymotrypsin-like proteasome activity [ 160 , 161 ]. As for ovarian cancer, several in vitro studies demonstrated that quercetin inhibits cancer angiogenesis [ 162 ] and causes suppression of cell survival, proliferation, migration, and adhesion of the ovarian cancer cell line PA-1 [ 163 ]. However, in colon cancer, quercetin inhibits the cell viability of colon 26 (CT26) and colon 38 (MC38) cell lines, while assisting the expression of epithelial–mesenchymal transition (EMT) markers, such as E-, N-cadherin, β-catenin, and snail. In addition, quercetin also inhibits the migration and invasion abilities of the CT26 cell line through modulating the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) [ 164 ].

Regarding quercetin safety, clinical investigations have demonstrated that quercetin has no toxicity or negative effects [ 165 ]. Quercetin has been found in clinical tests to have anti-inflammation and antitumor properties, as well as to alleviate anemia and decrease blood pressure [ 165 ].

5.4. EGCG (Epigallocatechin Gallate)

EGCG, also known as epigallocatechin gallate, is a natural flavonoid under the subclass of falvan-3-ols (catechins). It is considered a polyphenolic product with a complex structure, and it contains a flavanol core (flavan-3-ols) structure esterified with gallic acid [ 166 ]. EGCG can be found in cocoa-based products, nuts, and some fruits, but green tea ( Camellia sinensis Theaceae) is still considered as the main source of this product [ 167 ]. EGCG is considered as the most abundant and therapeutic active catechin in this plant with a percent of nearly 65% among the other three other catechins (epicatechin (EC), epigallocatechin (EGC), and epicatechin gallate (ECG). Due to its phenolic structure, it is very efficient in radical scavenging, and it exhibits its antioxidant effect through several mechanisms, such as hydrogen atom transfer, electron transfer, and the chelation of catalytic metals [ 168 ]. Surprisingly, its antioxidant effect is even greater than vitamin E and vitamin C [ 169 , 170 ]. Moreover, it has a role in cancer, diabetes, obesity, cardiovascular, neurodegenerative, and metabolic diseases [ 102 , 171 , 172 ]; furthermore, it has antiviral, antibacterial, and anti-inflammatory properties [ 173 ].

As an anticancer product, EGCG exhibits its action through multiple mechanisms, such as affecting redox reactions and inducing apoptosis and cell arrest, impairing certain proteins and factors that have a role in cancer development, inhibiting angiogenesis, acting as a metal chelating agent, stabilizing p53 for its antitumor activity, and affecting cell proliferation.

EGCG inhibits redox-sensitive transcription factors, such as nuclear factor-κB (NF-κB) [ 174 ] and leads to a reduction of NF-κB DNA binding activity, decreasing in the expressions of pro-inflammatory mediators such as interleukin-1β (IL1β), IL-6, IL-8, and tumor necrosis factor-α (TNF-α), as well as downstream enzymes such as poly [ADPribose] polymerase (PARP), COX-2, and iNOS, which eventually leads to decreased infiltration of inflammatory cells [ 175 , 176 , 177 ].

In addition to this, EGCG induces the apoptosis and cell arrest of cancer cells through several mechanisms. For example, the activation of the apoptosis-related proteins caspase-3, caspase-9, and PARP-1, particularly in MCF-7 breast cancer cells [ 178 ], by induction of the apoptotic molecular signals such as Bax, caspases, and cytochrome c (cyt. c), especially in HuCC-T1 cholangiocarcinoma cells [ 179 ]; reduction of protein expression of adenosine triphosphate binding cassette subfamily G member 2 (ABCG2) and Bcl-2, also increasing Bax and caspase-3 expression, especially in human esophageal squamous carcinoma cells [ 180 ]; and suppression of epidermal growth factor receptor (EGFR)/Ras/Raf/mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK) signaling pathway, especially in thyroid cancer [ 181 ], by the inhibition of the activation of the PI3K/Akt serine/threonine kinase 1 signaling pathway in H1299 lung cancer cells [ 182 ]. In gastric cancer, Zhu et al. showed that EGCG had improved pathological lesions of the precancerous lesions of gastric cancer (PLGC) and enhanced the effect of apoptosis promotion in PLGC rats, and the apoptotic pathway activated by EGCG may be correlated to the inhibition of the PI3K/Akt/mTOR pathway [ 183 ]. In head and neck cancer, Amin et al. had shown that a mixture of EGCG and resveratrol induces synergistic apoptosis that is supported by caspase-3 and Poly ADP-ribose polymerase(PARP) cleavages and inhibition of tumor growth; the mixture also inhibited AKT-mTOR signaling with overexpression of constitutively active AKT protected cells from apoptosis [ 184 ].

An EGCG and epicatechin combination had shown a higher population of cells in S and G2/M phases when compared to the control, which resulted in inducing cell cycle arrest in HepG2 cells [ 185 ]. Moreover, in MCF-7 breast cancer cells, EGCG stimulates cell cycle arrest at the G2/M phase [ 178 ]. Furthermore, EGCG directly impairs the activity of urokinase, which is a protein that is overexpressed in cancer and has a crucial role in metastasis development; therefore, impairing its activity results in extracellular matrix degradation, consequently leading to an inhibition of cancer invasion [ 186 ]. EGCG is also effective in the inhibition of MMP-2 and MMP-9, which are responsible for degrading the basement membrane and assisting cell invasion and are commonly overexpressed in cancer [ 187 ]. EGCG also enhances the ratio of SKOV-3 cells in the G1-phase with an associated decline in the ratio of cells in the S phase and G2-phase of the cell cycle [ 188 ]. Additionally, EGCG can inhibit matrix metalloproteinases such as MMP-2 and MMP-9, which are usually elevated in cancer and considered as instruments for degrading the basement membrane and facilitating cell invasion [ 189 ]. Furthermore, EGCG inhibits signal transducer and activator of transcription 3 (STAT3), which is an oncogene that supports cell survival, proliferation, motility, and progression of the cancer cells [ 190 ]. In addition, EGCG plays an important role in the inhibition of activating protein-1 (AP-1) transcription factor, which is associated with the pathogenesis of cancer [ 191 ]. As well, it inhibits the VEGF by modulating the activity of hypoxia-inducible factor 1α (HIF-1α) and NF-kB factor [ 192 ]; so, as a result, it inhibits the cancer angiogenesis.

Besides this, EGCG also has a metal chelating feature, and given that certain receptor kinases rely on divalent cations for their action, EGCG can inhibit this reaction by chelating to these cations [ 193 ].

Additionally, Zhao et al. reported a direct interaction between EGCG and the tumor suppressor p53 with the disordered N-terminal domain (NTD). The EGCG-p53 interaction disrupts p53 interaction with its regulatory E3 ligase MDM2 and inhibits ubiquitination of p53 by MDM2 in an in vitro ubiquitination assay, likely stabilizing p53 for antitumor activity [ 194 ].

Related to breast cancer, Tanaka et al. revealed that EGCG had reduced rRNA transcription and cell proliferation through the activation of KDM2A in MCF-7 cells, and EGCG helps in KDM2A activation by the activation of both 5’ AMP-activated protein kinase (AMPK) and ROS production. Essentially, the inhibition of rRNA transcription and cell proliferation by EGCG was particularly detected in MCF-7 cells; however, it was not detected in non-tumorigenic MCF10A cells [ 195 ].

5.5. Allicin

Allicin, or diallyl thiosulfinate, is a sulfur-containing volatile oil, and it can be produced by tissue damage of the non-proteinogenic amino acid S-allyl cysteine sulfoxide (alliin), which is catalyzed by the alliinase enzyme [ 196 ]. It is extracted from garlic ( Allium sativum L.) and other Allium species such as onions ( Allium cepa L.) and shallots ( Allium ascalonicum L.). Allicin cannot be found while garlic is intact; thus, it is activated by chopping or cutting the garlic cloves [ 197 ]. Allicin’s presence is easily noticed because of its distinctive odor [ 198 ]. As well, allicin may act as an irritant that increases pain-sensing neurons, and self-medication has resulted in a rash of cases of self-harm [ 199 ]. Thus, while tiny levels are appreciated in culinary contexts, excessive allicin consumption is definitely hazardous [ 199 ].

Allicin exhibits potential as an anticancer, antifungal, and antibacterial product [ 197 ], and it also shows activity in cardiovascular diseases (CVD), as it induces vasodilation, inhibits platelet aggregation, prevents hyperlipidemia, and suppresses cardiac hypertrophy [ 200 ].

As an anticancer product, allicin induces its effects due to many mechanisms, such as inducing apoptosis and suppressing the migration and invasion of cancerous cells, having synergistic effects with cancer treatments.

According to its anticancer potential, allicin initiates autophagy-dependent cell killing by suppressing the Akt/mTOR signaling pathway [ 201 ]. Moreover, it induces apoptosis through the induction of the caspase-3 pathway [ 202 ], and Hussain et al. had indicated that apoptosis induction resulted in cycle cell arrest in the G2 /M phase [ 203 ]. Maitisha et al. had shown that allicin induces apoptosis and regulates biomarker expression in breast cancer in vitro due to modulation of the p53 signaling pathway [ 204 ]. Moreover, it was found that allicin is capable of inhibiting the expression of VCAM-1 in MCF-7 cells [ 205 ]. In addition, allicin can also inhibit telomerase activity and induce the apoptosis of gastric cancer SGC-7901 cells [ 206 ]. In glioma, Li et al. had shown that allicin had successfully inhibited proliferation and stimulated apoptosis in U251 glioma cells in vitro and also enhanced the activation of both intrinsic and extrinsic apoptosis signaling pathways in U251 cells [ 84 ]. Moreover, Cha had proved that allicin inhibits the cell viability of U87MG cells and stimulates cell death through apoptosis, which is mediated through the Bcl-2/Bax mitochondrial pathway, MAPK/ERK signaling pathway, and antioxidant enzyme systems [ 207 ]. In ovarian cancer, allicin can activate the JNK pathway, which leads to mitochondrial Bax translocation and mitochondrial release of cytochrome, thus inducing SKOV3 cell apoptosis in glioblastoma cancer cells.

In breast cancer cell lines, allicin induces cell cycle arrest through targeting the p53 pathway [ 204 ]. More and more, allicin suppresses the cell growth of human glioblastoma via inducing G2/M and S phase cell cycle arrest [ 208 ]. In cervical cancer, allicin suppresses the migration and invasion in cervical cancer cells mainly by inhibiting NRF2 [ 209 ]. In lung carcinoma, it was noticed that it prevents the invasion of lung adenocarcinoma cells by altering TIMP/MMP balance and by lowering the activity of the PI3K/AKT signaling pathway [ 62 ].

In gastric cancer, a combination of allicin with 5-Florouricil could decrease multidrug resistance in these cells by lowering the expression of WNT5A, Dickkopf-1(DKK1), multidrug resistance protein 1 (MDR1), P-glycoprotein 1 (P-GP), and CD44 gene levels [ 210 ]. Regarding osteosarcoma, Jiang indicated that a combination of artesunate and allicin was proved to have a synergistic effect on osteosarcoma cell proliferation and apoptosis [ 211 ]. In melanoma, Jobani had revealed that combination therapy together with allicin and ATRA (all-trans-retinoic acid) significantly decreased the IC50 (half-maximal inhibitory concentration) value obtained for ATRA alone in CD44+ melanoma cells [ 212 ]. In hepatocellular carcinoma, it was noticed that a combination of electromagnetic field and allicin can induce apoptosis in vitro and inhibition of proliferation in the HepG2 cell line [ 213 ].

5.6. Thymoquinone

Thymoquinone (TQ) is a non-toxic major bioactive ingredient obtained from the essential oil of black seed Nigella sativa L. It is a monoterpene with the chemical structure (2-Isopropyl-5-methyl-1, 4-benzoquinone), which has been extensively utilized in traditional medicine in the Middle East and Southeast Asian countries owing to its numerous biological actions [ 214 , 215 ]. Thymoquinone is nontoxic and has a wide range of applications in the treatment of many human disorders, including diabetes and cancer [ 216 ]. The pharmacological activities of TQ include antioxidant, anti-inflammatory, immunomodulatory, hepatoprotective, antihistaminic, antimicrobial, antidiabetic, anti-epileptic, and chemo-sensitizing, as well as very promising antitumor activity [ 217 , 218 , 219 ].

TQ anticancer studies have revealed several mechanisms of action, such as regulation of reactive species interfering with DNA structure, modulating various potential targets and their signaling pathways as well as inducing immune system responses in vitro and in vivo. The distinctive anticancer properties of TQ are mainly due to the induction of apoptotic mechanisms, such as activation of caspases, downregulation of precancerous genes, inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), antitumor cell proliferation, hypoxia, anti-metastasis, and reduction of side effects when using traditional chemotherapeutic drugs [ 220 , 221 ]. Altering of cell cycle progression is an important step in the inhibition of cancer development and progression. TQ induces G1 phase cell cycle arrest in human breast cancer, colon cancer, and osteosarcoma cells through inhibiting the activation of cyclin E or cyclin D and upregulating p27 and p21, a cyclin-dependent kinase (Cdk) inhibitor [ 222 ]. TQ conjugated with fatty acid has potential activity on cell proliferation, apoptosis, and signaling pathways [ 217 ]. Conjugation is performed to increase TQ’s capacity to penetrate cell membranes. Several conjugated forms were studied in HCT116 and HCT116 p53−/− colon cancer and HepG2 hepatoma cells in vitro. Treatment with TQ-4-α-linolenoylhydrazone or TQ-4-palmitoylhydrazone was effective in p53-competent HCT116 cells, mediated by an upregulation of p21cip1/waf1 and a downregulation of cyclin E, and associated with an S/G2 arrest of the cell cycle. HCT116 p53−/− and HepG2 cells showed only a minor response to TQ-4-α-linolenoylhydrazone [ 223 ]. TQ induces G0/G1 cell cycle arrest, increases the expression of p16, decreases the expression of cyclin D1 protein in DMBA-initiated TPA-promoted skin tumors in mice, inactivates CHEK1, and contributes to apoptosis in colorectal cancer cells [ 224 , 225 ], as well as inducing G1 phase cell cycle arrest in human breast cancer, colon cancer, and osteosarcoma cells through inhibiting the activation of cyclin E or cyclin D and upregulating p27 and p21, a cyclin-dependent kinase (Cdk) inhibitor [ 222 ]. Moreover, TQ causes cell arrest at different stages according to the concentration used (25 and 50 µM) in vivo in human mammary breast cancer epithelial cell lines, MCF-7 [ 226 ]. In esophageal cancer, TQ encourages G2/M phase cell cycle arrest by increasing the levels of p21 and p53 while remarkably decreasing cyclin A, cyclin B1, and cyclin E expression [ 227 ], as well as inducing DNA damage, apoptosis, increased iROS, and cytotoxicity in C6 glioma cells [ 228 ]. TQ reduces the elevated levels of serum TNF-α, IL-6, and iNOS enzyme production and enhances histopathological results in Wistar rats with methotrexate-induced injury to the hepatorenal system [ 229 ]. Additionally, TQ has a role in reducing the NO levels by downregulation of the expression of iNos, reducing Cox-2 expression and consequently generating PGE2 and reducing PDA cell synthesis of Cox-2 and MCP1 [ 230 , 231 ].

TQ has an effective role in the reduction of endothelial cell migration, tube formation, and suppression of tumor angiogenesis. TQ noticeably reduces the phosphorylation of EGFR at tyrosine-1173 residues and JAK2 in vitro in HCT 116 human colon cancer cells and downregulates the Jak2/STAT3 signaling pathway in human melanoma cells and HL60 leukemia cells [ 232 , 233 , 234 ]. TQ causes G2/M cell cycle arrest and stirred apoptosis, and it significantly lowers the nuclear expression of NF-κB. Moreover, TQ has a role in the elevation of PPAR-γ activity and downregulation of the gene’s expression for Bcl-2, Bcl-xL, and survivin. Furthermore, it has an antiproliferative effect, especially when combining it with doxorubicin and 5-fluorouracil, which results in increased cytotoxicity in the breast cancer xenograft mouse model [ 235 ]. Moreover, TQ has a role in the downregulation of the expression of STAT3-regulated gene products in gastric cancer in both in vivo and in vitro models [ 236 ]. Reports showed that TQ plays an essential role in the induction of apoptosis by decreasing the expression of antiapoptotic proteins, as well; it also significantly increased the expression of pro-apoptotic protein [ 237 ]. This process is mediated by the activation of caspases 8, 9, and 7 in a dose-dependent manner and increases the activity of PPAR-γ [ 238 , 239 , 240 ].

TQ prevents DNA damage caused by free radicals by scavenging the free radical activity [ 241 , 242 , 243 ]. TQ shows a significant effect in the decrease of expressions of CYP3A2 and CYP2C 11 enzymes [ 244 ]. TQ treatment showed activity in the reduction of CYp1A2, CYP 3A4, and CYp3A4 enzyme activity and the increase of the phase II enzyme GST. TQ has proven its role in tumor prevention through activation of antioxidant enzymes and its antioxidant activity [ 245 ]. TQ treatment illustrates that is has a valuable role in the increase of the PTEN mRNA. Moreover, it has a pivotal role in the inhibition of breast cancer cell proliferation and induction of apoptosis via activation of the P53 pathway in the MCF-7 cell line, the finding having revealed that a time-dependent increase of PTEN occurs in cells treated with TQ as compared with untreated cells [ 246 ]. TQ induces degradation of the tubulin subunit in the cells; it also inhibits the telomerase enzyme activity. Furthermore, it causes the suppression of androgen receptor expression and E2F-1, which is essential for the proliferation and viability of androgen-sensitive and androgen-independent prostate cancer cells [ 217 ].

Revolutionary findings have revealed TQ’s ability to regulate microRNA (miRNA) expression. MiRNAs are small noncoding RNAs that modulate gene expression and cellular signaling pathways through variation in the features of mRNA, thus moderating TQ’s anticancer effect through P53, PCNA, cyclin D1, Bcl-2, NF-κB, TWIST (Twist1,2), ZEB, eEF-2 K, PI3K/Akt, and Src/Fak signaling pathways [ 247 ]. Along with TQ’s impairment of autophagic flux and inhibition of the EMT and cell invasion via activation of the miR-877-5p/PD-L1 (programmed death ligand 1) axis in bladder carcinoma cells and the expression of Beclin-1 and LC3 in triple-negative breast cancer (TNBC) cells, it suppresses the pathways related to cell migration/invasion and angiogenesis, including Integrin-β1, VEGF, MMP-2, and MMP-9 [ 248 , 249 ]. Thymoquinone upregulates miR-125a-5p, attenuates STAT3 activation, and potentiates doxorubicin antitumor activity in murine solid Ehrlich carcinoma [ 250 ].

5.7. Emodin

Emodin is a Chinese herb-derived anthraquinone isolated from the roots and rhizomes of several plants such as Rheum palmatum , Polygonum cuspidatum, Polygonum multiflorum, Aloe vera , and Cassia obtusifolia , as well as different fungal species, including Aspergillus ochraceus , and Aspergillus wentii . Its chemical structure is (1,3,8-trihydroxy-6-methylanthraquinone) [ 251 , 252 , 253 ]. Emodin displays a variety of pharmacological activities, such as antiviral, antibacterial, anti-allergic, anti-osteoporotic, anti-diabetic, immunosuppressive, neuroprotective, hepatoprotective, anti-cardiovascular disease, antitumor, and anti-inflammatory activities [ 253 , 254 , 255 ].

According to Hsu and Chung’s review (2012), the molecular mechanisms of emodin comprise cell cycle arrest, apoptosis, and the promotion of the expression of hypoxia-inducible factor 1α, GST, P , N -acetyltransferase, and glutathione phase I and II detoxification enzymes while inhibiting angiogenesis, invasion, migration, chemical-induced carcinogen–DNA adduct formation, HER2/neu, CKII kinase, and p34cdc2 kinase in human cancer cells [ 256 ]. Emodin inhibits non-small lung cancer cells via modulation of the cell cycle by decreasing cells in the G2/M and S phases and increasing cells in the G1/G0 phase [ 257 ]. Moreover, emodin suppresses hepatocellular carcinoma by inducing G2/M and S phase arrest [ 258 ]. In glioma U251 cells, emodin resulted in the induction of cell cycle arrest. Zhou et al. found that the ratio of U251 cells was decreased in the G0/G1 phase compared to the control, and the ratio of cells in the G2/M and S phases was increased when treated with emodin [ 259 ]. It has been reported to inhibit tumor-associated angiogenesis through the inhibition of ERK phosphorylation and to suppress VEGFA transcription and thus tumor angiogenesis in triple-negative breast cancer (TNBC), in addition to its antiproliferative and antimetastatic effects [ 260 , 261 ]. Emodin also inhibits Aurora kinase A (AURKA), which plays an essential role in proliferation and is involved in cisplatin resistance in various cancer cells [ 262 ]. It downregulates the expression of survivin and β-catenin, inducing DNA damage and inhibiting the expression of DNA repair [ 256 ]. It also inhibits the activity of casein kinase II (CKII) by competing at ATP-binding sites [ 256 , 263 ]. Emodin induces necroptosis through ROS-mediated activation of the JNK signaling pathway as well as inhibits glycolysis by downregulation of GLUT1 through ROS-mediated inactivation of the PI3K/AKT signaling pathway [ 264 ]. According to some findings, it upregulates hypoxia inducible factor HIF-1 and intracellular SOD and boosts the efficacy of cytotoxic drugs [ 265 , 266 ]. Emodin may sensitize tumor cells to radiation therapy and chemotherapy and inhibit the pathways that lead to treatment resistance. It was found to reverse gemcitabine resistance in vitro in pancreatic cancer cell lines by decreasing the expression of MDR-1 ( P -gp), NF-κB, and Bcl-2, increasing the expression levels of Bax, cytochrome-C, and caspase-9 and -3, and promoting cell apoptosis unstimulated and in gemcitabine-induced-resistance pancreatic cancer cell lines [ 267 ]. Furthermore, in vitro and in vivo findings have concluded that emodin downregulates both XIAP and NF-κB and enhances apoptosis in mice bearing human pancreatic cancer cells [ 268 ]. Chemosensitization was also observed in gallbladder cancer, where an independent combination treatment of emodin with cisplatin, carboplatin, or oxaliplatin augmented chemosensitivity in vitro in SGC996 gallbladder cancer cells and in vivo in gallbladder-tumor-bearing mice. Wang et al., 2010, credited these findings to the reduced glutathione level, downregulation of multidrug resistance-related protein 1 (MRP1), and to the increased apoptosis caused by such combinations [ 269 ]. Additionally, enhanced chemosensitivity was observed in vitro in DU-145 cancer cell lines (multidrug resistant prostate carcinoma cell line) and in vivo in tumor-bearing mice when treated with a combination of emodin and cisplatin. The mechanism was shown to involve ROS-mediated suppression of multidrug resistance and hypoxia inducible factor-1 in over-activated HIF-1 cells [ 270 ].

