INTRODUCTION
Reactive Oxygen Species
Reactive Oxygen Species (ROS) are chemically reactive species containing diatomic oxygen, including peroxides, superoxide, hydroxyl radicals, and singlet oxygen. 1 ROS is an over-arching term for derivatives of molecular oxygen that were originally thought to be purely by-products of metabolic activities, such as aerobic respiration, in cells. ROS can include radicals, molecules with an unpaired electron, such as superoxide and hydroxyl radicals, or non-radical molecules, like hydrogen peroxide and hypochlorite. ROS are thought to be tumor-suppressing agents since they are produced as a result of the administration of most chemotherapeutic drugs to activate cell death. However, in some cases they exert pro-tumorigenic functions. 2 – 4 ROS are generated at the plasma membrane level by nicotinamide adenine dinucleotide phosphate (NADPH) or at the mitochondrial level by nicotinamide adenine dinucleotide (NAD) dependent reactions. The evaluation of molecular interactions between certain ROS molecules and particular targets in redox signaling pathways is the focus of research, as their manipulation can result in a wide range of physiological effects. As a result, significant progress has been made in our understanding of how these oxidants affect physiology and disease, including the neurological, cardiovascular, and immunological systems, skeletal muscle, metabolism, aging, and cancer. 5 Using drugs to simply increase or decrease ROS levels has had mediocre results. More targeted approaches were developed, and ROS-modulating drugs are being investigated in many diseases, including cancer.
Generation of ROS
ROS levels are maintained in a healthy cell via various detoxifying processes controlled by antioxidant enzymes. As a result, ROS homeostasis is successfully regulated which helps maintain the redox balance in healthy cells. Numerous endogenous and exogenous biological functions produce ROS, which lead to over- or under-production in response to various stimuli, and result in cellular responses ranging from normal signaling mechanisms to cell death and DNA damage ( Figure 1 ). At the mitochondrial level, specifically the inner mitochondrial membrane, where most ROS are generated during oxidative phosphorylation, there are three major complexes that result in the bulk of ROS production. Complex I (CI) of the electron transport chain (ETC) generates ROS during electron transfer from NADH to Coenzyme Q (CoQ), while CII produces ROS through potential electron leakage. CIII can result in ROS through leaking of a single electron that moves freely through CIII, resulting in non-enzymatic ROS production. 6
Due to the action of multiple antioxidant systems, which regulate ROS generation by altering metabolic and signaling pathways, normal cells can maintain oxidative equilibrium. 3 Antioxidant defense mechanisms encourage cell death when ROS levels are continually elevated. 7 However, oxidative stress causes harm to numerous molecules and cell structures, resulting in the emergence of pathological conditions like inflammation, aging, cancer, and neurological diseases. Further, ROS are strongly associated with carcinogenesis. To understand the mechanisms of tumor initiation and progression, as well as the development of treatments, it is crucial to summarize the most recent evidence on ROS biology.
Antioxidant Defense and Redox Homeostasis
Oxidative stress is generated when there is an imbalance between the production and elimination of ROS. As mentioned, low levels of ROS promote signal transduction to help the cancer cells proliferate, differentiate, migrate, and invade. 8 – 10 At high levels, however, ROS induces lipid peroxidation, DNA and RNA damage, protein backbone damage, and alteration of enzyme activity. 11 As such, it is vital for cell survival to prevent accumulation of ROS and maintain redox homeostasis. Various mechanisms, including hypoxia, metabolic defects, ER stress, and oncogenes affect basal levels of ROS. 5 Fortunately, there are several mechanisms by which cells deploy endogenous and exogenous antioxidants or free radical scavengers. 12
Within many cells, activation of the transcription factor, nuclear factor erythroid 2-related factor 2 (NRF2), plays a pivotal role in regulating antioxidant functions. 3 , 7 , 13 Under resting conditions, NRF2 is bound to and constitutively degraded by Kelch-like ECH-associated protein 1 (KEAP1)-Cullin 3 (CUL2) E3 ligase complex. However, when cells experience oxidative stress, NRF2 dissociates from KEAP1 and translocates to the nucleus. In the nucleus, NRF2 binds to and activates the antioxidant response element (ARE) in various antioxidant target genes. 4 , 14 , 15 AREs are enhancer sequences found in the promoter region of genes encoding for various antioxidant enzymes. These antioxidants include superoxide dismutases (SODs), catalase (CAT), glutathione reductase, glutathione peroxidases (GPx), UDP-glycosyltransferases (UGTs), NADPH quinone oxidoreductase 1 (NQO1), heme oxygenase (HMOX1), peroxiredoxins (PRx), thioredoxin (TRx), and thioredoxin reductase (TRxR). 16 , 17 SODs provide the first line of defense against free radicals through the conversion of O 2 − to H 2 O 2 . The H 2 O 2 is neutralized to yield water and O 2 by CAT. Non-enzymatic molecules play a key role in ROS maintenance including glutathione, flavonoids, and vitamins C and E. Overall, the antioxidant defense of tumor cells play a major role in their ability to survive, as there is a delicate balance between the production and neutralization of ROS.