5.8. Genistein

Genistein [4,5,7-trihydroxyisoflavone or 5,7-dihydroxy-3-(4-hydroxyphenyl) chromen-4-one] is an isoflavonoid with a 15-carbon skeleton and is classified as a phytoestrogen. It is found in food (especially legumes) in the glycosylated or free form. It is structurally similar to 17β-estradiol, which is the reason for its ability to bind to and modulate the activity of estrogen receptors [ 271 ]. It was isolated for the first time in the year 1899 from Genista tinctoria ; hence, it was named after the genus of this plant. However, it is the main secondary metabolite of the Trifolium species and in Glycine max (soybean). In fact, soybean, soy-based foods, and soy-based drinks are the best sources of genistein. Lupin ( Lupinus perennis ) is also a legume that holds similar nutritional value to that of soybean in terms of genistein content. Other important legumes are broad beans and chickpeas, which are known to contain significant amounts of genistein, although less than soybean and lupine. Genistein pharmacologically acts as an anticancer, estrogenic, and anti-osteoporotic agent [ 271 , 272 ].

Genistein exerts its anticancer effects by inducing apoptosis, decreasing proliferation, and inhibiting angiogenesis, as well as metastasis, which was illustrated by decreased tumor growth and development in the hepatocellular cancer models of nude mice [ 273 ] and Wistar rats [ 274 ], as well as in the gastric cancer model of Wistar rats [ 275 ]. Genistein’s role in prostate cancer was extensively studied in vivo in different animal models, such as the Lobund-Wistar rat (which is a unique rat model that spontaneously develops metastatic prostate cancer in 30% of its population), and in SCID mice transplanted with human prostate carcinoma cells (LNCaP, PC3, and DU-145). Some in vivo studies included normal rats to test for genistein’s toxic effect on the prostate and its effect on the expression of the androgen and estrogen receptor [ 276 , 277 , 278 ].

Genistein is involved in regulation of key biological processes including those in different types of cancer via epigenetic modulation in a direct or indirect manner through estrogen-receptor-dependent pathways, where it was reported to target estrogen receptor (ER), human epidermal growth factor receptor-2 (HER2), and breast cancer gene-1 (BRCA-1) in multiple BC cell lines [ 279 , 280 ]. Genistein was found to inhibit histone deacetylase (HDAC) enzymes, which are responsible of regulating histone acetylation of DNA [ 272 ], in MCF-7 and MDA-MB-468, and in immortalized but noncancer fibrocystic MCF10A breast cells at very low, dietary-relevant concentrations [ 281 ]. A particular HDAC enzyme is HDAC-6, which is known to acetylate and activate heat shock protein (Hsp90). Basak et al. 2008, reported that the increased ubiquitination of androgen receptors was due to the inhibition of Hsp90 chaperones in genistein-treated LNCaP prostate cancer cells. These results strongly support the hypothesis that genistein may be an effective chemopreventive agent for prostate cancer [ 282 ].

It inhibits cyclooxygenase-2 (COX-2) directly and indirectly by suppressing COX-2 stimulating factors such as activated protein-1 (AP-1) and Nf-κB. COX-2 overexpression has been described in pancreatic, colon, breast, and lung cancer, and its inhibition has been correlated with decreased development of cancerous tumors in the esophagus and in the colon [ 272 ]. Genistein inhibits CDK by upregulating p21, and it suppresses cyclin D1, which ultimately induces G2/M cell cycle arrest and decreases tumor cell progressions [ 272 , 277 , 283 , 284 , 285 ]. Moreover, in pancreatic cancer cells, it activates G0/G1 phase cell cycle arrest [ 286 ]. Genistein was reported to downregulate the expression levels of matrix metalloproteinase-2 (MMP-2) in glioblastoma, melanoma, and breast cancer, as well as regulate caspase-3 and p38MAPK pathways in prostate cancer cell lines. Matrix metalloproteinase (MMP) is the starting step in metastasis and angiogenesis cascade [ 272 , 287 , 288 ]. In addition, AP-1 is an angiogenic cytokine, which is inhibited by genistein; consequently, such an inhibitory effect will impede several targets, including cyclin D1, MMP, VEGF, Bcl-2, uPA, and Bcl-XL [ 272 ]. Genistein induces Cd74 downregulation, which regulates the NF-κB/Bcl-xL/TAp63 signaling pathway by contributing to its therapeutic effect on triple-negative breast cancer (TNBC) tumors. Additionally, genistein can modify expression levels of key epigenetic-associated genes such as DNA methyltransferases ( Dnmt3b ), ten-eleven translocation ( Tet3 ) methylcytosine dioxygenases and histone deacetyltransferase ( Hdac2 ), and their enzymatic activities, as well as genomic DNA methylation and histone methylation (H3K9) levels [ 289 ].

Moreover, genistein can influence metastasis and induce apoptosis by inhibiting Akt, as well as NF-κB cascades, in PC3 cell lines and MDA-MB-231 breast cancer cell lines, as well as inhibiting the IL-6/STAT3 pathway in MDA-MB-453 breast cancer cell lines, thus inhibiting cell proliferation [ 272 , 290 , 291 ]. Furthermore, genistein decreases phosphorylated-Akt in HT-29 colon cancer cells [ 292 ], in LNCaP prostate cancer cells [ 293 ], and in HeLa and CaSki cervical cancer cell lines [ 294 ], as well as in other cancer cell cultures [ 272 ].

This concluded that genistein modulates its anticancer activity via several signaling pathways both at transcription and translation levels through regulation of several key cellular pathways [ 295 ]. Moreover, Lui et al. 2021, successfully demonstrated that genistein can specifically bind to DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and block the DNA-PKcs/Akt2/Rac1 pathway, thereby effectively inhibiting radiation-induced invasion and migration of glioblastoma multiforme (GBM) cells in vitro and in vivo [ 296 ]. In addition, this phytochemical synergistically reverses the resistance mechanism of standard chemotherapeutic drugs, increasing their efficacy against BC [ 297 ].

5.9. Parthenolide

Parthenolide (PTL) is a natural product that belongs to the class of germacrane sesquiterpene lactones, and it is the most outstanding representative of its subclass of germacranolides [ 298 ]. The PTL is produced as a secondary metabolite by plants of the Asteraceae/Compositae (daisies) and Magnoliaceae family (magnolias) [ 299 ]. It is extracted from leaves of the medicinal plant feverfew ( Tanacetum parthenium ) [ 299 , 300 ]. Basically, PTL contains an α-methylene-γ-lactone ring and epoxide group, which contribute to its ability to interact with nucleophilic sites of biological molecules [ 298 , 299 , 300 ]. It displays redox-modulating, epigenetic, anti-inflammatory, and anti-bacterial biological activities [ 301 ]; thus, its use in the treatment of migraines and arthritis has been confirmed [ 299 , 302 ]. Moreover, it has shown potent anticancer activity against various types of cancer, including colorectal, pancreatic, lung, skin, melanoma, bladder, and breast cancer [ 303 , 304 ]. Parthenolide is not only a powerful anticancer drug, but it also has no appreciable toxicity to normal cells at the cytotoxic effective concentration [ 305 ].

One of the several mechanisms underlying the PTL’s antitumor activity is its ability to stimulate apoptosis through inhibition of the nuclear factor kappa B (NF-κB) pathway [ 306 ]. This pathway plays a major role in the expression of pro-inflammatory genes, including cytokines, chemokines, and adhesion molecules [ 307 ]. Essentially, the NF-κB pathway activates and induces cell survival in primary effusion lymphoma (PEL). PEL is a rare aggressive disorder that is frequently caused by human herpesvirus 8 (HHV-8) infection [ 308 , 309 ]. PTL can induce apoptosis by the initiation of DNA hypomethylation, histone acetylation, enhancement of oxidative stress via endoplasmic reticulum or thiol depletion, and activation of p53. In addition, PTL has shown its ability to significantly inhibit cell growth and induce G0/G1 cell cycle arrest [ 310 ] via several mechanisms such as transcriptional regulation, signal transduction modulation, and induction of oxidative stress [ 78 ]. In prostate cancer cells, PTL induces cell cycle arrest via the inhibition of miR-375 [ 311 ]. Additionally, PTL can inhibit ubiquitin-specific peptidase 7, which is a deubiquitinating enzyme, by direct interaction [ 9 ]. Needless to say, ubiquitination is crucial in various cellular biological activities; therefore, dysregulation of this process can lead to cancer development [ 312 ]. A study confirmed that PTL inhibits USP47, which regulates colorectal cancer stem cells (CCSCs). Therefore, PTL could effectively suppress CCSCs’ renewal and stemness maintenance, providing a potential therapy for colorectal cancer [ 313 ].

Another study showed that PTL significantly inhibited cell proliferation and migration in two lung cancer cell lines (A549 and H1299). In terms of the involved mechanism, PTL has the capability of blocking the phosphorylation of insulin-like growth factor 1 receptor, Akt, and forkhead box O3α [ 303 ]. Further, it was shown that PTL has powerful cytotoxicity towards human non-small cell lung cancer cells via targeting the B-Raf and inhibiting the MAPK/Erk signaling pathway [ 314 ]. Hence, PTL can be considered a novel therapeutic strategy for renal cell carcinoma. A study conducted by Li et al. revealed the ability of PTL to inhibit the oncogenic characteristics of 786-O and ACHN cells, decrease the viability of cancer cells, and suppress the formation of mammospheres [ 315 ]. PTL induces autophagy by inhibiting the PI3K/AKT/mTOR signaling pathway through the activation of phosphatase and tensin homolog expression [ 316 ]. Additionally, it can covalently modify the cysteine 427 of focal adhesion kinase 1 (FAK1), resulting in damaging FAK1-dependent signaling pathways [ 317 ]. Another inducing autophagy mechanism of PTL was confirmed in pancreatic cancer via the formation of autophagosomes and conversion of LC3A to LC3B form [ 318 ].

In addition, PTL treatment converses the epithelial to mesenchymal transition (EMT) process by significantly decreasing the mesenchymal marker vimentin and inducing the epithelial marker E-cadherin protein expression in both MCF-7 and MDA-MB-231 cells [ 319 ]. The reversal of EMT was concomitant with the reduction of the TGFβ protein, gene expression [ 320 ], and the EMT-inducing transcription factor TWIST1 gene expression. Therefore, it prevents cancer progression and metastasis [ 319 , 320 ]. Additionally, PTL decreased the viability of C918 and SP6.5 cells, which are human uveal melanoma cells [ 321 ].

Moreover, PTL is a strong inhibitor of Janus kinases (JAKs) [ 304 ]. PTL covalently alters the Cys243, Cys178, Cys335, and Cys480 of JAK2, leading to inhibition of their kinase activity and blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway [ 322 ].

In cervical cancer, PTL showed a potent anticancer activity through inhibiting HeLa cell viability in a dose-dependent manner and inducing the generation of ROS that result in loss of mitochondrial membrane potential [ 323 ].

5.10. Luteolin

Luteolin is a flavone compound that belongs to the flavonoids group [ 324 ]. Generally, it can be found in flowers ( Reseda luteola and Chrysanthemums ), herbs (parsley, peppermint, oregano, and thyme), vegetables (celery seeds, onion leaves, cabbages, sweet bell peppers, carrots, and broccoli), and spices (cardamom and anise) [ 324 , 325 ]. Chemically, it is a 3,4,5,7-tetrahydroxyflavone that has a C6-C3-C6 structure with two benzene rings and one oxygen-containing ring with a C2-C3 carbon double bond [ 326 ]. It has been proposed that luteolin has multiple cardio-protective [ 327 ], as well as anti-microbial [ 328 ], anti-inflammatory, anti-oxidant [ 329 , 330 ], and anticancer effects [ 331 ]. Moreover, luteolin displays anticancer activity against colon, liver, lung, skin, and breast cancer [ 332 , 333 ]. On the other hand, luteolin showed a wide range of safety toward normal cells. For example, when luteolin was delivered at a dose of 100 mg/day in human clinical studies, there was no dose-limiting harm (17).

Luteolin exhibits its anticancer properties through different mechanisms, including blocking the activity of epigenetic targets such as DNA methyltransferases, some classical histone deacetylases, and SIRT1 [ 331 ]. It also induces autophagy and cell apoptosis and inhibits invasion, network formation, and migration [ 334 ]. For example, this compound has the ability to inhibit U-251 cell migration and tumorigenesis [ 335 ]. Correspondingly, it causes apoptosis in tamoxifen-resistant breast cancer via activation of apoptosis-related proteins (cleaved poly (ADP-ribose) polymerase, cleaved-Caspase-7, 8, 9) [ 336 ]. Moreover, luteolin upregulates microRNA-6809-5p and inhibits hepatocellular carcinoma’s (HCC) cell growth [ 337 ]. Overexpression of miR-6809-5p suppresses the expression of flotillin 1 [ 338 ] and inactivates signaling pathways, including Erk1/2, p38, JNK, and NF-κB/p65 in HCC cells.

Consequently, it suppresses cancer development [ 337 ]. Likewise, luteolin has a dual action in downregulating/upregulating autophagy in cancer therapy [ 41 ]. For instance, in vitro study has shown that luteolin has an antitumor effect in the HCC cell line SMMC-7721 by inducing autophagy [ 339 ]. Similarly, in mice with liver cancer, luteolin has improved the host’s system via various mechanisms such as modifying the levels of α-fetoprotein and marker enzymes, as well as reducing the levels of glutathione and the inflammatory cytokines interleukin-2 and interferon-γ [ 340 ].

Moreover, luteolin increases the expression of miR-124-3p and activates the death receptor and mitogen-activated protein kinase (MAPK) signaling pathways in glioma [ 341 ]. Further, luteolin raises the level of intracellular ROS [ 325 ]. This can be achieved by activation of the lethal endoplasmic reticulum stress response, mitochondrial dysfunction in glioblastoma cells, as well as activation of ER stress-associated protein expressions [ 342 ]. In metastatic human colon cancer, luteolin reduces the viability and proliferation of SW620 cells and increases the expression of antioxidant enzymes. In addition, the expression of antiapoptotic protein Bcl-2 decreases, whereas the expression of proapoptotic proteins Bax and caspase-3 increases [ 343 ]. Additionally, this phytochemical inhibits the growth of HCT116 colon cancer cells via p53-dependent regulation of cell cycle arrest [ 344 ]. Additionally, in MDA-MB-231 breast cancer cells, luteolin has shown its ability to induce cell cycle arrest in the S phase in a dose-dependent manner [ 345 ]. Moreover, a study revealed that a combination of luteolin and baicalein (a 5,6,7-trihydroxyflavone) inhibits the growth of colon cancer cells of the drug-sensitive LoVo cell line and its drug-resistant LoVo/Dx subline as well [ 333 ].

Interestingly, luteolin and quercetin synergistically enhance the anticancer effect of 5-fluorouracil (5-FU) in HT 29 cells and result in minimizing the toxic effects of 5-FU in the treatment of colorectal cancer [ 44 ]. Luteolin can remarkably induce DNA double-strand breaks (DSBs) in DT40 cells and induce sensitivity and defects in DSB repair in Ku70 cells. Furthermore, it improves the formation of Top2cc in Ku70 cells [ 346 ]. Luteolin and its derivative apigenin significantly inhibit lung cancer cell growth and downregulate the IFN-γ-induced PD-L1 expression by suppressing the phosphorylation of STAT3 [ 347 ]. Luteolin has demonstrated its ability to suppress the expression of TAM receptor tyrosine kinases and the activation of Axl, which in turn leads to the inhibition of cell proliferation in both parental and non-small cell lung cancer cells [ 348 ]. Recent studies have shown that luteolin regulates cyclin D1, cyclin E, p21, and Bcl2, resulting in the prevention of cancer development in gastric cancer. In addition, luteolin controls metastasis by regulating MMPs expression and the EMT process [ 349 ].

Interestingly, Namkung et al. reported that luteolin potently inhibits Anoctamin 1 (ANO1) chloride channel activity and decreases its protein stability in prostate cancer [ 350 ]. It is acknowledged that overexpression of ANO1 is involved in the tumorigenesis of epithelial cancers [ 351 ]. Furthermore, luteolin significantly reduces ribosomal protein S19 expression by blocking the Akt/mTOR/c-Myc signaling pathway in cancer cells [ 352 ]. Table 1 summarizes the mentioned natural products with their main natural sources and anticancer mechanisms of action. Figure 2 demonstrates the effects of natural products on cancer hallmarks.

6. Clinical Studies

6.1. Curcumin

Meriva (curcumin phytosomes) was investigated in controlled semi-quantitative clinical research to determine its potential to relieve the side effects of cancer radiotherapy and chemotherapy. This formulation was also studied for six weeks as an adjuvant to chemotherapy in a group of solid tumor patients (at 1500 mg/day in three separate doses). Patients’ quality of life was greatly improved, and systemic inflammation was significantly reduced [ 354 ].

Curcumin’s safety and anticancer effectiveness in human colon cancer patients were proven in clinical research conducted by Shehzad and colleagues [ 355 ]. Curcumin was proven to accumulate at the colorectum and acquire the effective therapeutic concentration in a phase I clinical trial in which curcuma extract was provided orally to patients with colorectal cancer at dosages of up to 2.2 g daily (equal to 180 mg of curcumin) for several months [ 356 ].

There were improvements in all categories of the International Prostate Symptom Score in a pilot study to test the efficacy of Meriva in benign prostatic hyperplasia (BPH) (given 1000 mg/day in two divided doses) [ 357 ].

Docetaxel plus curcumin administered to individuals with advanced breast cancer with dose escalation demonstrated some improvements in biological and clinical responses in the majority of patients in a phase I trial [ 358 ]. Another study looked into the efficacy of combining curcumin and quercetin to regress adenomas in patients with familial adenomatous polyposis (FAP), an autosomal dominant condition characterized by colon and rectum cancer. For six months, FAP patients with prior colectomy were administered 480 mg curcumin and 20 mg quercetin orally three times daily. The quantity and size of these malignant polyps were dramatically reduced [ 359 ].

In a phase II experiment, twenty-five patients with advanced pancreatic cancer were given 8 g of curcumin capsules daily, with restaging every eight weeks [ 360 ]. There was no toxicity seen when the medication levels peaked at 22 to 41 ng/mL. This study found that, despite its low absorption, oral curcumin had biological action and was safe in some pancreatic cancer patients. Furthermore, the expressions of NF-κB, COX-2, phosphorylated signal transducer, and activator of transcription 3 (which were higher in patients compared to healthy volunteers) were found to be lowered in most patients’ peripheral blood mononuclear cells [ 360 ].

A randomized double-blind placebo-controlled parallel-group clinical study was conducted in a group of 150 women with advanced breast cancer to examine the efficacy and safety of an intravenous infusion of curcumin in conjunction with paclitaxel. Three months were spent monitoring the patients. This study concluded that using curcumin in conjunction with paclitaxel was preferable to using paclitaxel alone [ 361 ].

According to the research, derivatizing curcumin may be a viable option for increasing target selectivity and producing anticancer therapeutic candidates with greater potency [ 362 ]. Twenty patients with cancer anorexia–cachexia syndrome who were properly nourished via a feeding tube were included and randomly assigned in a 1:1 ratio to receive oral curcumin (at a dose of 4000 mg daily) ( n = 10) or placebo ( n = 10) for 8 weeks [ 363 ]. Curcumin has a statistically significant advantage on improving muscle mass when compared to the placebo. The addition of curcumin resulted in a considerable increase in muscle mass compared to the usual nutritional assistance. Furthermore, it may improve and postpone the decline of other body composition metrics, such as handgrip strength and absolute lymphocyte count [ 363 ].

6.2. Resveratrol

Resveratrol has been studied in clinical trials for its potential therapeutic efficacy in a variety of disorders such as cancer, obesity, neurological disorders, cardiovascular disorders, and infections. This review focuses on the role of resveratrol as an anticancer agent [ 364 ].

The safety of resveratrol has been tested in healthy persons, and it has been shown to be safe up to doses of 5 g/d [ 365 ]. The most prevalent tumors that have been shown to respond positively to resveratrol include colon cancer, breast cancer, and multiple myeloma [ 365 ].

The effects of resveratrol on the expression of several cancer-related genes, such as CCND-2, p16, RASSF-1α, and cancer-promoting prostaglandin E2 (PGE2), were investigated in a randomized placebo-controlled clinical research in women with a high risk of breast cancer [ 366 ]. For 12 weeks, the participants were given two capsules per day containing either placebo, 5 mg of trans-resveratrol, or 50 mg of trans-resveratrol. PGE2 levels were discovered to be reduced [ 366 ].

A phase I trial was carried out to evaluate the effect of low-dose resveratrol (80 mg/d) and resveratrol-containing freeze-dried grape powder (GP) (80 g/day, equivalent to 450 g fresh grapes) on colon cancer. After 14 days of treatment, there was an increase in the expression of Myc and cyclin D1 in colon cancer tissue. When compared to resveratrol, the GP had more dramatic effects [ 367 ]. Furthermore, in normal colonic mucosa, GP strongly lowered CD133 with a modest effect on LGR5 (downregulation of CD133 and LGR5 is associated with growth inhibition of colon cancer cells) [ 368 ].

Micronized resveratrol (SRT501) was employed in another investigation to improve resveratrol absorption across the gastrointestinal system. SRT501 was given to individuals with colorectal cancer and hepatic metastases at a dose of 5 g per day for two weeks. SRT501 was well tolerated and increased mean plasma resveratrol levels (3.6-fold) after a single dosage compared to non-micronized resveratrol [ 369 ].

Colorectal cancer is routinely treated with 5-fuorouracil, an efficient chemotherapy medication [ 370 ]. The use of resveratrol can improve 5-fluorouracil-induced cytotoxicity while also mitigating the undesirable side effects. The purpose of this study was to look at the possible therapeutic effects of resveratrol in conjunction with 5-FU against colorectal cancer [ 370 ]. Eleven participants participated in the three-year trial. Oral resveratrol administration has been found to help prevent colon cancer in people [ 306 ]. In addition, the FDA has approved a clinical trial for gastrointestinal tumors ( NCT01476592 ) [ 371 ]. The effect of resveratrol on notch-1 signaling, the effect on patient therapy, and patient toleration of resveratrol administration were all examined throughout this trial. It was discovered that resveratrol injection enhanced cleaved caspase-3 levels in malignant tissue, implying that apoptosis in cancer cells was boosted [ 371 ].

6.3. Quercetin

A phase I clinical investigation to assess quercetin’s safety profile found that it can be safely delivered as an intravenous bolus injection. Quercetin has also been proven to inhibit lymphocyte tyrosine kinase [ 372 ].

There is only one completed clinical trial using quercetin in cancer prevention and treatment (chemotherapy-induced oral mucositis), but no findings have been published ( https://clinicaltrials.gov/14J (accessed on 14 July 2022)).

6.4. EGCG (Epigallocatechin Gallate)

The only epidemiologic study (a nested case–control study within the Shanghai Cohort Study) that investigated the relation of specific tea catechins to esophageal cancer risk used validated urinary biomarkers for tea polyphenol uptake and metabolism. This study’s findings indicated a lower risk for both esophageal and gastric cancer with the existence of EGC in urine, with a greater inverse association in nonsmokers, non-alcohol drinkers, or those with lower serum levels of carotenes [ 373 ].

Similarly, a cohort study on 481,563 volunteers aged from 51–71 years also revealed a statistically significant inverse connection between hot tea drinking and risk of pharyngeal cancer after up to eight years of follow-up [ 374 ]. Moreover, a randomized placebo-controlled phase II clinical trial assessed the efficacy of green tea extract (both oral administration and topical treatment) on oral mucosa leukoplakia (precancerous lesion of oral cancer) in 59-patients, recording smaller oral lesions in 37.9% of patients who received green tea treatment [ 375 ].

Furthermore, a more recent pooled analysis of six cohort studies similarly revealed a statistically significant, inverse link between green tea drinking and stomach cancer risk in women (particularly among female nonsmokers) but not in males [ 376 ].

The relationship between green tea consumption and colorectal cancer risk was assessed in a prospective study (a cohort of 69,710 Chinese women aged 40 to 70 years, the majority of whom were lifelong nonsmokers or non-alcohol drinkers), with two to three years of a follow-up. The study’s results indicated that drinking tea on a regular basis considerably lowered the incidence of colorectal cancer [ 377 ].

In another prospective trial, tea catechins have been shown to protect against the development of colon cancer. This study investigated the relationship between urine levels of EGC, 4- O -methyl-epigallocatechin (4-MeEGC), and EC and its metabolites, in one hand, and the risk of developing colorectal cancer in the other. Results have shown that individuals with higher urine catechin levels had a decreased risk of developing colon cancer [ 373 ].

Moreover, in a pilot clinical research including ten female patients (age 38–55 years) with locally advanced noninflammatory breast cancer and undergoing radiation, patients were treated with oral EGCG capsules (400 mg) three times daily for two to eight weeks. Results of this study have shown that EGCG increased the efficacy of radiotherapy in breast cancer patients, which may be a promising possibility for using EGCG as a therapeutic adjuvant in the treatment of metastatic breast cancer [ 378 ].

On the other hand, a meta-analysis of seven epidemiological studies (two cohort, one nested case–control, and four case–control) to assess the influence of green tea consumption on breast cancer risk found an inverse correlation only in case–control data [ 379 ].

Regarding the effect of green tea on prostate cancer, in one study, which included 42 patients with androgen-independent prostate cancer, only one patient showed a 50% decrease in prostate-specific antigen (PSA) level, which lasted for two months [ 380 ]. In the other study, which looked at the efficacy and toxicity of standardized green tea extract on prostate cancer, delayed disease progression was displayed in 40% of patients who completed the treatment [ 381 ].

In regard to liver cancer, the findings of a randomized placebo-controlled phase II clinical research indicated that green tea polyphenols protect against two established liver cancer risk factors, aflatoxin and hepatitis B [ 382 ]. Moreover, a population-based case–control research observed a statistically significant inverse correlation between green tea drinking and the risk of pancreatic cancer [ 383 ].

In patients with papillomavirus-infected cervical lesions, EGCG delivered as a capsule (200 mg p.o. for 12 weeks) was found to be effective [ 384 ]. In some malignancies, EGCG promotes cell death via the intrinsic route and inhibits the EGFR, STAT3, and ERK pathways [ 384 ]. EGCG modifies and inhibits ERK1/2, NF-B, and Akt-mediated signaling in tumor cells, affecting the Bcl-2 family protein ratio and activating caspases [ 384 ].

Finally, a meta-analysis of 22 research studies established that drinking green tea considerably reduced the incidence of lung cancer. Nevertheless, this reduced risk was limited to nonsmokers, and the association was slightly higher in prospective cohort studies than in retrospective case–control studies [ 385 ].

6.5. Allicin

A double-blind randomized controlled trial involving individuals with colorectal adenomas found that taking a high dose of aged garlic extract was related with a significantly lower risk of developing new colorectal adenomas [ 386 ].

Garlic is aged for up to 20 months in aged garlic extract (AGE), a procedure that changes the odorous, harsh, and irritating components of garlic into stable and nontoxic sulfur compounds [ 387 ].

Colorectal cancer incidence and growth have been shown to be reduced by aged garlic extract [ 388 ]. In patients with advanced digestive system cancer, administering aged garlic boosted natural killer (NK) cell activity but did not improve quality of life (QoL) [ 389 ]. Furthermore, high dosages of allitridum and microdoses of selenium have been found to prevent stomach cancer, particularly in men [ 390 ].

A meta-analysis of 19 case–control and two cohort studies found a reduction in the incidence of stomach cancer with an increase of 20 g/day of total Allium vegetables such as garlic, onion, leeks, Chinese chives, scallions, and garlic stalks [ 391 ].

Other meta-analysis comprising 14 case–control studies on the effect of Allium vegetables on stomach cancer and five case–control studies on the effect of garlic on stomach cancer indicated that Allium vegetables may have a cancer-preventive effect on stomach cancer [ 392 ].

A study comprising 343 patients with esophageal squamous cell carcinoma and 755 cancer-free controls concluded that ingesting raw garlic/onion at least once per week significantly protects against esophageal squamous cell carcinoma [ 393 ].

Individuals in the highest of three intake groups of total Allium vegetables had a 53% lower incidence of prostate cancer compared to those in the lowest intake category in a population-based case–control study [ 394 ].

6.6. Thymoquinone

Despite a great number of in vitro and in vivo studies demonstrating thymoquinone’s potential as an anticancer drug, there is no therapeutic application. There are no thymoquinone clinical trials listed on ( https://clinicaltrials.gov/ (accessed on 14 July 2022)).

6.7. Emodin

Only one study on the effect of emodin on breast cancer was found on the https://clinicaltrials.gov/ (accessed on 15 July 2022) website when searching for clinical studies on the anticancer activity of emodin (ClinicalTrials.gov Identifier: NCT01287468 ).

6.8. Genistein

Breast cancer incidence was found to be lower in peri-menopausal women who ate more soy food [ 395 ]. Another meta-analysis of 9000 breast cancer patients found that increasing the genistein dose reduced breast cancer risk [ 396 ]. In vitro, however, low dosages of genistein prevent breast cancer cell proliferation, whereas high amounts enhance it [ 397 ].

The level of the prostate cancer biomarker prostate-specific antigen (PSA) in blood was reduced in a randomized placebo-controlled double-blind phase II clinical trial in which prostate cancer patients received genistein before radical prostatectomy compared to the control [ 398 ].

Genistein, in combination with gemcitabine and erlotinib, can help kill more tumor cells by making tumor cells more susceptible to the medications, according to a phase II trial (ClinicalTrials.gov Identifier: NCT00376948 ) on patients with locally advanced or metastatic pancreatic cancer.

A randomized phase II experiment on patients with early-stage prostate cancer (ClinicalTrials.gov Identifier: NCT01325311 ) found that cholecalciferol (200,000 IU) and genistein (as G-2535, which gives 600 mg of genistein) may reduce cancer cell development and be an effective treatment for prostate cancer.

It was discovered in a phase I/II pilot clinical trial (ClinicalTrials.gov Identifier: NCT01985763 ) to evaluate the efficacy of genistein in the treatment of metastatic colorectal cancer alone or in combination with 5-fluorouracil and platinum compounds that genistein can suppress Wnt signaling, a pathway induced in the majority of colorectal cancers, and can enhance growth inhibition when combined with 5-fluorouracil and platinum compounds. The most important clinical studies were mentioned in Table 2 .

6.9. Parthenolide

On the https://clinicaltrials.gov/ (accessed on 15 July 2022) website, there are no clinical studies that have been undertaken to assess parthenolide’s anticancer efficacy.

6.10. Luteolin

Only one clinical trial evaluating the efficacy of luteolin (nano-luteolin) on tongue cancer was found on clinicaltrials.gov, and it has passed its completion date with an unknown status.

7. Conclusions

Natural products extracted from plants are a rich source for anticancer agents. Multiple cancer hallmarks are targeted by plant-derived natural products through altering diverse signaling pathways. Some natural products such as curcumin and resveratrol exhibit the ability to target cancer through multiple mechanisms. Apoptosis induction is the most common pathway activated by plant-derived natural products. Targeting drug resistance and metastasis inhibition were also reported as anticancer mechanisms of these compounds. The use of plant-derived natural products as an adjuvant therapy with conventional treatments is a productive strategy that deserves further investigations to improve cancer treatment protocols.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Author Contributions

Conceptualization, W.H.T.; methodology, W.H.T., S.D. and A.I.M.; software, A.I.M.; validation, W.H.T.; formal analysis, R.A.H., D.A., S.F.A. and L.H.O.; investigation, S.K. and L.T.A.K.; resources, W.H.T. and L.T.A.K.; writing—original draft preparation, S.D., A.I.M., R.A.H., D.A., S.F.A., S.K. and L.H.O.; writing—review and editing, W.H.T. and A.I.M.; supervision, W.H.T.; project administration, L.T.A.K.; funding acquisition, W.H.T. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

1. Kocarnik J.M. Compton K. Dean F.E. Fu W. Gaw B.L. Harvey J.D. Henrikson H.J. Lu D. Pennini A. Xu R. Cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life years for 29 cancer groups from 2010 to 2019: A systematic analysis for the Global Burden of Disease Study 2019 JAMA Oncol. 2022 8 420 444 34967848 10.1001/jamaoncol.2021.6987 PMC8719276

2. Sung H. Ferlay J. Siegel R.L. Laversanne M. Soerjomataram I. Jemal A. Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries CA Cancer J. Clin. 2021 71 209 249 10.3322/caac.21660 33538338

3. Zou H. Li Y. Liu X. Wu Z. Li J. Ma Z. Roles of plant-derived bioactive compounds and related microRNAs in cancer therapy Phytother. Res. 2021 35 1176 1186 10.1002/ptr.6883 33000538

4. Iqbal J. Abbasi B.A. Mahmood T. Kanwal S. Ali B. Shah S.A. Khalil A.T. Plant-derived anticancer agents: A green anticancer approach Asian Pac. J. Trop. Biomed. 2017 7 1129 1150 10.1016/j.apjtb.2017.10.016

5. Leitzmann C. Characteristics and health benefits of phytochemicals Complementary Med. Res. 2016 23 69 74 10.1159/000444063 27160996

6. Avato P. Migoni D. Argentieri M. Fanizzi F.P. Tava A. Activity of saponins from Medicago species against HeLa and MCF-7 cell lines and their capacity to potentiate cisplatin effect Anti-Cancer Agents Med. Chem. (Former. Curr. Med. Chem.-Anti-Cancer Agents) 2017 17 1508 1518 10.2174/1871520617666170727152805 28748756

7. Joshi P. Vishwakarma R.A. Bharate S.B. Natural alkaloids as P-gp inhibitors for multidrug resistance reversal in cancer Eur. J. Med. Chem. 2017 138 273 292 10.1016/j.ejmech.2017.06.047 28675836

8. Talib W.H. Anticancer and antimicrobial potential of plant-derived natural products Phytochemicals—Bioactivities and Impact on Health Rasooli I. InTech Rijeka, Croatia 2011 141 158

9. Talib W.H. Alsalahat I. Daoud S. Abutayeh R.F. Mahmod A.I. Plant-Derived Natural Products in Cancer Research: Extraction, Mechanism of Action, and Drug Formulation Molecules 2020 25 5319 10.3390/molecules25225319 33202681 PMC7696819

10. Rayan A. Raiyn J. Falah M. Nature is the best source of anticancer drugs: Indexing natural products for their anticancer bioactivity PLoS ONE 2017 12 e0187925 10.1371/journal.pone.0187925 29121120 PMC5679595

11. Thakore P. Mani R.K. Kavitha S.J. A brief review of plants having anti-cancer property Int. J. Pharm. Res. Dev. 2012 3 129 136

12. Tariq A. Sadia S. Pan K. Ullah I. Mussarat S. Sun F. Abiodun O.O. Batbaatar A. Li Z. Song D. A systematic review on ethnomedicines of anti-cancer plants Phytother. Res. 2017 31 202 264 10.1002/ptr.5751 28093828

13. Rana P. Shrama A. Mandal C.C. Molecular insights into phytochemicals-driven break function in tumor microenvironment J. Food Biochem. 2021 45 e13824 10.1111/jfbc.13824 34219240

14. Ferguson L.R. Chen H. Collins A.R. Connell M. Damia G. Dasgupta S. Malhotra M. Meeker A.K. Amedei A. Amin A. Genomic instability in human cancer: Molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition Semin. Cancer Biol. 2015 35 S5 S24 10.1016/j.semcancer.2015.03.005 25869442 PMC4600419

15. Rusin M. Zajkowicz A. Butkiewicz D. Resveratrol induces senescence-like growth inhibition of U-2 OS cells associated with the instability of telomeric DNA and upregulation of BRCA1 Mech. Ageing Dev. 2009 130 528 537 10.1016/j.mad.2009.06.005 19559722

16. Talib W.H. Melatonin and cancer hallmarks Molecules 2018 23 518 10.3390/molecules23030518 PMC6017729 29495398

17. Hanahan D. Weinberg R.A. Hallmarks of cancer: The next generation Cell 2011 144 646 674 10.1016/j.cell.2011.02.013 21376230

18. Yaswen P. MacKenzie K.L. Keith W.N. Hentosh P. Rodier F. Zhu J. Firestone G.L. Matheu A. Carnero A. Bilsland A. Therapeutic targeting of replicative immortality Semin. Cancer Biol. 2015 35 S104 S128 10.1016/j.semcancer.2015.03.007 25869441 PMC4600408

19. Bodnar A.G. Ouellette M. Frolkis M. Holt S.E. Chiu C.-P. Morin G.B. Harley C.B. Shay J.W. Lichtsteiner S. Wright W.E. Extension of life-span by introduction of telomerase into normal human cells Science 1998 279 349 352 10.1126/science.279.5349.349 9454332

20. Bensinger S.J. Christofk H.R. New aspects of the Warburg effect in cancer cell biology Semin. Cell Dev. Biol. 2012 23 352 361 10.1016/j.semcdb.2012.02.003 22406683

21. Dang C.V. Kim J.-w. Gao P. Yustein J. The interplay between MYC and HIF in cancer Nat. Rev. Cancer 2008 8 51 56 10.1038/nrc2274 18046334

22. Chakraborty C. Sharma A.R. Sharma G. Lee S.-S. The Interplay among miRNAs, Major Cytokines, and Cancer-Related Inflammation Mol. Ther. Nucleic Acids 2020 20 606 620 10.1016/j.omtn.2020.04.002 32348938 PMC7191126

23. Hou J. Karin M. Sun B. Targeting cancer-promoting inflammation—Have anti-inflammatory therapies come of age? Nat. Rev. Clin. Oncol. 2021 18 261 279 10.1038/s41571-020-00459-9 33469195 PMC8978805

24. Chakraborty S. Njah K. Hong W. Agrin Mediates Angiogenesis in the Tumor Microenvironment Trends Cancer 2020 6 81 85 10.1016/j.trecan.2019.12.002 32061308

25. Bergers G. Benjamin L.E. Tumorigenesis and the angiogenic switch Nat. Rev. Cancer 2003 3 401 410 10.1038/nrc1093 12778130

26. Martin T.A. Ye L. Sanders A.J. Lane J. Jiang W.G. Cancer invasion and metastasis: Molecular and cellular perspective Madame Curie Bioscience Database [Internet] Landes Bioscience Georgetown, TX, USA 2013

27. Habli Z. Toumieh G. Fatfat M. Rahal O.N. Gali-Muhtasib H. Emerging cytotoxic alkaloids in the battle against cancer: Overview of molecular mechanisms Molecules 2017 22 250 10.3390/molecules22020250 28208712 PMC6155614

28. N Nwodo J. Ibezim A. Simoben C.V. Ntie-Kang F. Exploring cancer therapeutics with natural products from African medicinal plants, part II: Alkaloids, terpenoids and flavonoids Anti-Cancer Agents Med. Chem. (Former. Curr. Med. Chem.-Anti-Cancer Agents) 2016 16 108 127 10.2174/1871520615666150520143827 25991425

29. Khan H. Saeedi M. Nabavi S.M. Mubarak M.S. Bishayee A. Glycosides from medicinal plants as potential anticancer agents: Emerging trends towards future drugs Curr. Med. Chem. 2019 26 2389 2406 29611474 10.2174/0929867325666180403145137

30. Moraes D.F.C. Mesquita L.S.S.d. Amaral F.M.M.d. Sousa Ribeiro M.N.d. Malik S. Anticancer drugs from plants Biotechnology and Production of Anti-Cancer Compounds Springer Berlin/Heidelberg, Germany 2017 121 142

31. Habtemariam S. Lentini G. Plant-derived anticancer agents: Lessons from the pharmacology of geniposide and its aglycone, genipin Biomedicines 2018 6 39 10.3390/biomedicines6020039 29587429 PMC6027249

32. Dey P. Kundu A. Kumar A. Gupta M. Lee B.M. Bhakta T. Dash S. Kim H.S. Analysis of alkaloids (indole alkaloids, isoquinoline alkaloids, tropane alkaloids) Recent Advances in Natural Products Analysis Elsevier Amsterdam, The Netherlands 2020 505 567

33. da Costa R. Passos G.F. Quintao N.L. Fernandes E.S. Maia J.R.L. Campos M.M. Calixto J.B. Taxane-induced neurotoxicity: Pathophysiology and therapeutic perspectives Br. J. Pharmacol. 2020 177 3127 3146 10.1111/bph.15086 32352155 PMC7312267

34. Zhang X. Rakesh K. Shantharam C. Manukumar H. Asiri A. Marwani H. Qin H.-L. Podophyllotoxin derivatives as an excellent anticancer aspirant for future chemotherapy: A key current imminent needs Bioorganic Med. Chem. 2018 26 340 355 10.1016/j.bmc.2017.11.026 29269253

35. Ramos A.C. Peláez R. López J.L. Caballero E. Medarde M. San Feliciano A. Heterolignanolides. Furo-and thieno-analogues of podophyllotoxin and thuriferic acid Tetrahedron 2001 57 3963 3977 10.1016/S0040-4020(01)00271-X

36. Montecucco A. Zanetta F. Biamonti G. Molecular mechanisms of etoposide EXCLI J. 2015 14 95 26600742 10.17179/excli2015-561 PMC4652635

37. George B.P. Chandran R. Abrahamse H. Role of Phytochemicals in Cancer Chemoprevention: Insights Antioxidants 2021 10 1455 10.3390/antiox10091455 34573087 PMC8466984

38. Bishayee A. Sethi G. Bioactive natural products in cancer prevention and therapy: Progress and promise Seminars in Cancer Biology Elsevier Amsterdam, The Netherlands 2016 1 3 10.1016/j.semcancer.2016.08.006 27565447

39. Aggarwal B.B. Kumar A. Bharti A.C. Anticancer potential of curcumin: Preclinical and clinical studies Anticancer Res. 2003 23 363 398 12680238

40. Kaltschmidt B. Greiner J.F.W. Kadhim H.M. Kaltschmidt C. Subunit-Specific Role of NF-κB in Cancer Biomedicines 2018 6 44 10.3390/biomedicines6020044 29673141 PMC6027219

41. Sanlier N. Kocabas Ş. Erdogan K. Sanlier N.T. Effects of curcumin, its analogues, and metabolites on various cancers: Focusing on potential mechanisms Food Rev. Int. 2022 1 21 10.1080/87559129.2022.2067173