CANCER and ROS
Cancer is a disease in which the body’s cells divide uncontrollably and spread throughout the body. Cancer remains one of the leading causes of death globally, second only to cardiovascular disease. Approximately 1,958,310 new cases and 609,829 deaths are projected to occur in the United States in 2023. 18 Numerous research studies and trials are conducted to better understand and develop new treatment for this deadly disease.
For decades, the activation of oncogenes and inactivation of tumor suppressor genes were thought to be the main cause of cancer development and progression− a phenomenon known as the ‘oncogene addiction’. 19 However, recent studies emphasized the importance of the metabolic changes that cancer cells undergo, as these changes help to evade normal cellular limitations and aid in cancer cell proliferation. 20 Most notable is the increase in aerobic glycolysis, known as the Warburg effect. Cancer cells typically exhibit higher metabolic rates than normal cells, and the amount of ROS production is increased as a result. 7 This increase in ROS is countered by the cells’ ability to upregulate their antioxidant mechanisms. 3 There is a delicate balance between the production and neutralization of ROS, resulting in a paradoxical effect on cancer cells. Previous research showed that at moderate to low levels, ROS promoted signal transduction to help the cancer cells proliferation, differentiation, migration, and invasion. 8 , 10 , 19 At high levels, however, ROS is detrimental to cancer cells survival due to DNA, lipid, and protein damage. Increased levels of ROS induced apoptosis in multiple myeloma and colorectal cancer cells in previous studies. 21 , 22 Therefore, inducing a high concentration of ROS in cancer cells provides a potential strategy for cancer therapy.
In the early stages of cancer, ROS has pro-oncogenic actions, and antioxidant levels are decreased. Increased ROS production due to elevated metabolic function leads to constitutive activation of various signaling pathways. PI3K/Akt/mTOR mediated survival signaling is commonly seen upon increases of ROS in cancer cells and results in tumor growth and progression. 23 , 24 ROS also contributes to tumor progression through action against proteins such as PTEN and PTP1B to downregulate apoptosis and inhibit anti-growth signaling. 25 , 26 However, high levels of ROS present in cancer cells is harmful to tumor progression and tumor cell viability. Abnormal levels of antioxidative enzymes are often found among cancer patients along with elevated levels of ROS and increased oxidative stress. 12 , 27 Lowering the amounts of ROS within cells through antioxidants is used to prevent the proliferation of cancer cells from occurring. 28 However, raising intracellular levels of ROS leaves cells with lower defenses and increases the chances of death caused by oxidative stress. Increasing levels of ROS may potentially result in cell death for cancer cells while saving normal cells. However, increasing ROS levels could lead to elevated mutational burden in cancer cells, warranting pro-tumorigenic effects. 28
ROS and CANCER THERAPY
The sliding scale of ROS involvement in cancer makes ROS an interesting target of cancer therapies. New research suggested that instead of solely targeting oncogenes or tumor suppressor genes, the strengthened immune surveillance, aneuploidy, and increased metabolism in cancer cells that ensure survival should also be targeted. Manipulation of ROS pathways is a potential step to provide effective forms of cancer therapy. 29 , 30
In the early stages of cancer, it is beneficial to maintain low ROS levels to reduce the survival of tumor-initiating cells (TICs) due to TICs’ ability to survive in high levels of ROS through an upregulation of antioxidant levels. 31 If high levels of ROS are present in the early stages of tumor development, then pre-neoplastic cells develop strong antioxidant mechanisms, allowing for the development of drug-resistant tumor cells. 30 Targeting these antioxidant mechanisms allow for cancer cell-specific therapies.