42. Shen J. Zhang Y. Yu H. Shen B. Liang Y. Jin R. Liu X. Shi L. Cai X. Role of DUSP1/MKP1 in tumorigenesis, tumor progression and therapy Cancer Med. 2016 5 2061 2068 10.1002/cam4.772 27227569 PMC4884638

43. Truong V.L. Jun M. Jeong W.S. Role of resveratrol in regulation of cellular defense systems against oxidative stress Biofactors 2018 44 36 49 10.1002/biof.1399 29193412

44. Shao B.-Z. Xu Z.-Q. Han B.-Z. Su D.-F. Liu C. NLRP3 inflammasome and its inhibitors: A review Front. Pharmacol. 2015 6 262 10.3389/fphar.2015.00262 26594174 PMC4633676

45. Manju S. Ethiraj K. Elias G. Safer anti-inflammatory therapy through dual COX-2/5-LOX inhibitors: A structure-based approach Eur. J. Pharm. Sci. 2018 121 356 381 29883727 10.1016/j.ejps.2018.06.003

46. Elshaer M. Chen Y. Wang X.J. Tang X. Resveratrol: An overview of its anti-cancer mechanisms Life Sci. 2018 207 340 349 10.1016/j.lfs.2018.06.028 29959028

47. Rather R.A. Bhagat M. Quercetin as an innovative therapeutic tool for cancer chemoprevention: Molecular mechanisms and implications in human health Cancer Med. 2020 9 9181 9192 10.1002/cam4.1411 31568659 PMC7774748

48. Rafiq R.A. Quadri A. Nazir L.A. Peerzada K. Ganai B.A. Tasduq S.A. A potent inhibitor of phosphoinositide 3-kinase (PI3K) and mitogen activated protein (MAP) kinase signalling, quercetin (3, 3′, 4′, 5, 7-pentahydroxyflavone) promotes cell death in ultraviolet (UV)-B-irradiated B16F10 melanoma cells PLoS ONE 2015 10 e0131253 10.1371/journal.pone.0131253 26148186 PMC4493061

49. Granado-Serrano A.B. Martín M.A. Bravo L. Goya L. Ramos S. Quercetin induces apoptosis via caspase activation, regulation of Bcl-2, and inhibition of PI-3-kinase/Akt and ERK pathways in a human hepatoma cell line (HepG2) J. Nutr. 2006 136 2715 2721 10.1093/jn/136.11.2715 17056790

50. Rabiya A. Paithankar V. Kochar A.C. Bobade N. Review on Chemoprevention of Cancer by Dietry Phytochemicals World J. Pharm. Res. 2020 9 743 755

51. Almatroodi S.A. Almatroudi A. Khan A.A. Alhumaydhi F.A. Alsahli M.A. Rahmani A.H. Potential therapeutic targets of epigallocatechin gallate (EGCG), the most abundant catechin in green tea, and its role in the therapy of various types of cancer Molecules 2020 25 3146 10.3390/molecules25143146 PMC7397003 32660101

52. Tedeschi E. Suzuki H. Menegazzi M. Antiinflammatory action of EGCG, the main component of green tea, through STAT-1 inhibition Ann. N. Y. Acad. Sci. 2002 973 435 437 10.1111/j.1749-6632.2002.tb04678.x 12485906

53. Sen T. Dutta A. Chatterjee A. Epigallocatechin-3-gallate (EGCG) downregulates gelatinase-B (MMP-9) by involvement of FAK/ERK/NFκB and AP-1 in the human breast cancer cell line MDA-MB-231 Anti-Cancer Drugs 2010 21 632 644 10.1097/CAD.0b013e32833a4385 20527725

54. Masuda M. Wakasaki T. Toh S. Shimizu M. Adachi S. Chemoprevention of head and neck cancer by green tea extract: EGCG—the role of EGFR signaling and “lipid raft” J. Oncol. 2011 2011 540148 10.1155/2011/540148 21274257 PMC3022184

55. Zhang X. Zhang H. Tighiouart M. Lee J.E. Shin H.J. Khuri F.R. Yang C.S. Chen Z. Shin D.M. Synergistic inhibition of head and neck tumor growth by green tea (−)-epigallocatechin-3-gallate and EGFR tyrosine kinase inhibitor Int. J. Cancer 2008 123 1005 1014 10.1002/ijc.23585 18546267 PMC2555987

56. Pahlke G. Ngiewih Y. Kern M. Jakobs S. Marko D. Eisenbrand G. Impact of quercetin and EGCG on key elements of the Wnt pathway in human colon carcinoma cells J. Agric. Food Chem. 2006 54 7075 7082 10.1021/jf0612530 16968065

57. Hossain M.M. Banik N.L. Ray S.K. Survivin knockdown increased anti-cancer effects of (−)-epigallocatechin-3-gallate in human malignant neuroblastoma SK-N-BE2 and SH-SY5Y cells Exp. Cell Res. 2012 318 1597 1610 10.1016/j.yexcr.2012.03.033 22507272 PMC3374045

58. Vézina A. Chokor R. Annabi B. EGCG targeting efficacy of NF-κB downstream gene products is dictated by the monocytic/macrophagic differentiation status of promyelocytic leukemia cells Cancer Immunol. Immunother. 2012 61 2321 2331 10.1007/s00262-012-1301-x 22707304 PMC11028810

59. Kim H.S. Kim M.H. Jeong M. Hwang Y.S. Lim S.H. Shin B.A. Ahn B.W. Jung Y.D. EGCG blocks tumor promoter-induced MMP-9 expression via suppression of MAPK and AP-1 activation in human gastric AGS cells Anticancer Res. 2004 24 747 754 15161022

60. Lee Y.-H. Kwak J. Choi H.-K. Choi K.-C. Kim S. Lee J. Jun W. Park H.-J. Yoon H.-G. EGCG suppresses prostate cancer cell growth modulating acetylation of androgen receptor by anti-histone acetyltransferase activity Int. J. Mol. Med. 2012 30 69 74 22505206 10.3892/ijmm.2012.966

61. Li Y. Yuan Y.-Y. Meeran S.M. Tollefsbol T.O. Synergistic epigenetic reactivation of estrogen receptor-α (ERα) by combined green tea polyphenol and histone deacetylase inhibitor in ERα-negative breast cancer cells Mol. Cancer 2010 9 1 12 10.1186/1476-4598-9-274 20946668 PMC2967543

62. Huang L. Song Y. Lian J. Wang Z. Allicin inhibits the invasion of lung adenocarcinoma cells by altering tissue inhibitor of metalloproteinase/matrix metalloproteinase balance via reducing the activity of phosphoinositide 3-kinase/AKT signaling Oncol. Lett. 2017 14 468 474 10.3892/ol.2017.6129 28693193 PMC5494782

63. Patra S. Nayak R. Patro S. Pradhan B. Sahu B. Behera C. Bhutia S.K. Jena M. Chemical diversity of dietary phytochemicals and their mode of chemoprevention Biotechnol. Rep. 2021 30 e00633 10.1016/j.btre.2021.e00633 PMC8167155 34094892

64. Bat-Chen W. Golan T. Peri I. Ludmer Z. Schwartz B. Allicin purified from fresh garlic cloves induces apoptosis in colon cancer cells via Nrf2 Nutr. Cancer 2010 62 947 957 10.1080/01635581.2010.509837 20924970

65. Gomathinayagam R. Ha J.H. Jayaraman M. Song Y.S. Isidoro C. Dhanasekaran D.N. Chemopreventive and anticancer effects of thymoquinone: Cellular and molecular targets J. Cancer Prev. 2020 25 136 10.15430/JCP.2020.25.3.136 33033708 PMC7523033

66. Mercan T. Yamasan B. Erkan O. Özdemir S. Thymoquinone alters ionic currents and decreases β adrenergic response in rat ventricle myocytes J. Mol. Cell. Cardiol. 2018 120 22 10.1016/j.yjmcc.2018.05.074

67. Shao Y.-y. Li B. Huang Y.-m. Luo Q. Xie Y.-m. Chen Y.-h. Thymoquinone attenuates brain injury via an antioxidative pathway in a status epilepticus rat model Transl. Neurosci. 2017 8 9 14 10.1515/tnsci-2017-0003 28400978 PMC5384046

68. Lee K.H. Lee M.S. Cha E.Y. Sul J.Y. Lee J.S. Kim J.S. Park J.B. Kim J.Y. Inhibitory effect of emodin on fatty acid synthase, colon cancer proliferation and apoptosis Mol. Med. Rep. 2017 15 2163 2173 10.3892/mmr.2017.6254 28260110 PMC5364834

69. Gu J. Cui C.-f. Yang L. Wang L. Jiang X.-h. Emodin inhibits colon cancer cell invasion and migration by suppressing epithelial–mesenchymal transition via the Wnt/β-Catenin pathway Oncol. Res. 2019 27 193 10.3727/096504018X15150662230295 29301594 PMC7848449

70. Saunders I.T. Mir H. Kapur N. Singh S. Emodin inhibits colon cancer by altering BCL-2 family proteins and cell survival pathways Cancer Cell Int. 2019 19 1 15 10.1186/s12935-019-0820-3 31011292 PMC6466701

71. Sun Y. Wang X. Zhou Q. Lu Y. Zhang H. Chen Q. Zhao M. Su S. Inhibitory effect of emodin on migration, invasion and metastasis of human breast cancer MDA-MB-231 cells in vitro and in vivo Oncol. Rep. 2015 33 338 346 10.3892/or.2014.3585 25370743

72. Kaneshiro T. Morioka T. Inamine M. Kinjo T. Arakaki J. Chiba I. Sunagawa N. Suzui M. Yoshimi N. Anthraquinone derivative emodin inhibits tumor-associated angiogenesis through inhibition of extracellular signal-regulated kinase 1/2 phosphorylation Eur. J. Pharmacol. 2006 553 46 53 10.1016/j.ejphar.2006.09.026 17056031

73. Srinivas G. Babykutty S. Sathiadevan P.P. Srinivas P. Molecular mechanism of emodin action: Transition from laxative ingredient to an antitumor agent Med. Res. Rev. 2007 27 591 608 10.1002/med.20095 17019678

74. El-Far Y.M. Khodir A.E. Emarah Z.A. Ebrahim M.A. Al-Gayyar M.M. Chemopreventive and hepatoprotective effects of genistein via inhibition of oxidative stress and the versican/PDGF/PKC signaling pathway in experimentally induced hepatocellular carcinoma in rats by thioacetamide Redox Rep. 2022 27 9 20 10.1080/13510002.2022.2031515 35080474 PMC8794077

75. Sahin K. Yenice E. Bilir B. Orhan C. Tuzcu M. Sahin N. Ozercan I.H. Kabil N. Ozpolat B. Kucuk O. Genistein Prevents Development of Spontaneous Ovarian Cancer and Inhibits Tumor Growth in Hen ModelGenistein Prevents Development of Ovarian Cancer Cancer Prev. Res. 2019 12 135 146 10.1158/1940-6207.CAPR-17-0289 30651293

76. Ullrich A. Schlessinger J. Signal transduction by receptors with tyrosine kinase activity Cell 1990 61 203 212 10.1016/0092-8674(90)90801-K 2158859

77. Tian B. Xiao Y. Ma J. Ou W. Wang H. Wu J. Tang J. Zhang B. Liao X. Yang D. Parthenolide inhibits angiogenesis in esophageal squamous cell carcinoma through suppression of VEGF OncoTargets Ther. 2020 13 7447 10.2147/OTT.S256291 PMC7398702 32801767

78. Carlisi D. Lauricella M. D’Anneo A. De Blasio A. Celesia A. Pratelli G. Notaro A. Calvaruso G. Giuliano M. Emanuele S. Parthenolide and its soluble analogues: Multitasking compounds with antitumor properties Biomedicines 2022 10 514 10.3390/biomedicines10020514 35203723 PMC8962426

79. D’anneo A. Carlisi D. Lauricella M. Puleio R. Martinez R. Di Bella S. Di Marco P. Emanuele S. Di Fiore R. Guercio A. Parthenolide generates reactive oxygen species and autophagy in MDA-MB231 cells. A soluble parthenolide analogue inhibits tumour growth and metastasis in a xenograft model of breast cancer Cell Death Dis. 2013 4 e891 10.1038/cddis.2013.415 24176849 PMC3920954

80. Kato H. Naiki-Ito A. Suzuki S. Inaguma S. Komura M. Nakao K. Naiki T. Kachi K. Kato A. Matsuo Y. DPYD, down-regulated by the potentially chemopreventive agent luteolin, interacts with STAT3 in pancreatic cancer Carcinogenesis 2021 42 940 950 10.1093/carcin/bgab017 33640964 PMC8283735

81. Raina R. Pramodh S. Rais N. Haque S. Shafarin J. Bajbouj K. Hamad M. Hussain A. Luteolin inhibits proliferation, triggers apoptosis and modulates Akt/mTOR and MAP kinase pathways in HeLa cells Oncol. Lett. 2021 21 192 10.3892/ol.2021.12452 33574931 PMC7816384

82. Lal J. Turmeric, curcumin and our life: A review Bull. Environ. Pharm. Life Sci. 2012 1 11 17

83. Talib W.H. Al-Hadid S.A. Ali M.B.W. Al-Yasari I.H. Abd Ali M.R. Role of curcumin in regulating p53 in breast cancer: An overview of the mechanism of action Breast Cancer Targets Ther. 2018 10 207 10.2147/BCTT.S167812 30568488 PMC6276637

84. Xu X.-Y. Meng X. Li S. Gan R.-Y. Li Y. Li H.-B. Bioactivity, health benefits, and related molecular mechanisms of curcumin: Current progress, challenges, and perspectives Nutrients 2018 10 1553 10.3390/nu10101553 PMC6213156 30347782

85. Hewlings S.J. Kalman D.S. Curcumin: A review of its effects on human health Foods 2017 6 92 10.3390/foods6100092 29065496 PMC5664031

86. Rathore S. Mukim M. Sharma P. Devi S. Nagar J.C. Khalid M. Curcumin: A review for health benefits Int. J. Res. Rev. 2020 7 273 290

87. Ismail N.I. Othman I. Abas F. H Lajis N. Naidu R. Mechanism of apoptosis induced by curcumin in colorectal cancer Int. J. Mol. Sci. 2019 20 2454 10.3390/ijms20102454 31108984 PMC6566943

88. Sahebkar A. Serban M.-C. Ursoniu S. Banach M. Effect of curcuminoids on oxidative stress: A systematic review and meta-analysis of randomized controlled trials J. Funct. Foods 2015 18 898 909 10.1016/j.jff.2015.01.005

89. Menon V.P. Sudheer A.R.J. Antioxidant and anti-inflammatory properties of curcumin The Molecular Targets Therapeutic Uses of Curcumin in Health Disease Springer Berlin/Heidelberg, Germany 2007 105 125 10.1007/978-0-387-46401-5_3 17569207

90. Panahi Y. Alishiri G.H. Parvin S. Sahebkar A. Mitigation of systemic oxidative stress by curcuminoids in osteoarthritis: Results of a randomized controlled trial J. Diet. Suppl. 2016 13 209 220 10.3109/19390211.2015.1008611 25688638

91. Notarbartolo M. Poma P. Perri D. Dusonchet L. Cervello M. D’Alessandro N. Antitumor effects of curcumin, alone or in combination with cisplatin or doxorubicin, on human hepatic cancer cells. Analysis of their possible relationship to changes in NF-kB activation levels and in IAP gene expression Cancer Lett. 2005 224 53 65 10.1016/j.canlet.2004.10.051 15911101

92. Yang C.-W. Chang C.-L. Lee H.-C. Chi C.-W. Pan J.-P. Yang W.-C.J. Curcumin induces the apoptosis of human monocytic leukemia THP-1 cells via the activation of JNK/ERK pathways BMC Complementary Altern. Med. 2012 12 1 8 10.1186/1472-6882-12-22 PMC3342909 22443687

93. Kabir M. Rahman M. Akter R. Behl T. Kaushik D. Mittal V. Pandey P. Akhtar M.F. Saleem A. Albadrani G.M. Potential role of curcumin and its nanoformulations to treat various types of cancers Biomolecules 2021 11 392 10.3390/biom11030392 33800000 PMC8001478

94. Hu S. Xu Y. Meng L. Huang L. Sun H. Curcumin inhibits proliferation and promotes apoptosis of breast cancer cells Exp. Ther. Med. 2018 16 1266 1272 10.3892/etm.2018.6345 30116377 PMC6090267

95. Li Y. Wang J. Li X. Jia Y. Huai L. He K. Yu P. Wang M. Xing H. Rao Q. Role of the Wilms’ tumor 1 gene in the aberrant biological behavior of leukemic cells and the related mechanisms Oncol. Rep. 2014 32 2680 2686 10.3892/or.2014.3529 25310451

96. Lu Y. Wei C. Xi Z. Curcumin suppresses proliferation and invasion in non-small cell lung cancer by modulation of MTA1-mediated Wnt/β-catenin pathway In Vitro Cell. Dev. Biol. Anim. 2014 50 840 850 10.1007/s11626-014-9779-5 24938356

97. Mirzaei H. Masoudifar A. Sahebkar A. Zare N. Sadri Nahand J. Rashidi B. Mehrabian E. Mohammadi M. Mirzaei H.R. Jaafari M.R. MicroRNA: A novel target of curcumin in cancer therapy J. Cell. Physiol. 2018 233 3004 3015 10.1002/jcp.26055 28617957

98. Goradel N.H. Hour F.G. Negahdari B. Malekshahi Z.V. Hashemzehi M. Masoudifar A. Mirzaei H. Stem cell therapy: A new therapeutic option for cardiovascular diseases J. Cell. Biochem. 2018 119 95 104 10.1002/jcb.26169 28543595

99. Tan B.L. Norhaizan M.E. Curcumin combination chemotherapy: The implication and efficacy in cancer Molecules 2019 24 2527 10.3390/molecules24142527 31295906 PMC6680685

100. Zhang P. Lai Z.-L. Chen H.-F. Zhang M. Wang A. Jia T. Sun W.-Q. Zhu X.-M. Chen X.-F. Zhao Z.J. Curcumin synergizes with 5-fluorouracil by impairing AMPK/ULK1-dependent autophagy, AKT activity and enhancing apoptosis in colon cancer cells with tumor growth inhibition in xenograft mice J. Exp. Clin. Cancer Res. 2017 36 1 12 29273065 10.1186/s13046-017-0661-7 PMC5741949

101. Guorgui J. Wang R. Mattheolabakis G. Mackenzie G.G. Curcumin formulated in solid lipid nanoparticles has enhanced efficacy in Hodgkin’s lymphoma in mice Arch. Biochem. Biophys. 2018 648 12 19 10.1016/j.abb.2018.04.012 29679536

102. Banerjee S. Singh S.K. Chowdhury I. Lillard Jr J.W. Singh R. Combinatorial effect of curcumin with docetaxel modulates apoptotic and cell survival molecules in prostate cancer Front. Biosci. 2017 9 235 10.2741/e798 PMC5545125 28199187

103. Park B.H. Lim J.E. Jeon H.G. Seo S.I. Lee H.M. Choi H.Y. Jeon S.S. Jeong B.C. Curcumin potentiates antitumor activity of cisplatin in bladder cancer cell lines via ROS-mediated activation of ERK1/2 Oncotarget 2016 7 63870 10.18632/oncotarget.11563 27564099 PMC5325410

104. Abadi A.J. Mirzaei S. Mahabady M.K. Hashemi F. Zabolian A. Hashemi F. Raee P. Aghamiri S. Ashrafizadeh M. Aref A.R. Curcumin and its derivatives in cancer therapy: Potentiating antitumor activity of cisplatin and reducing side effects Phytother. Res. 2022 36 189 213 10.1002/ptr.7305 34697839

105. Ashrafizadeh M. Zarrabi A. Hashemi F. Zabolian A. Saleki H. Bagherian M. Azami N. Bejandi A.K. Hushmandi K. Ang H.L. Polychemotherapy with curcumin and doxorubicin via biological nanoplatforms: Enhancing antitumor activity Pharmaceutics 2020 12 1084 10.3390/pharmaceutics12111084 PMC7697177 33187385

106. Hassanalilou T. Ghavamzadeh S. Khalili L. Curcumin and gastric cancer: A review on mechanisms of action J. Gastrointest. Cancer 2019 50 185 192 10.1007/s12029-018-00186-6 30725357

107. Tang X.-Q. Bi H. Feng J.-Q. Cao J.-G. Effect of curcumin on multidrug resistance in resistant human gastric carcinoma cell line SGC7901/VCR Acta Pharmacol. Sin. 2005 26 1009 1016 10.1111/j.1745-7254.2005.00149.x 16038636

108. Zhang N. Gao M. Wang Z. Zhang J. Cui W. Li J. Zhu X. Zhang H. Yang D.-H. Xu X.J. Curcumin reverses doxorubicin resistance in colon cancer cells at the metabolic level J. Pharm. Biomed. Anal. 2021 201 114129 10.1016/j.jpba.2021.114129 34000577

109. Alsamydai A. Jaber N. Pharmacological aspects of curcumin Int. J. Pharm. 2018 5 313 326

110. Meng T. Xiao D. Muhammed A. Deng J. Chen L. He J. Anti-inflammatory action and mechanisms of resveratrol Molecules 2021 26 229 10.3390/molecules26010229 33466247 PMC7796143

111. Kukreja A. Wadhwa N. Tiwari A. Therapeutic role of resveratrol and piceatannol in disease prevention Blood Disord. Transfus. 2014 5 9 10.4172/2155-9864.1000240

112. Gülçin İ. Antioxidant properties of resveratrol: A structure–activity insight Innov. Food Sci. Emerg. Technol. 2010 11 210 218 10.1016/j.ifset.2009.07.002