Oncogenes and tumor suppressor genes heavily impact the initiation and progression of tumorigenesis. Studies showed that oncogenes affect NRF2 regulation, and FOXO transcription factors enhanced oncogenic functions due to oncogenic factors like b-catenin. 5 Tumor suppressors were found to activate or suppress antioxidant gene expression. 5 For example, BRCA1 is a required regulator of NRF2 if an efficient antioxidant response is to be produced. But, ataxia telangiectasia mutate (ATM), another tumor suppressor gene that regulates ROS levels, is found to cause bone marrow failure in mice. 5 PKM2 functions as an oncogene and plays a significant role when ROS levels are high, leading to increased NADPH synthesis, allowing for solid tumors to detach from their matrix. 5 , 32
ROS scavengers present a potential anticancer therapeutic strategy. Numerous studies have been conducted in which antioxidants, often Vitamin E, C, and selenium were implemented and found to have positive results, such as reduced mortality rates. Another potential anti-cancer therapy focuses on increasing ROS by using drugs that target two of the three major antioxidant pathways. Currently, chemotherapy induces oxidative stress leading to cell death from potential excessive ROS levels in cancer cells. Platinum conjugated complexes and anthracy-clines are also used to produce excess levels of ROS. 5 Arsenic trioxide and 2-methoxyestradiol showed positive results against different cancers through increased levels of ROS. 33 , 34 Another effective method for killing cancer cells is using an agent that increases oxidative stress and inhibits HSP90. Inhibiting the enzyme poly (ADP-ribose) polymerase (PARP) is effective in treating breast cancer, and ionizing radiation is found to dramatically increase ROS levels, especially through the activation of NADPH oxidase via radiation exposure. 5 Taking advantage of multiple aspects of ROS manipulation in cancer therapy has led to multiple treatments, including a variety that were successful in a clinical trial setting ( Table 1 ).
ROS Therapy Clinical Trials
Vitamin C or ascorbic acid was involved in various clinical trials; however, the ongoing clinical trial NCT03418038 is observing deeper exploratory effects. Aside from safety and response rates, TET2MT allele, DNA methylation, and plasma cytokine activity are also being studied. Mangafodipir is a traditional MRI contrast agent, however it exhibits antioxidant properties through manganese superoxide dismutase mimetic activity. 35 Clinical trial NCT00727922 aimed to show Mangafodipir’s neuroprotective properties in cancer patients who underwent oxaliplatin treatment. Mangafodipir showed significant results with 77% of patients treated with both oxaliplatin and Mangafodipir exhibiting improved or stabilized neuropathy. 36 A study that aimed to show the relationship between resectable colon cancer patients and Niclosamide treatment ( NCT02687009 ) was opened for recruitment in 2016. The phase 1 study was canceled due to low recruitment, however recent evidence suggests Niclosamide, an effective Wnt signaling pathway regulator, as a candidate for colon cancer management as Wnt signaling is heavily upregulated in most patients. 37 , 38 Besides its’ antioxidant properties, Quercetin exhibited the ability to regulate various cancer signaling pathways including PI3K/Akt/mTOR, MAPK/ERK, and Wnt signaling showing anti-metastatic, anti-angiogenic, and anti-proliferative potential. 39 Quercetin is part of clinical trial NCT04733534 , an ongoing study aimed at improving the quality of life in adult survivors of childhood cancers. Improvement of frailty and markers observing senescence, inflammation, bone resorption, insulin resistance, and cognitive function are under study. Dimethyl Fumarate was studied in concert with Temozolomide and radiation therapy for patients with glioblastoma multiforme in clinical trial NCT02337426 . A maximum tolerated dose was recommended at 240 mg three times daily, and patients saw varying degrees of progression-free survival with a median of 8.7 months and a median survival rate of 13.8 months was noted. 40 Clinical trial NCT04566328 observed Bortezomib in combination with dexamethasone, daratumumab, and lenalidomide for patients with multiple myeloma. The study is still recruiting, and primary endpoints include overall survival with secondary endpoints aimed at adverse events, including neurotoxicity, recovery rate, and non-hematologic adverse events. Arsenic Trioxide is an interesting anti-cancer candidate that was tested with a variety of cancers for its ability to affect cancer stem-like cells, induce cell cycle arrest and apoptosis, chemo-sensitize, and decrease angiogenic potential. 41 Many clinical trials involving arsenic trioxide were undertaken, one recruiting trial ( NCT04897490 ) evaluates first line arsenic trioxide and all trans retinoic acid treatment for patients with acute promyelocytic leukemia. Primary outcomes include evaluation of overall survival and event free survival with secondary measures observing molecular remission rate, toxicity, and FLT3 as a prognostic marker. Curcumin (Cur) is involved in a plethora of clinical trials ( Table 1 ) touching on a wide range of cancers. Taking advantage of Cur’s innate antioxidant and anticancer abilities clinical trials are observing improvements in recurrence-free survival in pancreatic cancer ( NCT02064673 ), safety and tolerability in metastatic treatment-resistant colorectal cancer ( NCT01490996 ), tumor-induced inflammation reduction in endometrial carcinoma ( NCT02017353 ), and efficacy and bioavailability in glioblastoma ( NCT01712542 ). 41 The mechanisms by which Cur affects this array of systems and cancers are discussed in detail below.