113. de Sá Coutinho D. Pacheco M.T. Frozza R.L. Bernardi A. Anti-inflammatory effects of resveratrol: Mechanistic insights Int. J. Mol. Sci. 2018 19 1812 10.3390/ijms19061812 PMC6032205 29925765

114. Cho S. Namkoong K. Shin M. Park J. Yang E. Ihm J. Thu V.T. Kim H.K. Han J. Cardiovascular protective effects and clinical applications of resveratrol J. Med. Food 2017 20 323 334 10.1089/jmf.2016.3856 28346848

115. Kasiotis K.M. Pratsinis H. Kletsas D. Haroutounian S.A. Resveratrol and related stilbenes: Their anti-aging and anti-angiogenic properties Food Chem. Toxicol. 2013 61 112 120 10.1016/j.fct.2013.03.038 23567244

116. Ko J.-H. Sethi G. Um J.-Y. Shanmugam M.K. Arfuso F. Kumar A.P. Bishayee A. Ahn K.S. The role of resveratrol in cancer therapy Int. J. Mol. Sci. 2017 18 2589 10.3390/ijms18122589 29194365 PMC5751192

117. Talib W.H. Alsayed A.R. Farhan F. Al Kury L.T. Resveratrol and tumor microenvironment: Mechanistic basis and therapeutic targets Molecules 2020 25 4282 10.3390/molecules25184282 PMC7571133 32961987

118. Xia N. Daiber A. Förstermann U. Li H. Antioxidant effects of resveratrol in the cardiovascular system Br. J. Pharmacol. 2017 174 1633 1646 10.1111/bph.13492 27058985 PMC5446570

119. Gu S. Chen C. Jiang X. Zhang Z. Resveratrol synergistically triggers apoptotic cell death with arsenic trioxide via oxidative stress in human lung adenocarcinoma A549 cells Biol. Trace Elem. Res. 2015 163 112 123 10.1007/s12011-014-0186-2 25431299

120. Hogg S.J. Chitcholtan K. Hassan W. Sykes P.H. Garrill A.J. Resveratrol, acetyl-resveratrol, and polydatin exhibit antigrowth activity against 3D cell aggregates of the SKOV-3 and OVCAR-8 ovarian cancer cell lines Obstet. Gynecol. Int. 2015 2015 279591 10.1155/2015/279591 26617640 PMC4651797

121. Varoni E.M. Lo Faro A.F. Sharifi-Rad J. Iriti M. Anticancer molecular mechanisms of resveratrol Front. Nutr. 2016 3 8 10.3389/fnut.2016.00008 27148534 PMC4828556

122. Ren Z. Wang L. Cui J. Huoc Z. Xue J. Cui H. Mao Q. Yang R. Resveratrol inhibits NF-κB signaling through suppression of p65 and IB kinase activities Die Pharm.-Int. J. Pharm. Sci. 2013 68 689 694 24020126

123. Li D. Wang G. Jin G. Yao K. Zhao Z. Bie L. Guo Y. Li N. Deng W. Chen X. Resveratrol suppresses colon cancer growth by targeting the AKT/STAT3 signaling pathway Int. J. Mol. Med. 2019 43 630 640 10.3892/ijmm.2018.3969 30387805

124. Heo J.R. Kim S.M. Hwang K.A. Kang J.H. Choi K.C. Resveratrol induced reactive oxygen species and endoplasmic reticulum stress-mediated apoptosis, and cell cycle arrest in the A375SM malignant melanoma cell line Int. J. Mol. Med. 2018 42 1427 1435 10.3892/ijmm.2018.3732 29916532 PMC6089775

125. Li L. Qiu R.L. Lin Y. Cai Y. Bian Y. Fan Y. Gao X.J. Resveratrol suppresses human cervical carcinoma cell proliferation and elevates apoptosis via the mitochondrial and p53 signaling pathways Oncol. Lett. 2018 15 9845 9851 10.3892/ol.2018.8571 29928358 PMC6004645

126. Liu Y. Tong L. Luo Y. Li X. Chen G. Wang Y. Resveratrol inhibits the proliferation and induces the apoptosis in ovarian cancer cells via inhibiting glycolysis and targeting AMPK/mTOR signaling pathway J. Cell. Biochem. 2018 119 6162 6172 10.1002/jcb.26822 29663499

127. Li W. Ma J. Ma Q. Li B. Han L. Liu J. Xu Q. Duan W. Yu S. Wang F. Resveratrol inhibits the epithelial-mesenchymal transition of pancreatic cancer cells via suppression of the PI-3K/Akt/NF-κB pathway Curr. Med. Chem. 2013 20 4185 4194 10.2174/09298673113209990251 23992306 PMC4085327

128. Li J. Chong T. Wang Z. Chen H. Li H. Cao J. Zhang P. Li H. A novel anti-cancer effect of resveratrol: Reversal of epithelial-mesenchymal transition in prostate cancer cells Mol. Med. Rep. 2014 10 1717 1724 10.3892/mmr.2014.2417 25069516 PMC4148361

129. Chhabra G. Singh C.K. Amiri D. Akula N. Ahmad N. Recent advancements on immunomodulatory mechanisms of resveratrol in tumor microenvironment Molecules 2021 26 1343 10.3390/molecules26051343 33802331 PMC7959117

130. Lee Y. Shin H. Kim J. In vivo anti-cancer effects of resveratrol mediated by NK cell activation J. Innate Immun. 2021 13 94 106 10.1159/000510315 32937636 PMC8077674

131. Cocetta V. Quagliariello V. Fiorica F. Berretta M. Montopoli M. Resveratrol as chemosensitizer agent: State of art and future perspectives Int. J. Mol. Sci. 2021 22 2049 10.3390/ijms22042049 33669559 PMC7922064

132. Robertson I. Hau T.W. Sami F. Ali M.S. Badgujar V. Murtuja S. Hasnain M.S. Khan A. Majeed S. Ansari M.T. The science of resveratrol, formulation, pharmacokinetic barriers and its chemotherapeutic potential Int. J. Pharm. 2022 121605 10.1016/j.ijpharm.2022.121605 35227804

133. Harborne J.B. Williams C.A. Advances in flavonoid research since 1992 Phytochemistry 2000 55 481 504 10.1016/S0031-9422(00)00235-1 11130659

134. Williams C.A. Grayer R.J. Anthocyanins and other flavonoids Nat. Prod. Rep. 2004 21 539 573 10.1039/b311404j 15282635

135. Ross J.A. Kasum C.M. Dietary flavonoids: Bioavailability, metabolic effects, and safety Annu. Rev. Nutr. 2002 22 19 34 10.1146/annurev.nutr.22.111401.144957 12055336

136. Hollman P.C. Bijsman M.N. Van Gameren Y. Cnossen E.P. De Vries J.H. Katan M.B. The sugar moiety is a major determinant of the absorption of dietary flavonoid glycosides in man Free. Radic. Res. 1999 31 569 573 10.1080/10715769900301141 10630681

137. Chang Q. Wong Y.-S. Identification of flavonoids in Hakmeitau beans (Vigna sinensis) by high-performance liquid chromatography− electrospray mass spectrometry (LC-ESI/MS) J. Agric. Food Chem. 2004 52 6694 6699 10.1021/jf049114a 15506802

138. Middleton E. Kandaswami C. The Flavonoids: Advances in Research Since 1986 Harborne J.B. Chapman & Hall London, UK 1994

139. Häkkinen S.H. Kärenlampi S.O. Heinonen I.M. Mykkänen H.M. Törrönen A.R. Content of the flavonols quercetin, myricetin, and kaempferol in 25 edible berries J. Agric. Food Chem. 1999 47 2274 2279 10.1021/jf9811065 10794622

140. Williamson G. Manach C. Bioavailability and bioefficacy of polyphenols in humans. II. Review of 93 intervention studies Am. J. Clin. Nutr. 2005 81 243S 255S 10.1093/ajcn/81.1.243S 15640487

141. Wiczkowski W. Romaszko J. Bucinski A. Szawara-Nowak D. Honke J. Zielinski H. Piskula M.K. Quercetin from shallots ( Allium cepa L. var. aggregatum) is more bioavailable than its glucosides J. Nutr. 2008 138 885 888 10.1093/jn/138.5.885 18424596

142. Varsha K. Sharma A. Kaur A. Madan J. Pandey R.S. Jain U.K. Chandra R. Chapter 28—Natural plant-derived anticancer drugs nanotherapeutics: A review on preclinical to clinical success Nanostructures for Cancer Therapy Ficai A. Grumezescu A.M. Elsevier Amsterdam, The Netherlands 2017 775 809 10.1016/B978-0-323-46144-3.00028-3

143. Li Y. Yao J. Han C. Yang J. Chaudhry M.T. Wang S. Liu H. Yin Y. Quercetin, inflammation and immunity Nutrients 2016 8 167 10.3390/nu8030167 26999194 PMC4808895

144. Bule M. Abdurahman A. Nikfar S. Abdollahi M. Amini M. Antidiabetic effect of quercetin: A systematic review and meta-analysis of animal studies Food Chem. Toxicol. 2019 125 494 502 10.1016/j.fct.2019.01.037 30735748

145. Wang H. Yuan Z. Chen Z. Yao F. Hu Z. Wu B. Effect of quercetin on glioma cell U87 apoptosis and feedback regulation of MDM2-p53 Nan Fang Yi Ke Da Xue Xue Bao J. South. Med. Univ. 2014 34 686 689 24849437

146. Xiang T. Fang Y. Wang S.-X. Quercetin suppresses HeLa cells by blocking PI3K/Akt pathway J. Huazhong Univ. Sci. Technol. 2014 34 740 744 10.1007/s11596-014-1345-6 25318886

147. Russo M. Palumbo R. Tedesco I. Mazzarella G. Russo P. Iacomino G. Russo G.L. Quercetin and anti-CD95 (Fas/Apo1) enhance apoptosis in HPB-ALL cell line FEBS Lett. 1999 462 322 328 10.1016/S0014-5793(99)01544-6 10622719

148. Aalinkeel R. Bindukumar B. Reynolds J.L. Sykes D.E. Mahajan S.D. Chadha K.C. Schwartz S.A. The dietary bioflavonoid, quercetin, selectively induces apoptosis of prostate cancer cells by down-regulating the expression of heat shock protein 90 Prostate 2008 68 1773 1789 10.1002/pros.20845 18726985 PMC2826114

149. Kim G.N. Jang H.D. Protective Mechanism of Quercetin and Rutin Using Glutathione Metabolism on H2O2-induced Oxidative Stress in HepG2 Cells Ann. N. Y. Acad. Sci. 2009 1171 530 537 10.1111/j.1749-6632.2009.04690.x 19723100

150. Fernald K. Kurokawa M. Evading apoptosis in cancer Trends Cell Biol. 2013 23 620 633 10.1016/j.tcb.2013.07.006 23958396 PMC4091735

151. Granato M. Rizzello C. Montani M.S.G. Cuomo L. Vitillo M. Santarelli R. Gonnella R. D’Orazi G. Faggioni A. Cirone M. Quercetin induces apoptosis and autophagy in primary effusion lymphoma cells by inhibiting PI3K/AKT/mTOR and STAT3 signaling pathways J. Nutr. Biochem. 2017 41 124 136 10.1016/j.jnutbio.2016.12.011 28092744

152. Wang Z.X. Ma J. Li X.Y. Wu Y. Shi H. Chen Y. Lu G. Shen H.M. Lu G.D. Zhou J. Quercetin induces p53-independent cancer cell death through lysosome activation by the transcription factor EB and Reactive Oxygen Species-dependent ferroptosis Br. J. Pharmacol. 2021 178 1133 1148 10.1111/bph.15350 33347603

153. Iriti M. Kubina R. Cochis A. Sorrentino R. Varoni E.M. Kabała-Dzik A. Azzimonti B. Dziedzic A. Rimondini L. Wojtyczka R.D. Rutin, a quercetin glycoside, restores chemosensitivity in human breast cancer cells Phytother. Res. 2017 31 1529 1538 10.1002/ptr.5878 28752532

154. Bulavin D.V. Phillips C. Nannenga B. Timofeev O. Donehower L.A. Anderson C.W. Appella E. Fornace A.J. Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK–mediated activation of the p16Ink4a-p19Arf pathway Nat. Genet. 2004 36 343 350 10.1038/ng1317 14991053

155. Hong Y. Lee J. Moon H. Ryu C.H. Seok J. Jung Y.-S. Ryu J. Baek S.J. Quercetin induces anticancer activity by upregulating pro-NAG-1/GDF15 in differentiated thyroid cancer cells Cancers 2021 13 3022 10.3390/cancers13123022 34208730 PMC8233818

156. Wong M.L. Prawira A. Kaye A.H. Hovens C.M. Tumour angiogenesis: Its mechanism and therapeutic implications in malignant gliomas J. Clin. Neurosci. 2009 16 1119 1130 10.1016/j.jocn.2009.02.009 19556134

157. Adams R.H. Alitalo K. Molecular regulation of angiogenesis and lymphangiogenesis Nat. Rev. Mol. Cell Biol. 2007 8 464 478 10.1038/nrm2183 17522591

158. Li S. Pei Y. Wang W. Liu F. Zheng K. Zhang X. Quercetin suppresses the proliferation and metastasis of metastatic osteosarcoma cells by inhibiting parathyroid hormone receptor 1 Biomed. Pharmacother. 2019 114 108839 10.1016/j.biopha.2019.108839 30978523

159. Ryu S. Park S. Lim W. Song G. Quercetin augments apoptosis of canine osteosarcoma cells by disrupting mitochondria membrane potential and regulating PKB and MAPK signal transduction J. Cell. Biochem. 2019 120 17449 17458 10.1002/jcb.29009 31131468

160. Mutlu Altundağ E. Kasacı T. Yılmaz A.M. Karademir B. Koçtürk S. Taga Y. Yalçın A.S. Quercetin-induced cell death in human papillary thyroid cancer (B-CPAP) cells J. Thyroid. Res. 2016 2016 9843675 10.1155/2016/9843675 27057371 PMC4745605

161. Quagliariello V. Armenia E. Aurilio C. Rosso F. Clemente O. de Sena G. Barbarisi M. Barbarisi A. New treatment of medullary and papillary human thyroid cancer: Biological effects of hyaluronic acid hydrogel loaded with quercetin alone or in combination to an inhibitor of aurora kinase J. Cell. Physiol. 2016 231 1784 1795 10.1002/jcp.25283 26660542

162. Gao X. Wang B. Wei X. Men K. Zheng F. Zhou Y. Zheng Y. Gou M. Huang M. Guo G. Anticancer effect and mechanism of polymer micelle-encapsulated quercetin on ovarian cancer Nanoscale 2012 4 7021 7030 10.1039/c2nr32181e 23044718

163. Dhanaraj T. Mohan M. Arunakaran J. Quercetin attenuates metastatic ability of human metastatic ovarian cancer cells via modulating multiple signaling molecules involved in cell survival, proliferation, migration and adhesion Arch. Biochem. Biophys. 2021 701 108795 10.1016/j.abb.2021.108795 33577840

164. Kee J.-Y. Han Y.-H. Kim D.-S. Mun J.-G. Park J. Jeong M.-Y. Um J.-Y. Hong S.-H. Inhibitory effect of quercetin on colorectal lung metastasis through inducing apoptosis, and suppression of metastatic ability Phytomedicine 2016 23 1680 1690 10.1016/j.phymed.2016.09.011 27823633

165. Rotimi D.E. Olaolu T.D. Adeyemi O.S. Pharmacological action of quercetin against testicular dysfunction: A mini review J. Integr. Med. 2022 S2095 S4964 10.1016/j.joim.2022.07.001 35850969

166. Botten D. Fugallo G. Fraternali F. Molteni C. Structural properties of green tea catechins J. Phys. Chem. B 2015 119 12860 12867 10.1021/acs.jpcb.5b08737 26369298

167. Rodríguez-Carrasco Y. Gaspari A. Graziani G. Santini A. Ritieni A. Fast analysis of polyphenols and alkaloids in cocoa-based products by ultra-high performance liquid chromatography and Orbitrap high resolution mass spectrometry (UHPLC-Q-Orbitrap-MS/MS) Food Res. Int. 2018 111 229 236 10.1016/j.foodres.2018.05.032 30007681

168. Lambert J.D. Elias R. The antioxidant and pro-oxidant activities of green tea polyphenols: A role in cancer prevention Arch. Biochem. Biophys. 2010 501 65 72 10.1016/j.abb.2010.06.013 20558130 PMC2946098

169. Mukai K. Mitani S. Ohara K. Nagaoka S.-I. Structure–activity relationship of the tocopherol-regeneration reaction by catechins Free. Radic. Biol. Med. 2005 38 1243 1256 10.1016/j.freeradbiomed.2005.01.011 15808422

170. Rice-evans C.A. Miller N.J. Bolwell P.G. Bramley P.M. Pridham J.B. The relative antioxidant activities of plant-derived polyphenolic flavonoids Free. Radic. Res. 1995 22 375 383 10.3109/10715769509145649 7633567

171. Legeay S. Rodier M. Fillon L. Faure S. Clere N. Epigallocatechin gallate: A review of its beneficial properties to prevent metabolic syndrome Nutrients 2015 7 5443 5468 10.3390/nu7075230 26198245 PMC4517007

172. Xicota L. Rodriguez-Morato J. Dierssen M. de la Torre R. Potential role of (-)-epigallocatechin-3-gallate (EGCG) in the secondary prevention of Alzheimer disease Curr. Drug Targets 2017 18 174 195 10.2174/1389450116666150825113655 26302801

173. H Farzaei M. Rahimi R. Abdollahi M. The role of dietary polyphenols in the management of inflammatory bowel disease Curr. Pharm. Biotechnol. 2015 16 196 210 10.2174/1389201016666150118131704 25601607

174. Yamamoto Y. Gaynor R.B. Therapeutic potential of inhibition of the NF-κB pathway in the treatment of inflammation and cancer J. Clin. Investig. 2001 107 135 142 10.1172/JCI11914 11160126 PMC199180

175. Kanlaya R. Thongboonkerd V. Molecular mechanisms of epigallocatechin-3-gallate for prevention of chronic kidney disease and renal fibrosis: Preclinical evidence Curr. Dev. Nutr. 2019 3 nzz101 10.1093/cdn/nzz101 31555758 PMC6752729

176. Wang Y. Wang B. Du F. Su X. Sun G. Zhou G. Bian X. Liu N. Epigallocatechin-3-Gallate Attenuates Oxidative Stress and Inflammation in Obstructive Nephropathy via NF-κB and Nrf2/HO-1 Signalling Pathway Regulation Basic Clin. Pharmacol. Toxicol. 2015 117 164 172 10.1111/bcpt.12383 25625183

177. Riegsecker S. Wiczynski D. Kaplan M.J. Ahmed S. Potential benefits of green tea polyphenol EGCG in the prevention and treatment of vascular inflammation in rheumatoid arthritis Life Sci. 2013 93 307 312 10.1016/j.lfs.2013.07.006 23871988 PMC3768132

178. Zan L. Chen Q. Zhang L. Li X. Epigallocatechin gallate (EGCG) suppresses growth and tumorigenicity in breast cancer cells by downregulation of miR-25 Bioengineered 2019 10 374 382 10.1080/21655979.2019.1657327 31431131 PMC6738446

179. Kwak T.W. Park S.B. Kim H.-J. Jeong Y.-I. Kang D.H. Anticancer activities of epigallocatechin-3-gallate against cholangiocarcinoma cells OncoTargets Ther. 2017 10 137 10.2147/OTT.S112364 28053547 PMC5189709

180. Liu L. Ju Y. Wang J. Zhou R. Epigallocatechin-3-gallate promotes apoptosis and reversal of multidrug resistance in esophageal cancer cells Pathol.-Res. Pract. 2017 213 1242 1250 10.1016/j.prp.2017.09.006 28964574

181. Wu D. Liu Z. Li J. Zhang Q. Zhong P. Teng T. Chen M. Xie Z. Ji A. Li Y. Epigallocatechin-3-gallate inhibits the growth and increases the apoptosis of human thyroid carcinoma cells through suppression of EGFR/RAS/RAF/MEK/ERK signaling pathway Cancer Cell Int. 2019 19 1 17 10.1186/s12935-019-0762-9 30858760 PMC6394055

182. Gu J. Qiao K. Sun P. Chen P. Li Q. Study of EGCG induced apoptosis in lung cancer cells by inhibiting PI3K/Akt signaling pathway Eur. Rev. Med. Pharmacol. Sci. 2018 22 4557 4563 30058690 10.26355/eurrev_201807_15511

183. Zhu F. Xu Y. Pan J. Li M. Chen F. Xie G. Epigallocatechin gallate protects against MNNG-induced precancerous lesions of gastric carcinoma in rats via PI3K/Akt/mTOR pathway Evid.-Based Complementary Altern. Med. 2021 2021 8846813 10.1155/2021/8846813 PMC7880711 33628319

184. Amin A. Wang D. Nannapaneni S. Lamichhane R. Chen Z.G. Shin D.M. Combination of resveratrol and green tea epigallocatechin gallate induces synergistic apoptosis and inhibits tumor growth in vivo in head and neck cancer models Oncol. Rep. 2021 45 1 10 10.3892/or.2021.8038 33864659 PMC8025073

185. Khiewkamrop P. Phunsomboon P. Richert L. Pekthong D. Srisawang P. Epistructured catechins, EGCG and EC facilitate apoptosis induction through targeting de novo lipogenesis pathway in HepG2 cells Cancer Cell Int. 2018 18 1 13 10.1186/s12935-018-0539-6 29588626 PMC5863485

186. Jankun J. Selman S.H. Swiercz R. Skrzypczak-Jankun E. Why drinking green tea could prevent cancer Nature 1997 387 561 10.1038/42381 9177339

187. Garbisa S. Sartor L. Biggin S. Salvato B. Benelli R. Albini A. Tumor gelatinases and invasion inhibited by the green tea flavanol epigallocatechin-3-gallate Cancer 2001 91 822 832 10.1002/1097-0142(20010215)91:4<822::AID-CNCR1070>3.0.CO;2-G 11241252

188. Rao S.D. Pagidas K. Epigallocatechin-3-gallate, a natural polyphenol, inhibits cell proliferation and induces apoptosis in human ovarian cancer cells Anticancer Res. 2010 30 2519 2523 20682977

189. Liotta L.A. Tryggvason K. Garbisa S. Hart I. Foltz C. Shafie S. Metastatic potential correlates with enzymatic degradation of basement membrane collagen Nature 1980 284 67 68 10.1038/284067a0 6243750

190. Jin G. Yang Y. Liu K. Zhao J. Chen X. Liu H. Bai R. Li X. Jiang Y. Zhang X. Combination curcumin and (−)-epigallocatechin-3-gallate inhibits colorectal carcinoma microenvironment-induced angiogenesis by JAK/STAT3/IL-8 pathway Oncogenesis 2017 6 e384 10.1038/oncsis.2017.84 28967875 PMC5668882

191. Dong Z. Ma W.-y. Huang C. Yang C.S. Inhibition of tumor promoter-induced activator protein 1 activation and cell transformation by tea polyphenols,(-)-epigallocatechin gallate, and theaflavins Cancer Res. 1997 57 4414 4419 9331105

192. Shimizu M. Shirakami Y. Sakai H. Yasuda Y. Kubota M. Adachi S. Tsurumi H. Hara Y. Moriwaki H. (−)-Epigallocatechin gallate inhibits growth and activation of the VEGF/VEGFR axis in human colorectal cancer cells Chem.-Biol. Interact. 2010 185 247 252 10.1016/j.cbi.2010.03.036 20346928

193. Mahadevan D. Thanki N. Aroca P. McPhie P. Yu J.-C. Beeler J. Santos E. Wlodawer A. Heidaran M. A Divalent Metal Ion Binding Site in the Kinase Insert Domain of the. alpha.-Platelet-Derived Growth Factor Receptor Regulates Its Association with SH2 Domains Biochemistry 1995 34 2095 2106 10.1021/bi00007a002 7857921

194. Zhao J. Blayney A. Liu X. Gandy L. Jin W. Yan L. Ha J.-H. Canning A.J. Connelly M. Yang C. EGCG binds intrinsically disordered N-terminal domain of p53 and disrupts p53-MDM2 interaction Nat. Commun. 2021 12 1 11 10.1038/s41467-021-21258-5 33579943 PMC7881117

195. Tanaka Y. Tsuneoka M. Gallic Acid Derivatives Propyl Gallate and Epigallocatechin Gallate Reduce rRNA Transcription via Induction of KDM2A Activation Biomolecules 2022 12 30 10.3390/biom12010030 PMC8773796 35053178

196. Borlinghaus J. Albrecht F. Gruhlke M.C. Nwachukwu I.D. Slusarenko A.J. Allicin: Chemistry and biological properties Molecules 2014 19 12591 12618 10.3390/molecules190812591 25153873 PMC6271412

197. Cavallito C.J. Bailey J.H. Allicin, the antibacterial principle of Allium sativum. I. Isolation, physical properties and antibacterial action J. Am. Chem. Soc. 1944 66 1950 1951 10.1021/ja01239a048

198. Izigov N. Farzam N. Savion N. S-allylmercapto-N-acetylcysteine up-regulates cellular glutathione and protects vascular endothelial cells from oxidative stress Free. Radic. Biol. Med. 2011 50 1131 1139 10.1016/j.freeradbiomed.2011.01.028 21281712

199. Borlinghaus J. Foerster J. Kappler U. Antelmann H. Noll U. Gruhlke M.C.H. Slusarenko A.J. Allicin, the odor of freshly crushed garlic: A review of recent progress in understanding allicin’s effects on cells Molecules 2021 26 1505 10.3390/molecules26061505 33801955 PMC8001868

200. Chan J.Y.Y. Yuen A.C.Y. Chan R.Y.K. Chan S.W.J.P.R. A review of the cardiovascular benefits and antioxidant properties of allicin Phytother. Res. 2013 27 637 646 10.1002/ptr.4796 22888009

201. Xiang Y. Zhao J. Zhao M. Wang K. Allicin activates autophagic cell death to alleviate the malignant development of thyroid cancer Exp. Ther. Med. 2018 15 3537 3543 10.3892/etm.2018.5828 29545880 PMC5841025

202. Padilla-Camberos E. Zaitseva G. Padilla C. Puebla A.M. Antitumoral activity of allicin in murine lymphoma L5178Y Asian Pac. J. Cancer Prev. 2010 11 1241 1244 21198270

203. Hussain Z.V.M. Sivanandhan S.K. Antiproliferative and Apoptotic Induction of Allicin in Human Lung Cancer Cell Lines Indian J. Pharm. Educ. Res. 2021 55 566 573 10.5530/ijper.55.2.95

204. Maitisha G. Aimaiti M. An Z. Li X. Allicin induces cell cycle arrest and apoptosis of breast cancer cells in vitro via modulating the p53 pathway Mol. Biol. Rep. 2021 48 7261 7272 10.1007/s11033-021-06722-1 34626309

205. Lee C.G. Lee H.-W. Kim B.-O. Rhee D.-K. Pyo S. Allicin inhibits invasion and migration of breast cancer cells through the suppression of VCAM-1: Regulation of association between p65 and ER-α J. Funct. Foods 2015 15 172 185 10.1016/j.jff.2015.03.017

206. Sun L. Wang X. Effects of allicin on both telomerase activity and apoptosis in gastric cancer SGC-7901 cells World J. Gastroenterol. 2003 9 1930 10.3748/wjg.v9.i9.1930 12970878 PMC4656646

207. Cha J.H. Choi Y.J. Cha S.H. Choi C.H. Cho W.H. Allicin inhibits cell growth and induces apoptosis in U87MG human glioblastoma cells through an ERK-dependent pathway Oncol. Rep. 2012 28 41 48 10.3892/or.2012.1772 22552443

208. Weeranantanapan O. Satsantitham K. Sritangos P. Chudapongse N. Allicin suppresses human glioblastoma cell growth by inducing cell cycle arrest and apoptosis, and by promoting autophagy Arch. Biol. Sci. 2020 72 313 319 10.2298/ABS200414025W

209. Zhang Q. Yang D. Allicin suppresses the migration and invasion in cervical cancer cells mainly by inhibiting NRF2 Exp. Ther. Med. 2019 17 1523 1528 10.3892/etm.2018.7104 30783417 PMC6364242

210. Khakbaz P. Panahizadeh R. Vatankhah M.A. Najafzadeh N. Allicin Reduces 5-fluorouracil-resistance in Gastric Cancer Cells through Modulating MDR1, DKK1, and WNT5A Expression Drug Res. 2021 71 448 454 10.1055/a-1525-1499 34261152

211. Jiang W. Huang Y. Wang J.-P. Yu X.-Y. Zhang L.-Y. The synergistic anticancer effect of artesunate combined with allicin in osteosarcoma cell line in vitro and in vivo Asian Pac. J. Cancer Prev. 2013 14 4615 4619 10.7314/APJCP.2013.14.8.4615 24083713

212. Jobani B.M. Najafzadeh N. Mazani M. Arzanlou M. Vardin M.M. Molecular mechanism and cytotoxicity of allicin and all-trans retinoic acid against CD44+ versus CD117+ melanoma cells Phytomedicine 2018 48 161 169 10.1016/j.phymed.2018.05.013 30195874

213. Mohamed A.F. Anwer M. Effect of Electromagnetic Field and Allicin as Natural Extract on Hepatocellular Carcinoma (HepG2) Med. J. Cairo Univ. 2020 88 815 825

214. Ahmad A. Mishra R.K. Vyawahare A. Kumar A. Rehman M.U. Qamar W. Khan A.Q. Khan R. Thymoquinone (2-Isopropyl-5-methyl-1, 4-benzoquinone) as a chemopreventive/anticancer agent: Chemistry and biological effects Saudi Pharm. J. 2019 27 1113 1126 10.1016/j.jsps.2019.09.008 31885471 PMC6921197

215. Dajani E.Z. Shahwan T.G. Dajani N.E. Overview of the preclinical pharmacological properties of Nigella sativa (black seeds): A complementary drug with historical and clinical significance J. Physiol. Pharm. 2016 67 801 817 28195061

216. Jain A. Dhruw L. Sinha P. Pradhan A. Sharma R. Gupta B. Thymoquinone Nutraceuticals Elsevier Amsterdam, The Netherlands 2021 891 901

217. Younus H. Sawhney Molecular and Therapeutic: Actions of Thymoquinone Springer Berlin/Heidelberg, Germany 2018

218. Alobaedi O.H. Talib W.H. Basheti I.A. Antitumor effect of thymoquinone combined with resveratrol on mice transplanted with breast cancer Asian Pac. J. Trop. Med. 2017 10 400 408 10.1016/j.apjtm.2017.03.026 28552110

219. Darakhshan S. Pour A.B. Colagar A.H. Sisakhtnezhad S. Thymoquinone and its therapeutic potentials Pharmacol. Res. 2015 95 138 158 10.1016/j.phrs.2015.03.011 25829334

220. Phua C.Y.H. Teoh Z.L. Goh B.-H. Yap W.H. Tang Y.-Q. Triangulating the pharmacological properties of thymoquinone in regulating reactive oxygen species, inflammation, and cancer: Therapeutic applications and mechanistic pathways Life Sci. 2021 287 120120 10.1016/j.lfs.2021.120120 34762903

221. Homayoonfal M. Asemi Z. Yousefi B. Potential anticancer properties and mechanisms of thymoquinone in osteosarcoma and bone metastasis Cell. Mol. Biol. Lett. 2022 27 1 28 10.1186/s11658-022-00320-0 35236304 PMC8903697

222. Alhmied F. Alammar A. Alsultan B. Alshehri M. Pottoo F.H. Molecular mechanisms of thymoquinone as anticancer agent Comb. Chem. High Throughput Screen. 2021 24 1644 1653 10.2174/1386207323999201027225305 33115388

223. Wirries A. Breyer S. Quint K. Schobert R. Ocker M. Thymoquinone hydrazone derivatives cause cell cycle arrest in p53-competent colorectal cancer cells Exp. Ther. Med. 2010 1 369 375 10.3892/etm_00000058 22993551 PMC3445902

224. Gali-Muhtasib H. Kuester D. Mawrin C. Bajbouj K. Diestel A. Ocker M. Habold C. Foltzer-Jourdainne C. Schoenfeld P. Peters B. Thymoquinone triggers inactivation of the stress response pathway sensor CHEK1 and contributes to apoptosis in colorectal cancer cells Cancer Res. 2008 68 5609 5618 10.1158/0008-5472.CAN-08-0884 18632613

225. Gali-Muhtasib H.U. Abou Kheir W.G. Kheir L.A. Darwiche N. Crooks P.A. Molecular pathway for thymoquinone-induced cell-cycle arrest and apoptosis in neoplastic keratinocytes Anti-Cancer Drugs 2004 15 389 399 10.1097/00001813-200404000-00012 15057144

226. Motaghed M. Al-Hassan F.M. Hamid S.S. Cellular responses with thymoquinone treatment in human breast cancer cell line MCF-7 Pharmacogn. Res. 2013 5 200 10.4103/0974-8490.112428 PMC3719263 23900121

227. Ma J. Zhang Y. Deng H. Liu Y. Lei X. He P. Dong W. Thymoquinone inhibits the proliferation and invasion of esophageal cancer cells by disrupting the AKT/GSK-3β/Wnt signaling pathway via PTEN upregulation Phytother. Res. 2020 34 3388 3399 10.1002/ptr.6795 32901987

228. Guler E.M. Sisman B.H. Kocyigit A. Hatiboglu M.A. Investigation of cellular effects of thymoquinone on glioma cell Toxicol. Rep. 2021 8 162 170 10.1016/j.toxrep.2020.12.026 33489775 PMC7806546

229. El-Sheikh A.A.K. Morsy M.A. Abdalla A.M. Hamouda A.H. Alhaider I.A. Mechanisms of thymoquinone hepatorenal protection in methotrexate-induced toxicity in rats Mediat. Inflamm. 2015 2015 859383 10.1155/2015/859383 26089605 PMC4455533

230. Chehl N. Chipitsyna G. Gong Q. Yeo C.J. Arafat H.A. Anti-inflammatory effects of the Nigella sativa seed extract, thymoquinone, in pancreatic cancer cells Hpb 2009 11 373 381 10.1111/j.1477-2574.2009.00059.x 19768141 PMC2742606

231. El Mezayen R. El Gazzar M. Nicolls M.R. Marecki J.C. Dreskin S.C. Nomiyama H. Effect of thymoquinone on cyclooxygenase expression and prostaglandin production in a mouse model of allergic airway inflammation Immunol. Lett. 2006 106 72 81 10.1016/j.imlet.2006.04.012 16762422

232. Kundu J. Choi B.Y. Jeong C.-H. Kundu J.K. Chun K.-S. Thymoquinone induces apoptosis in human colon cancer HCT116 cells through inactivation of STAT3 by blocking JAK2-and Src-mediated phosphorylation of EGF receptor tyrosine kinase Oncol. Rep. 2014 32 821 828 10.3892/or.2014.3223 24890449

233. Raut P.K. Lee H.S. Joo S.H. Chun K.-S. Thymoquinone induces oxidative stress-mediated apoptosis through downregulation of Jak2/STAT3 signaling pathway in human melanoma cells Food Chem. Toxicol. 2021 157 112604 10.1016/j.fct.2021.112604 34627931

234. Almajali B. Al-Jamal H.A.N. Taib W.R.W. Ismail I. Johan M.F. Doolaanea A.A. Ibrahim W.N. Tajudin S.A. Thymoquinone suppresses cell proliferation and enhances apoptosis of HL60 leukemia cells through re-expression of JAK/STAT negative regulators Asian Pac. J. Cancer Prev. 2021 22 879 10.31557/APJCP.2021.22.3.879 33773553 PMC8286695

235. Woo C.C. Loo S.Y. Gee V. Yap C.W. Sethi G. Kumar A.P. Tan K.H.B. Anticancer activity of thymoquinone in breast cancer cells: Possible involvement of PPAR-γ pathway Biochem. Pharmacol. 2011 82 464 475 10.1016/j.bcp.2011.05.030 21679698

236. Zhu W.-Q. Wang J. Guo X.-F. Liu Z. Dong W.-G. Thymoquinone inhibits proliferation in gastric cancer via the STAT3 pathway in vivo and in vitro World J. Gastroenterol. 2016 22 4149 10.3748/wjg.v22.i16.4149 27122665 PMC4837432

237. Talib W.H. Regressions of breast carcinoma syngraft following treatment with piperine in combination with thymoquinone Sci. Pharm. 2017 85 27 10.3390/scipharm85030027 PMC5620515 28671634

238. Ayan M. Tas U. Sogut E. Caylı S. Kaya H. Esen M. Erdemir F. Uysal M. Protective effect of thymoquinone against testicular torsion induced oxidative injury Andrologia 2016 48 143 151 10.1111/and.12424 25906970

239. Fouad A.A. Jresat I. Thymoquinone therapy abrogates toxic effect of cadmium on rat testes Andrologia 2015 47 417 426 10.1111/and.12281 24735446

240. Mabrouk A. Ben Cheikh H. Thymoquinone supplementation ameliorates lead-induced testis function impairment in adult rats Toxicol. Ind. Health 2016 32 1114 1121 10.1177/0748233714548474 25216800

241. Ahmad I. Muneer K.M. Tamimi I.A. Chang M.E. Ata M.O. Yusuf N. Thymoquinone suppresses metastasis of melanoma cells by inhibition of NLRP3 inflammasome Toxicol. Appl. Pharmacol. 2013 270 70 76 10.1016/j.taap.2013.03.027 23583630

242. Badary O.A. Taha R.A. Gamal El-Din A.M. Abdel-Wahab M.H. Thymoquinone is a potent superoxide anion scavenger Drug Chem. Toxicol. 2003 26 87 98 10.1081/DCT-120020404 12816394

243. Nagi M.N. Mansour M.A. Protective effect of thymoquinone against doxorubicin–induced cardiotoxicity in rats: A possible mechanism of protection Pharmacol. Res. 2000 41 283 289 10.1006/phrs.1999.0585 10675279

244. Ahmad A. Khan R.M.A. Alkharfy K.M. Raish M. Al-Jenoobi F.I. Al-Mohizea A.M. Effects of thymoquinone on the pharmacokinetics and pharmacodynamics of glibenclamide in a rat model Nat. Prod. Commun. 2015 10 1934578X1501000821 10.1177/1934578X1501000821 26434126

245. Elbarbry F. Ragheb A. Marfleet T. Shoker A. Modulation of hepatic drug metabolizing enzymes by dietary doses of thymoquinone in female New Zealand White rabbits Phytother. Res. 2012 26 1726 1730 10.1002/ptr.4628 22422469

246. Arafa E.-S.A. Zhu Q. Shah Z.I. Wani G. Barakat B.M. Racoma I. El-Mahdy M.A. Wani A.A. Thymoquinone up-regulates PTEN expression and induces apoptosis in doxorubicin-resistant human breast cancer cells Mutat. Res. Fundam. Mol. Mech. Mutagenesis 2011 706 28 35 10.1016/j.mrfmmm.2010.10.007 21040738 PMC3037029

247. Homayoonfal M. Asemi Z. Yousefi B. Targeting microRNAs with thymoquinone: A new approach for cancer therapy Cell. Mol. Biol. Lett. 2021 26 1 22 10.1186/s11658-021-00286-5 34627167 PMC8502376

248. Zhou X. Wang F. Wu H. Chen X. Zhang Y. Lin J. Cai Y. Xiang J. He N. Hu Z. Thymoquinone Suppresses the Proliferation, Migration and Invasiveness through Regulating ROS, Autophagic Flux and miR-877-5p in Human Bladder Carcinoma Cells Int. J. Biol. Sci. 2021 17 3456 10.7150/ijbs.60401 34512159 PMC8416733

249. Ünal T.D. Hamurcu Z. Delibaşı N. Çınar V. Güler A. Gökçe S. Nurdinov N. Ozpolat B. Thymoquinone inhibits proliferation and migration of MDA-MB-231 triple negative breast cancer cells by suppressing autophagy, Beclin-1 and LC3 Anti-Cancer Agents Med. Chem. (Former. Curr. Med. Chem.-Anti-Cancer Agents) 2021 21 355 364 10.2174/1871520620666200807221047 32767958

250. Atteia H.H. Arafa M.H. Mohammad N.S. Amin D.M. Sakr A.T. Thymoquinone upregulates miR-125a-5p, attenuates STAT3 activation, and potentiates doxorubicin antitumor activity in murine solid Ehrlich carcinoma J. Biochem. Mol. Toxicol. 2021 35 e22924 10.1002/jbt.22924 34605108

251. Lu P. Zhao X. Cui T. Full Length Research Paper Production of emodin from Aspergillus ochraceus at preparative scale Afr. J. Biotechnol. 2010 9 512 517

252. Tang T. Yin L. Yang J. Shan G. Emodin, an anthraquinone derivative from Rheum officinale Baill, enhances cutaneous wound healing in rats Eur. J. Pharmacol. 2007 567 177 185 10.1016/j.ejphar.2007.02.033 17540366

253. Dong X. Fu J. Yin X. Cao S. Li X. Lin L. Huyiligeqi Ni J. Emodin: A review of its pharmacology, toxicity and pharmacokinetics Phytother. Res. 2016 30 1207 1218 10.1002/ptr.5631 27188216 PMC7168079

254. Li Q. Gao J. Pang X. Chen A. Wang Y. Molecular mechanisms of action of emodin: As an anti-cardiovascular disease drug Front. Pharmacol. 2020 11 559607 10.3389/fphar.2020.559607 32973538 PMC7481471

255. Huang H.-C. Chang J.-H. Tung S.-F. Wu R.-T. Foegh M.L. Chu S.-H. Immunosuppressive effect of emodin, a free radical generator Eur. J. Pharmacol. 1992 211 359 364 10.1016/0014-2999(92)90393-I 1535596

256. Hsu S.-C. Chung J.-G. Anticancer potential of emodin BioMedicine 2012 2 108 116 10.1016/j.biomed.2012.03.003 32289000 PMC7104001

257. Li M. Jin S. Cao Y. Xu J. Zhu S. Li Z. Emodin regulates cell cycle of non-small lung cancer (NSCLC) cells through hyaluronan synthase 2 (HA2)-HA-CD44/receptor for hyaluronic acid-mediated motility (RHAMM) interaction-dependent signaling pathway Cancer Cell Int. 2021 21 1 12 10.1186/s12935-020-01711-z 33407495 PMC7789699

258. Qin B. Zeng Z. Xu J. Shangwen J. Ye Z.J. Wang S. Wu Y. Peng G. Wang Q. Gu W. Emodin inhibits invasion and migration of hepatocellular carcinoma cells via regulating autophagy-mediated degradation of snail and β-catenin BMC Cancer 2022 22 1 17 10.1186/s12885-022-09684-0 35715752 PMC9206273

259. Zhou J. Li G. Han G. Feng S. Liu Y. Chen J. Liu C. Zhao L. Jin F. Emodin induced necroptosis in the glioma cell line U251 via the TNF-α/RIP1/RIP3 pathway Investig. New Drugs 2020 38 50 59 10.1007/s10637-019-00764-w 30924024 PMC6985083

260. Oei A.L.M. Sweep F.C.G.J. Thomas C.M.G. Boerman O.C. Massuger L.F.A.G. The use of monoclonal antibodies for the treatment of epithelial ovarian cancer Int. J. Oncol. 2008 32 1145 1157 10.3892/ijo_32_6_1145 18497976

261. Zou G. Zhang X. Wang L. Li X. Xie T. Zhao J. Yan J. Wang L. Ye H. Jiao S. Herb-sourced emodin inhibits angiogenesis of breast cancer by targeting VEGFA transcription Theranostics 2020 10 6839 10.7150/thno.43622 32550907 PMC7295066

262. Wu F.L. Chu P.Y. Chen G.Y. Wang K. Hsu W.Y. Ahmed A. Ma W.L. Cheng W.C. Wu Y.C. Yang J.C. Natural anthraquinone compound emodin as a novel inhibitor of aurora A kinase: A pilot study Chem. Biol. Drug Des. 2022 99 126 135 10.1111/cbdd.13938 34411446

263. Yim H. Lee Y.H. Lee C.H. Lee S.K. Emodin, an anthraquinone derivative isolated from the rhizomes of Rheum palmatum, selectively inhibits the activity of casein kinase II as a competitive inhibitor Planta Med. 1999 65 9 13 10.1055/s-1999-13953 10083837

264. Wang K.-j. Meng X.-y. Chen J.-f. Wang K.-y. Zhou C. Yu R. Ma Q. Emodin induced necroptosis and inhibited glycolysis in the renal cancer cells by enhancing ROS Oxidative Med. Cell. Longev. 2021 2021 8840590 10.1155/2021/8840590 33532038 PMC7837784

265. Yon J.-M. Baek I.-J. Lee B.J. Yun Y.W. Nam S.-Y. Emodin and [6]-gingerol lessen hypoxia-induced embryotoxicities in cultured mouse whole embryos via upregulation of hypoxia-inducible factor 1α and intracellular superoxide dismutases Reprod. Toxicol. 2011 31 513 518 10.1016/j.reprotox.2011.02.011 21382473

266. Zhang Z. Yan J. Chang Y. ShiDu Yan S. Shi H. Hypoxia inducible factor-1 as a target for neurodegenerative diseases Curr. Med. Chem. 2011 18 4335 4343 10.2174/092986711797200426 21861815 PMC3213300

267. Liu D.-L. Bu H. Li H. Chen H. Guo H.-C. Wang Z.-H. Tong H.-F. Ni Z.-L. Liu H.-B. Lin S.-Z. Emodin reverses gemcitabine resistance in pancreatic cancer cells via the mitochondrial apoptosis pathway in vitro Int. J. Oncol. 2012 40 1049 1057 10.3892/ijo.2011.1285 22159556 PMC3584653

268. Wang Z.-H. Chen H. Guo H.-C. Tong H.-F. Liu J.-X. Wei W.-T. Tan W. Ni Z.-L. Liu H.-B. Lin S.-Z. Enhanced antitumor efficacy by the combination of emodin and gemcitabine against human pancreatic cancer cells via downregulation of the expression of XIAP in vitro and in vivo Int. J. Oncol. 2011 39 1123 1131 21743963 10.3892/ijo.2011.1115

269. Wang W. Sun Y.-p. Huang X.-z. He M. Chen Y.-y. Shi G.-y. Li H. Yi J. Wang J. Emodin enhances sensitivity of gallbladder cancer cells to platinum drugs via glutathion depletion and MRP1 downregulation Biochem. Pharmacol. 2010 79 1134 1140 10.1016/j.bcp.2009.12.006 20005210

270. Huang X.-z. Wang J. Huang C. Chen Y.-y. Shi G.-y. Hu Q.-s. Yi J. Emodin enhances cytotoxicity of chemotherapeutic drugs in prostate cancer cells: The mechanisms involve ROS-mediated suppression of multidrug resistance and hypoxia inducible factor-1 Cancer Biol. Ther. 2008 7 468 475 10.4161/cbt.7.3.5457 18285700

271. Spagnuolo C. Russo G.L. Orhan I.E. Habtemariam S. Daglia M. Sureda A. Nabavi S.F. Devi K.P. Loizzo M.R. Tundis R. Genistein and cancer: Current status, challenges, and future directions Adv. Nutr. 2015 6 408 419 10.3945/an.114.008052 26178025 PMC4496735

272. Mukund V. Mukund D. Sharma V. Mannarapu M. Alam A. Genistein: Its role in metabolic diseases and cancer Crit. Rev. Oncol. Hematol. 2017 119 13 22 10.1016/j.critrevonc.2017.09.004 29065980

273. Gu Y. Zhu C.-F. Iwamoto H. Chen J.-S. Genistein inhibits invasive potential of human hepatocellular carcinoma by altering cell cycle, apoptosis, and angiogenesis World J. Gastroenterol. 2005 11 6512 10.3748/wjg.v11.i41.6512 16425425 PMC4355795

274. Chodon D. Banu S.M. Padmavathi R. Sakthisekaran D. Inhibition of cell proliferation and induction of apoptosis by genistein in experimental hepatocellular carcinoma Mol. Cell. Biochem. 2007 297 73 80 10.1007/s11010-006-9324-2 17006617

275. Tatsuta M. Iishi H. Baba M. Yano H. Uehara H. Nakaizumi A. Attenuation by genistein of sodium-chloride-enhanced gastric carcinogenesis induced by N-methyl-N′-nitro-N-nitrosoguanidine in Wistar rats Int. J. Cancer 1999 80 396 399 10.1002/(SICI)1097-0215(19990129)80:3<396::AID-IJC10>3.0.CO;2-1 9935180

276. Mentor-Marcel R. Lamartiniere C.A. Eltoum I.-E. Greenberg N.M. Elgavish A. Genistein in the diet reduces the incidence of poorly differentiated prostatic adenocarcinoma in transgenic mice (TRAMP) Cancer Res. 2001 61 6777 6782 11559550

277. Perabo F.G.E. Von Löw E.C. Ellinger J. Von Rücker A. Müller S.C. Bastian P.J. Soy isoflavone genistein in prevention and treatment of prostate cancer Prostate Cancer Prostatic Dis. 2008 11 6 12 10.1038/sj.pcan.4501000 17923857

278. Pollard M. Wolter W. Prevention of spontaneous prostate-related cancer in Lobund-Wistar rats by a soy protein isolate/isoflavone diet Prostate 2000 45 101 105 10.1002/1097-0045(20001001)45:2<101::AID-PROS3>3.0.CO;2-P 11027408

279. Sohel M. Biswas P. Al Amin M. Dey D. Sultana H. Aktar S. Khan M.S. Hossain M.A. Paul P. Nurul I.M. Genistein Mediated Molecular Pharmacology, Cell-Specific Anti-Breast Cancer Mechanism with Synergistic Effect and in silico Safety Measurement Preprints 2021 2021090123 10.20944/preprints202109.0123.v1

280. Banerjee S. Li Y. Wang Z. Sarkar F.H. Multi-targeted therapy of cancer by genistein Cancer Lett. 2008 269 226 242 10.1016/j.canlet.2008.03.052 18492603 PMC2575691

281. King-Batoon A. Leszczynska J.M. Klein C.B. Modulation of gene methylation by genistein or lycopene in breast cancer cells Environ. Mol. Mutagenesis 2008 49 36 45 10.1002/em.20363 18181168

282. Basak S. Pookot D. Noonan E.J. Dahiya R. Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function Mol. Cancer Ther. 2008 7 3195 3202 10.1158/1535-7163.MCT-08-0617 18852123

283. Estrela J.M. Mena S. Obrador E. Benlloch M. Castellano G. Salvador R. Dellinger R.W. Polyphenolic phytochemicals in cancer prevention and therapy: Bioavailability versus bioefficacy J. Med. Chem. 2017 60 9413 9436 10.1021/acs.jmedchem.6b01026 28654265

284. Meeran S.M. Katiyar S.K. Cell cycle control as a basis for cancer chemoprevention through dietary agents Front. Biosci. J. Virtual Libr. 2008 13 2191 10.2741/2834 17981702 PMC2387048

285. Sarkar F.H. Adsule S. Padhye S. Kulkarni S. Li Y. The role of genistein and synthetic derivatives of isoflavone in cancer prevention and therapy Mini Rev. Med. Chem. 2006 6 401 407 10.2174/138955706776361439 16613577

286. Bi Y.-l. Min M. Shen W. Liu Y. Genistein induced anticancer effects on pancreatic cancer cell lines involves mitochondrial apoptosis, G0/G1cell cycle arrest and regulation of STAT3 signalling pathway Phytomedicine 2018 39 10 16 10.1016/j.phymed.2017.12.001 29433670

287. Farina H.G. Pomies M. Alonso D.F. Gomez D.E. Antitumor and antiangiogenic activity of soy isoflavone genistein in mouse models of melanoma and breast cancer Oncol. Rep. 2006 16 885 891 10.3892/or.16.4.885 16969510

288. Shafiee G. Saidijam M. Tayebinia H. Khodadadi I. Beneficial effects of genistein in suppression of proliferation, inhibition of metastasis, and induction of apoptosis in PC3 prostate cancer cells Arch. Physiol. Biochem. 2020 128 694 702 10.1080/13813455.2020.1717541 31985311

289. Sharma M. Arora I. Chen M. Wu H. Crowley M.R. Tollefsbol T.O. Li Y. Therapeutic Effects of Dietary Soybean Genistein on Triple-Negative Breast Cancer via Regulation of Epigenetic Mechanisms Nutrients 2021 13 3944 10.3390/nu13113944 34836197 PMC8623013

290. Gong L. Li Y. Nedeljkovic-Kurepa A. Sarkar F.H. Inactivation of NF-κB by genistein is mediated via Akt signaling pathway in breast cancer cells Oncogene 2003 22 4702 4709 10.1038/sj.onc.1206583 12879015

291. Sharma S. Malhotra L. Yadav P. Mishra V. Sharma R.S. Samath E.A. Genistein: A novel inhibitor of IL-6/IL-6R interface of the Interleukin-6–mediated STAT3 dependent pathway of carcinogenesis J. Mol. Struct. 2022 1258 132668 10.1016/j.molstruc.2022.132668

292. Nakamura Y. Yogosawa S. Izutani Y. Watanabe H. Otsuji E. Sakai T. A combination of indole-3-carbinol and genistein synergistically induces apoptosis in human colon cancer HT-29 cells by inhibiting Akt phosphorylation and progression of autophagy Mol. Cancer 2009 8 1 15 10.1186/1476-4598-8-100 19909554 PMC2784428

293. Oh H.Y. Leem J. Yoon S.J. Yoon S. Hong S.J. Lipid raft cholesterol and genistein inhibit the cell viability of prostate cancer cells via the partial contribution of EGFR-Akt/p70S6k pathway and down-regulation of androgen receptor Biochem. Biophys. Res. Commun. 2010 393 319 324 10.1016/j.bbrc.2010.01.133 20138837

294. Kim S.H. Kim S.H. Kim Y.B. Jeon Y.T. Lee S.C. Song Y.S. Genistein inhibits cell growth by modulating various mitogen-activated protein kinases and AKT in cervical cancer cells Ann. N. Y. Acad. Sci. 2009 1171 495 500 10.1111/j.1749-6632.2009.04899.x 19723095

295. Javed Z. Khan K. Herrera-Bravo J. Naeem S. Iqbal M.J. Sadia H. Qadri Q.R. Raza S. Irshad A. Akbar A. Genistein as a regulator of signaling pathways and microRNAs in different types of cancers Cancer Cell Int. 2021 21 1 12 10.1186/s12935-021-02091-8 34289845 PMC8296701

296. Liu X. Wang Q. Liu B. Zheng X. Li P. Zhao T. Jin X. Ye F. Zhang P. Chen W. Genistein inhibits radiation-induced invasion and migration of glioblastoma cells by blocking the DNA-PKcs/Akt2/Rac1 signaling pathway Radiother. Oncol. 2021 155 93 104 10.1016/j.radonc.2020.10.026 33129924

297. Sohel M. Biswas P. Al Amin M. Hossain M.A. Sultana H. Dey D. Aktar S. Setu A. Khan M.S. Paul P. Genistein, a Potential Phytochemical against Breast Cancer Treatment-Insight into the Molecular Mechanisms Processes 2022 10 415 10.3390/pr10020415

298. Mahood H.E. Abbas M.K. Zahid N.A. Micropropagation of Feverfew (Tanacetum parthenium) and Quantification of Parthenolide Content in Its Micropropagated and Conventionally Grown Plants Horticulturae 2022 8 50 10.3390/horticulturae8010050

299. Freund R.R. Gobrecht P. Fischer D. Arndt H.-D. Advances in chemistry and bioactivity of parthenolide Nat. Prod. Rep. 2020 37 541 565 10.1039/C9NP00049F 31763637

300. Sztiller-Sikorska M. Czyz M. Parthenolide as cooperating agent for anti-cancer treatment of various malignancies Pharmaceuticals 2020 13 194 10.3390/ph13080194 32823992 PMC7466132

301. Liu Y.-J. Tang B. Wang F.-C. Tang L. Lei Y.-Y. Luo Y. Huang S.-J. Yang M. Wu L.-Y. Wang W. Parthenolide ameliorates colon inflammation through regulating Treg/Th17 balance in a gut microbiota-dependent manner Theranostics 2020 10 5225 10.7150/thno.43716 32373209 PMC7196297

302. Siddiqui N.A. Alam P. Alrehaily A.J. Alqahtani A.S. Akhtar A. Alhowiriny T.A. Almarfadi O.M. Mothana R.A. Optimization of ultrasound-assisted parthenolide extraction from Tarchonanthus camphoratus leaves using response surface methodology: HPTLC and cytotoxicity analysis Arab. J. Chem. 2021 14 103194 10.1016/j.arabjc.2021.103194

303. Sun L. Yuan W. Wen G. Yu B. Xu F. Gan X. Tang J. Zeng Q. Zhu L. Chen C. Parthenolide inhibits human lung cancer cell growth by modulating the IGF-1R/PI3K/Akt signaling pathway Oncol. Rep. 2020 44 1184 1193 10.3892/or.2020.7649 32705224

304. Bose S. Banerjee S. Mondal A. Chakraborty U. Pumarol J. Croley C.R. Bishayee A. Targeting the JAK/STAT signaling pathway using phytocompounds for cancer prevention and therapy Cells 2020 9 1451 10.3390/cells9061451 PMC7348822 32545187

305. Lu L. Feng Q. Su T. Cheng Y. Huang Z. Huang Q. Liu Z. Pharmacoepigenetics of Chinese Herbal Components in Cancer Pharmacoepigenetics Elsevier Amsterdam, The Netherlands 2019 859 869

306. Jafari N. Nazeri S. Enferadi S.T. Parthenolide reduces metastasis by inhibition of vimentin expression and induces apoptosis by suppression elongation factor α− 1 expression Phytomedicine 2018 41 67 73 10.1016/j.phymed.2018.01.022 29519321

307. Singh S. Singh T.G. Role of nuclear factor kappa B (NF-κB) signalling in neurodegenerative diseases: An mechanistic approach Curr. Neuropharmacol. 2020 18 918 935 10.2174/1570159X18666200207120949 32031074 PMC7709146

308. Zanelli M. Sanguedolce F. Zizzo M. Palicelli A. Bassi M.C. Santandrea G. Martino G. Soriano A. Caprera C. Corsi M. Primary effusion lymphoma occurring in the setting of transplanted patients: A systematic review of a rare, life-threatening post-transplantation occurrence BMC Cancer 2021 21 1 13 10.1186/s12885-021-08215-7 33906629 PMC8077837

309. Narkhede M. Arora S. Ujjani C. Primary effusion lymphoma: Current perspectives OncoTargets Ther. 2018 11 3747 10.2147/OTT.S167392 29988764 PMC6029609

310. Karam L. Abou Staiteieh S. Chaaban R. Hayar B. Ismail B. Neipel F. Darwiche N. Abou Merhi R. Anticancer activities of parthenolide in primary effusion lymphoma preclinical models Mol. Carcinog. 2021 60 567 581 10.1002/mc.23324 34101920

311. Moorthy R.K. Jayamohan S. Kannan M.K. Arockiam A.J.V. Parthenolide Induces Apoptosis and Cell Cycle Arrest by the Suppression of miR-375 Through Nucleolin in Prostate Cancer J. Pharm. Res. Int. 2021 215 227 10.9734/jpri/2021/v33i45A32736

312. Sun T. Liu Z. Yang Q. The role of ubiquitination and deubiquitination in cancer metabolism Mol. Cancer 2020 19 1 19 10.1186/s12943-020-01262-x 33004065 PMC7529510

313. Zhang S. Ju X. Yang Q. Zhu Y. Fan D. Su G. Kong L. Li Y. USP47 maintains the stemness of colorectal cancer cells and is inhibited by parthenolide Biochem. Biophys. Res. Commun. 2021 562 21 28 10.1016/j.bbrc.2021.05.017 34030041

314. Lin M. Bi H. Yan Y. Huang W. Zhang G. Zhang G. Tang S. Liu Y. Zhang L. Ma J. Parthenolide suppresses non-small cell lung cancer GLC-82 cells growth via B-Raf/MAPK/Erk pathway Oncotarget 2017 8 23436 10.18632/oncotarget.15584 28423582 PMC5410316

315. Liu D. Han Y. Liu L. Ren X. Zhang H. Fan S. Qin T. Li L. Parthenolide inhibits the tumor characteristics of renal cell carcinoma Int. J. Oncol. 2021 58 100 110 10.3892/ijo.2020.5148 33367934

316. Han Y. Yang J. Sun Y. Fan S. Lu Y. Li L. Parthenolide induces autophagy and apoptosis of breast cancer cells associated with the PI3K/AKT/mTOR pathway Res. Sq. 2021 preprint

317. Berdan C.A. Ho R. Lehtola H.S. To M. Hu X. Huffman T.R. Petri Y. Altobelli C.R. Demeulenaere S.G. Olzmann J.A. Parthenolide covalently targets and inhibits focal adhesion kinase in breast cancer cells Cell Chem. Biol. 2019 26 1027 1035.e22 10.1016/j.chembiol.2019.03.016 31080076 PMC6756182

318. Liu W. Wang X. Sun J. Yang Y. Li W. Song J. Parthenolide suppresses pancreatic cell growth by autophagy-mediated apoptosis OncoTargets Ther. 2017 10 453 10.2147/OTT.S117250 28176967 PMC5271392

319. Sufian H.B. Santos J.M. Khan Z.S. Munir M.T. Zahid M.K. Al-Harrasi A. Gollahon L.S. Hussain F. Rahman S.M. Parthenolide Inhibits Migration and Reverses the EMT Process in Breast Cancer Cells by Suppressing TGFβ and TWIST1 Res. Sq. 2021 preprint

320. Zhu S.M. Park Y.R. Seo S.Y. Kim I.H. Lee S.T. Kim S.W. Parthenolide inhibits transforming growth factor β1-induced epithelial-mesenchymal transition in colorectal cancer cells Intest. Res. 2019 17 527 10.5217/ir.2019.00031 31426622 PMC6821947

321. Che S.-T. Bie L. Li X. Qi H. Yu P. Zuo L. Parthenolide inhibits the proliferation and induces the apoptosis of human uveal melanoma cells Int. J. Ophthalmol. 2019 12 1531 10.18240/ijo.2019.10.03 31637187 PMC6796085

322. Liu M. Xiao C. Sun M. Tan M. Hu L. Yu Q. Parthenolide inhibits STAT3 signaling by covalently targeting janus kinases Molecules 2018 23 1478 10.3390/molecules23061478 29921758 PMC6100543

323. Jeyamohan S. Moorthy R.K. Kannan M.K. Arockiam A.J.V. Parthenolide induces apoptosis and autophagy through the suppression of PI3K/Akt signaling pathway in cervical cancer Biotechnol. Lett. 2016 38 1251 1260 10.1007/s10529-016-2102-7 27099069

324. Aziz N. Kim M.-Y. Cho J.Y. Anti-inflammatory effects of luteolin: A review of in vitro, in vivo, and in silico studies J. Ethnopharmacol. 2018 225 342 358 10.1016/j.jep.2018.05.019 29801717

325. Gendrisch F. Esser P.R. Schempp C.M. Wölfle U. Luteolin as a modulator of skin aging and inflammation Biofactors 2021 47 170 180 10.1002/biof.1699 33368702

326. Gupta G. Tiwari J. Dahiya R. Sharma R.K. Mishra A. Dua K. Recent updates on neuropharmacological effects of luteolin EXCLI J. 2018 17 211 214 29743859 10.17179/excli2018-1041 PMC5938528

327. Luo Y. Shang P. Li D. Luteolin: A flavonoid that has multiple cardio-protective effects and its molecular mechanisms Front. Pharmacol. 2017 8 692 10.3389/fphar.2017.00692 29056912 PMC5635727

328. Qian W. Liu M. Fu Y. Zhang J. Liu W. Li J. Li X. Li Y. Wang T. Antimicrobial mechanism of luteolin against Staphylococcus aureus and Listeria monocytogenes and its antibiofilm properties Microb. Pathog. 2020 142 104056 10.1016/j.micpath.2020.104056 32058023

329. Ahmadi S.M. Farhoosh R. Sharif A. Rezaie M. Structure-antioxidant activity relationships of luteolin and catechin J. Food Sci. 2020 85 298 305 10.1111/1750-3841.14994 31957877

330. Tian C. Liu X. Chang Y. Wang R. Lv T. Cui C. Liu M. Investigation of the anti-inflammatory and antioxidant activities of luteolin, kaempferol, apigenin and quercetin S. Afr. J. Bot. 2021 137 257 264 10.1016/j.sajb.2020.10.022

331. Ganai S.A. Sheikh F.A. Baba Z.A. Mir M.A. Mantoo M.A. Yatoo M.A. Anticancer activity of the plant flavonoid luteolin against preclinical models of various cancers and insights on different signalling mechanisms modulated Phytother. Res. 2021 35 3509 3532 10.1002/ptr.7044 33580629

332. Yan H. Wei P. Song J. Jia X. Zhang Z. Enhanced anticancer activity in vitro and in vivo of luteolin incorporated into long-circulating micelles based on DSPE-PEG2000 and TPGS J. Pharm. Pharmacol. 2016 68 1290 1298 10.1111/jphp.12598 27465923

333. Palko-Labuz A. Sroda-Pomianek K. Uryga A. Kostrzewa-Suslow E. Michalak K. Anticancer activity of baicalein and luteolin studied in colorectal adenocarcinoma LoVo cells and in drug-resistant LoVo/Dx cells Biomed. Pharmacother. 2017 88 232 241 10.1016/j.biopha.2017.01.053 28110189

334. Mishan M.A. Khazeei Tabari M.A. Mahrooz A. Bagheri A. Role of microRNAs in the anticancer effects of the flavonoid luteolin: A systematic review Eur. J. Cancer Prev. 2021 30 413 421 10.1097/CEJ.0000000000000645 33720053

335. Franco Y.E. de Lima C.A. Rosa M.N. Silva V.A. Reis R.M. Priolli D.G. Carvalho P.O. do Nascimento J.R. da Rocha C.Q. Longato G.B. Investigation of U-251 cell death triggered by flavonoid luteolin: Towards a better understanding on its anticancer property against glioblastomas Nat. Prod. Res. 2021 35 4807 4813 10.1080/14786419.2020.1727470 32081041

336. Wu H.-T. Liu Y.-E. Hsu K.-W. Wang Y.-F. Chan Y.-C. Chen Y. Chen D.-R. MLL3 induced by luteolin causes apoptosis in tamoxifen-resistant breast cancer cells through H3K4 monomethylation and suppression of the PI3K/AKT/mTOR pathway Am. J. Chin. Med. 2020 48 1221 1241 10.1142/S0192415X20500603 32668964

337. Yang P.-W. Lu Z.-Y. Pan Q. Chen T.-T. Feng X.-J. Wang S.-M. Pan Y.-C. Zhu M.-H. Zhang S.-H. MicroRNA-6809-5p mediates luteolin-induced anticancer effects against hepatoma by targeting flotillin 1 Phytomedicine 2019 57 18 29 10.1016/j.phymed.2018.10.027 30668319

338. Khodayari N. Oshins R. Holliday L.S. Clark V. Xiao Q. Marek G. Mehrad B. Brantly M. Alpha-1 antitrypsin deficient individuals have circulating extracellular vesicles with profibrogenic cargo Cell Commun. Signal. 2020 18 1 18 10.1186/s12964-020-00648-0 32887613 PMC7487708

339. Cao Z. Zhang H. Cai X. Fang W. Chai D. Wen Y. Chen H. Chu F. Zhang Y. Luteolin promotes cell apoptosis by inducing autophagy in hepatocellular carcinoma Cell. Physiol. Biochem. 2017 43 1803 1812 10.1159/000484066 29049999

340. Zhang Q. Yang J. Wang J. Modulatory effect of luteolin on redox homeostasis and inflammatory cytokines in a mouse model of liver cancer Oncol. Lett. 2016 12 4767 4772 10.3892/ol.2016.5291 28101223 PMC5228171

341. You Y. Wang R. Shao N. Zhi F. Yang Y. Luteolin suppresses tumor proliferation through inducing apoptosis and autophagy via MAPK activation in glioma OncoTargets Ther. 2019 12 2383 10.2147/OTT.S191158 PMC6445239 30992674

342. Imran M. Rauf A. Abu-Izneid T. Nadeem M. Shariati M.A. Khan I.A. Imran A. Orhan I.E. Rizwan M. Atif M. Luteolin, a flavonoid, as an anticancer agent: A review Biomed. Pharmacother. 2019 112 108612 10.1016/j.biopha.2019.108612 30798142

343. Potočnjak I. Šimić L. Gobin I. Vukelić I. Domitrović R. Antitumor activity of luteolin in human colon cancer SW620 cells is mediated by the ERK/FOXO3a signaling pathway Toxicol. Vitr. 2020 66 104852 10.1016/j.tiv.2020.104852 32268164

344. Yoo H.S. Won S.B. Kwon Y.H. Luteolin induces apoptosis and autophagy in HCT116 colon cancer cells via p53-dependent pathway Nutr. Cancer 2021 74 677 686 10.1080/01635581.2021.1903947 33757400

345. Huang L. Jin K. Lan H. Luteolin inhibits cell cycle progression and induces apoptosis of breast cancer cells through downregulation of human telomerase reverse transcriptase Oncol. Lett. 2019 17 3842 3850 10.3892/ol.2019.10052 30930986 PMC6425390

346. Xiang C. Wu X. Zhao Z. Feng X. Bai X. Liu X. Zhao J. Takeda S. Qing Y. Nonhomologous end joining and homologous recombination involved in luteolin-induced DNA damage in DT40 cells Toxicol. Vitr. 2020 65 104825 10.1016/j.tiv.2020.104825 32169435

347. Jiang Z.-B. Wang W.-J. Xu C. Xie Y.-J. Wang X.-R. Zhang Y.-Z. Huang J.-M. Huang M. Xie C. Liu P. Luteolin and its derivative apigenin suppress the inducible PD-L1 expression to improve anti-tumor immunity in KRAS-mutant lung cancer Cancer Lett. 2021 515 36 48 10.1016/j.canlet.2021.05.019 34052328

348. Lee Y.J. Lim T. Han M.S. Lee S.-H. Baek S.H. Nan H.-Y. Lee C. Anticancer effect of luteolin is mediated by downregulation of TAM receptor tyrosine kinases, but not interleukin-8, in non-small cell lung cancer cells Oncol. Rep. 2017 37 1219 1226 10.3892/or.2016.5336 28035396

349. Pu Y. Zhang T. Wang J. Mao Z. Duan B. Long Y. Xue F. Liu D. Liu S. Gao Z. Luteolin exerts an anticancer effect on gastric cancer cells through multiple signaling pathways and regulating miRNAs J. Cancer 2018 9 3669 10.7150/jca.27183 30405835 PMC6215998

350. Seo Y. Ryu K. Park J. Jeon D.-k. Jo S. Lee H.K. Namkung W. Inhibition of ANO1 by luteolin and its cytotoxicity in human prostate cancer PC-3 cells PLoS ONE 2017 12 e0174935 10.1371/journal.pone.0174935 28362855 PMC5376326

351. Song Y. Gao J. Guan L. Chen X. Gao J. Wang K. Inhibition of ANO1/TMEM16A induces apoptosis in human prostate carcinoma cells by activating TNF-α signaling Cell Death Dis. 2018 9 1 14 10.1038/s41419-018-0735-2 29899325 PMC5999606

352. Chen K.-C. Hsu W.-H. Ho J.-Y. Lin C.-W. Chu C.-Y. Kandaswami C.C. Lee M.-T. Cheng C.-H. Flavonoids Luteolin and Quercetin Inhibit RPS19 and contributes to metastasis of cancer cells through c-Myc reduction J. Food Drug Anal. 2018 26 1180 1191 10.1016/j.jfda.2018.01.012 29976410 PMC9303038

353. Liu Q. Hodge J. Wang J. Wang Y. Wang L. Singh U.P. Li Y. Yao Y. Wang D. Ai W. Emodin reduces breast cancer lung metastasis by suppressing macrophage-induced breast cancer cell epithelial-mesenchymal transition and cancer stem cell formation Theranostics 2020 10 8365 10.7150/thno.45395 32724475 PMC7381725

354. Belcaro G. Hosoi M. Pellegrini L. Appendino G. Ippolito E. Ricci A. Ledda A. Dugall M. Cesarone M.R. Maione C. A controlled study of a lecithinized delivery system of curcumin (Meriva®) to alleviate the adverse effects of cancer treatment Phytother. Res. 2014 28 444 450 10.1002/ptr.5014 23775598

355. Shehzad A. Wahid F. Lee Y.S. Curcumin in cancer chemoprevention: Molecular targets, pharmacokinetics, bioavailability, and clinical trials Arch. Der. Pharm. 2010 343 489 499 10.1002/ardp.200900319 20726007

356. Johnson J.J. Mukhtar H. Curcumin for chemoprevention of colon cancer Cancer Lett. 2007 255 170 181 10.1016/j.canlet.2007.03.005 17448598

357. Ledda A. Belcaro G. Dugall M. Luzzi R. Scoccianti M. Togni S. Appendino G. Ciammaichella G. Meriva®, a lecithinized curcumin delivery system, in the control of benign prostatic hyperplasia: A pilot, product evaluation registry study Panminerva Med. 2012 54 17 23241931

358. Bayet-Robert M. Kwiatowski F. Leheurteur M. Gachon F. Planchat E. Abrial C. Mouret-Reynier M.-A. Durando X. Barthomeuf C. Chollet P. Phase I dose escalation trial of docetaxel plus curcumin in patients with advanced and metastatic breast cancer Cancer Biol. Ther. 2010 9 8 14 10.4161/cbt.9.1.10392 19901561

359. Cruz–Correa M. Shoskes D.A. Sanchez P. Zhao R. Hylind L.M. Wexner S.D. Giardiello F.M. Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis Clin. Gastroenterol. Hepatol. 2006 4 1035 1038 10.1016/j.cgh.2006.03.020 16757216

360. Dhillon N. Aggarwal B.B. Newman R.A. Wolff R.A. Kunnumakkara A.B. Abbruzzese J.L. Ng C.S. Badmaev V. Kurzrock R. Phase II trial of curcumin in patients with advanced pancreatic cancer Clin. Cancer Res. 2008 14 4491 4499 10.1158/1078-0432.CCR-08-0024 18628464

361. Saghatelyan T. Tananyan A. Janoyan N. Tadevosyan A. Petrosyan H. Hovhannisyan A. Hayrapetyan L. Arustamyan M. Arnhold J. Rotmann A.-R. Efficacy and safety of curcumin in combination with paclitaxel in patients with advanced, metastatic breast cancer: A comparative, randomized, double-blind, placebo-controlled clinical trial Phytomedicine 2020 70 153218 10.1016/j.phymed.2020.153218 32335356

362. Bachmeier B.E. Blaheta R. Curcumin 3.0—Therapeutic and Diagnostic Potential in Cancer and Beyond Int. J. Mol. Sci. 2022 23 5398 10.3390/ijms23105398 35628207 PMC9140690

363. Thambamroong T. Seetalarom K. Saichaemchan S. Pumsutas Y. Prasongsook N. Efficacy of Curcumin on Treating Cancer Anorexia-Cachexia Syndrome in Locally or Advanced Head and Neck Cancer: A Double-Blind, Placebo-Controlled Randomised Phase IIa Trial (CurChexia) J. Nutr. Metab. 2022 2022 5425619 10.1155/2022/5425619 35694030 PMC9184232

364. Singh A.P. Singh R. Verma S.S. Rai V. Kaschula C.H. Maiti P. Gupta S.C. Health benefits of resveratrol: Evidence from clinical studies Med. Res. Rev. 2019 39 1851 1891 10.1002/med.21565 30741437

365. Brown V.A. Patel K.R. Viskaduraki M. Crowell J.A. Perloff M. Booth T.D. Vasilinin G. Sen A. Schinas A.M. Piccirilli G. Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: Safety, pharmacokinetics, and effect on the insulin-like growth factor axis Cancer Res. 2010 70 9003 9011 10.1158/0008-5472.CAN-10-2364 20935227 PMC2982884

366. Zhu W. Qin W. Zhang K. Rottinghaus G.E. Chen Y.-C. Kliethermes B. Sauter E.R. Trans-resveratrol alters mammary promoter hypermethylation in women at increased risk for breast cancer Nutr. Cancer 2012 64 393 400 10.1080/01635581.2012.654926 22332908 PMC3392022

367. Nguyen A.V. Martinez M. Stamos M.J. Moyer M.P. Planutis K. Hope C. Holcombe R.F. Results of a phase I pilot clinical trial examining the effect of plant-derived resveratrol and grape powder on Wnt pathway target gene expression in colonic mucosa and colon cancer Cancer Manag. Res. 2009 1 25 21188121 PMC3004662

368. Shen W.-W. Zeng Z. Zhu W.-X. Fu G.-H. MiR-142-3p functions as a tumor suppressor by targeting CD133, ABCG2, and Lgr5 in colon cancer cells J. Mol. Med. 2013 91 989 1000 10.1007/s00109-013-1037-x 23619912

369. Howells L.M. Berry D.P. Elliott P.J. Jacobson E.W. Hoffmann E. Hegarty B. Brown K. Steward W. Gescher A.J. Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases—safety, pharmacokinetics, and pharmacodynamics Cancer Prev. Res. 2011 4 1419 1425 10.1158/1940-6207.CAPR-11-0148 PMC3173869 21680702

370. Moutabian H. Majdaeen M. Ghahramani-Asl R. Yadollahi M. Gharepapagh E. Ataei G. Falahatpour Z. Bagheri H. Farhood B. A systematic review of the therapeutic effects of resveratrol in combination with 5-fluorouracil during colorectal cancer treatment: With a special focus on the oxidant, apoptotic, and anti-inflammatory activities Cancer Cell Int. 2022 22 1 14 10.1186/s12935-022-02561-7 35366874 PMC8976963

371. Jurczyk M. Kasperczyk J. Wrześniok D. Beberok A. Jelonek K. Nanoparticles Loaded with Docetaxel and Resveratrol as an Advanced Tool for Cancer Therapy Biomedicines 2022 10 1187 10.3390/biomedicines10051187 35625921 PMC9138983

372. Ferry D.R. Smith A. Malkhandi J. Fyfe D.W. deTakats P.G. Anderson D. Baker J. Kerr D.J. Phase I clinical trial of the flavonoid quercetin: Pharmacokinetics and evidence for in vivo tyrosine kinase inhibition Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 1996 2 659 668 9816216

373. Sun C.-L. Yuan J.-M. Lee M.-J. Yang C.S. Gao Y.-T. Ross R.K. Yu M.C. Urinary tea polyphenols in relation to gastric and esophageal cancers: A prospective study of men in Shanghai, China Carcinogenesis 2002 23 1497 1503 10.1093/carcin/23.9.1497 12189193

374. Ren J. Freedman N. Kamangar F. Dawsey S. Hollenbeck A. Schatzkin A. Abnet C. Tea, coffee, carbonated soft drinks and upper gastrointestinal tract cancer risk in a large United States prospective cohort study Eur. J. Cancer 2010 46 1873 1881 10.1016/j.ejca.2010.03.025 20395127 PMC2891563

375. Li N. Sun Z. Han C. Chen J. The chemopreventive effects of tea on human oral precancerous mucosa lesions Proc. Soc. Exp. Biol. Med. 1999 220 218 224 10202392 10.1046/j.1525-1373.1999.d01-37.x

376. Inoue M. Sasazuki S. Wakai K. Suzuki T. Matsuo K. Shimazu T. Tsuji I. Tanaka K. Mizoue T. Nagata C. Green tea consumption and gastric cancer in Japanese: A pooled analysis of six cohort studies Gut 2009 58 1323 1332 10.1136/gut.2008.166710 19505880

377. Lee K.J. Inoue M. Otani T. Iwasaki M. Sasazuki S. Tsugane S. Group J.S. Coffee consumption and risk of colorectal cancer in a population-based prospective cohort of Japanese men and women Int. J. Cancer 2007 121 1312 1318 10.1002/ijc.22778 17450527

378. Zhang G. Wang Y. Zhang Y. Wan X. Li J. Liu K. Wang F. Liu Q. Yang C. Yu P. Anti-cancer activities of tea epigallocatechin-3-gallate in breast cancer patients under radiotherapy Curr. Mol. Med. 2012 12 163 176 10.2174/156652412798889063 22280355 PMC3305796

379. Ogunleye A.A. Xue F. Michels K.B. Green tea consumption and breast cancer risk or recurrence: A meta-analysis Breast Cancer Res. Treat. 2010 119 477 484 10.1007/s10549-009-0415-0 19437116

380. Jatoi A. Ellison N. Burch P.A. Sloan J.A. Dakhil S.R. Novotny P. Tan W. Fitch T.R. Rowland K.M. Young C.Y. A phase II trial of green tea in the treatment of patients with androgen independent metastatic prostate carcinoma Cancer Interdiscip. Int. J. Am. Cancer Soc. 2003 97 1442 1446 10.1002/cncr.11200 12627508

381. Choan E. Segal R. Jonker D. Malone S. Reaume N. Eapen L. Gallant V. A prospective clinical trial of green tea for hormone refractory prostate cancer: An evaluation of the complementary/alternative therapy approach Urologic Oncology: Seminars and Original Investigations Elsevier Amsterdam, The Netherlands 2005 108 113 10.1016/j.urolonc.2004.10.008 15869995

382. McGlynn K.A. Petrick J.L. El-Serag H.B. Epidemiology of hepatocellular carcinoma Hepatology 2021 73 4 13 10.1002/hep.31288 PMC7577946 32319693

383. Ji B.T. Chow W.H. Hsing A.W. McLaughlin J.K. Dai Q. Gao Y.T. Blot W.J. Fraumeni Jr J.F. Green tea consumption and the risk of pancreatic and colorectal cancers Int. J. Cancer 1997 70 255 258 10.1002/(SICI)1097-0215(19970127)70:3<255::AID-IJC1>3.0.CO;2-W 9033623

384. Alam M. Ali S. Ashraf G.M. Bilgrami A.L. Yadav D.K. Hassan M.I. Epigallocatechin 3-gallate: From green tea to cancer therapeutics Food Chem. 2022 132135 10.1016/j.foodchem.2022.132135 35063850

385. Tang N. Wu Y. Zhou B. Wang B. Yu R. Green tea, black tea consumption and risk of lung cancer: A meta-analysis Lung Cancer 2009 65 274 283 10.1016/j.lungcan.2008.12.002 19128856

386. Tanaka S. Haruma K. Kunihiro M. Nagata S. Kitadai Y. Manabe N. Sumii M. Yoshihara M. Kajiyama G. Chayama K. Effects of aged garlic extract (AGE) on colorectal adenomas: A double-blinded study Hiroshima J. Med. Sci. 2004 53 39 45 15726891

387. Miraghajani M. Rafie N. Hajianfar H. Larijani B. Azadbakht L. Aged garlic and cancer: A systematic review Int. J. Prev. Med. 2018 9 84 30487964 10.4103/ijpvm.IJPVM_437_17 PMC6212616

388. Tanaka S. Haruma K. Yoshihara M. Kajiyama G. Kira K. Amagase H. Chayama K. Aged garlic extract has potential suppressive effect on colorectal adenomas in humans J. Nutr. 2006 136 821S 826S 10.1093/jn/136.3.821S 16484573

389. Ishikawa H. Saeki T. Otani T. Suzuki T. Shimozuma K. Nishino H. Fukuda S. Morimoto K. Aged garlic extract prevents a decline of NK cell number and activity in patients with advanced cancer J. Nutr. 2006 136 816S 820S 10.1093/jn/136.3.816S 16484572

390. Li H. Li H.-Q. Wang Y. Xu H.-X. Fan W.-T. Wang M.-L. Sun P.-H. Xie X.-Y. An intervention study to prevent gastric cancer by micro-selenium and large dose of allitridum Chin. Med. J. 2004 117 1155 1160 15361287

391. Zhou Y. Zhuang W. Hu W. Liu G.J. Wu T.X. Wu X.T. Consumption of large amounts of Allium vegetables reduces risk for gastric cancer in a meta-analysis Gastroenterology 2011 141 80 89 10.1053/j.gastro.2011.03.057 21473867

392. Nicastro H.L. Ross S.A. Milner J.A. Garlic and Onions: Their Cancer Prevention PropertiesGarlic and Onions: Their Cancer Prevention Properties Cancer Prev. Res. 2015 8 181 189 10.1158/1940-6207.CAPR-14-0172 PMC4366009 25586902

393. Chen Y.-K. Lee C.-H. Wu I.-C. Liu J.-S. Wu D.-C. Lee J.-M. Goan Y.-G. Chou S.-H. Huang C.-T. Lee C.-Y. Food intake and the occurrence of squamous cell carcinoma in different sections of the esophagus in Taiwanese men Nutrition 2009 25 753 761 10.1016/j.nut.2009.02.002 19394796

394. Hsing A.W. Chokkalingam A.P. Gao Y.-T. Madigan M.P. Deng J. Gridley G. Fraumeni Jr J.F. Allium vegetables and risk of prostate cancer: A population-based study J. Natl. Cancer Inst. 2002 94 1648 1651 10.1093/jnci/94.21.1648 12419792

395. Chen M. Rao Y. Zheng Y. Wei S. Li Y. Guo T. Yin P. Association between soy isoflavone intake and breast cancer risk for pre-and post-menopausal women: A meta-analysis of epidemiological studies PLoS ONE 2014 9 e89288 24586662 10.1371/journal.pone.0089288 PMC3930722

396. Trock B.J. Hilakivi-Clarke L. Clarke R. Meta-analysis of soy intake and breast cancer risk J. Natl. Cancer Inst. 2006 98 459 471 10.1093/jnci/djj102 16595782

397. Jiang Y. Gong P. Madak-Erdogan Z. Martin T. Jeyakumar M. Carlson K. Khan I. Smillie T.J. Chittiboyina A.G. Rotte S.C. Mechanisms enforcing the estrogen receptor β selectivity of botanical estrogens FASEB J. 2013 27 4406 4418 10.1096/fj.13-234617 23882126 PMC3804744

398. Lazarevic B. Boezelijn G. Diep L.M. Kvernrod K. Ogren O. Ramberg H. Moen A. Wessel N. Berg R.E. Egge-Jacobsen W. Efficacy and safety of short-term genistein intervention in patients with localized prostate cancer prior to radical prostatectomy: A randomized, placebo-controlled, double-blind Phase 2 clinical trial Nutr. Cancer 2011 63 889 898 10.1080/01635581.2011.582221 21714686