CURCUMIN in CANCER THERAPY
Phytochemicals are plant metabolites that possess innate antioxidant properties. Plant by-products offer a unique approach to cancer therapeutics, and multiple drugs like vincristine and paclitaxel are already used in various cancers. 42 There is a high demand for medicines from plant origins; most have relatively low toxicity levels toward normal cells and offer safer alternatives over traditional chemically derived drugs. 43
Cur is a phytochemical derived from Curcuma longa . A commonly used spice originating from Asia, Cur received attention as an anti-cancer therapy. Cur has a history of use in medicines in Asian countries where it was used as an anti-inflammatory and anti-dysenteric, and has recently shown antioxidant properties in the context of various disease instances. 44 , 45 Cur has become a popular drug for cancer therapy over the last few decades and multiple analogs have arisen based on Cur structure. Mechanistically, Cur has shown the ability to regulate a plethora of molecular targets lending to its anti-cancer properties ( Figure 2 ). The transcription factor NF-kB is one of the longest known targets of Cur and its suppression in a variety of cancers including leukemia and melanoma. 46 , 47 NF-Kβ suppression from Cur interaction led to the identification of Cur’s immunomodulatory effects on various cytokines and immune related proteins such as IL-6, TNF-α, and PD-L1 and is suggested as a potential adjuvant treatment for immunotherapy. 48 – 50 Regulation of several signaling pathways is evidence of the wide range of effects by Cur. PI3K/Akt, MAPK, and JAK/STAT regulation were noted in a variety of cancers with a long list of downstream target modulation occurring as a result of upstream Cur interference. 51
The ROS interacting effects of Cur and its analogs were realized as important mechanisms in their ability to combat cancers. At a mechanistic level, multiple explanations are given for Cur and its capacity to perform ROS modulation. Both the keto-enol and phenolic group of Cur are thought to be the site responsible for radical scavenging, and other groups have suggested that hydrogen cleavage is the preferred ROS interaction mechanism of Cur. 52 In clinical trials, Cur is shown to increase total antioxidant capacity (TAC) and decrease malondialdehyde. 53 It also affects energy metabolism and increases overall ROS accumulation in SiHa cervical cancer cells resulting in increased autophagy and G2/M phase cell cycle arrest. 54 Cur targets multiple enzymes in ROS metabolic pathways. In leukemic cells, Cur showed an inhibition of CBR1/3, NQO1/2, PRDX1, and ADH1A some of which were also upregulated in patient leukemia samples. 55 Through induction of ROS in colorectal cancer cell lines Cur was able to activate KEAP1/NRF2/ARE pathways and serve as an effective therapeutic especially in combination with 5-FU. 56 Cur is an option for resensitization of chemo-resistant cancer cells. Against drug resistant MCF7/TH, A549/ADR, and HCT116R Cur modulated oxidative stress and increased apoptosis through multiple mechanisms including increases in SOD and CAT and an upregulation of SIRT1. 57
Cur has the ability to overcome carboplatin resistance in triple negative breast cancer cell lines. Recently, Cur demonstrated its ability to overcome carboplatin resistance through increased ROS production leading to downregulation of RAD51 and an upregulation of γ H2AX. 58 Wu et al. demonstrated that Cur had a similar result against chemo-resistant lung cancer cells. There was a drastic increase in apoptosis of A549/D16 cells due to ROS guided p38 MAPK phosphorylation. 59 This affect was exaggerated when used in combination with Docetaxel and Vincristine with little toxicity arising upon the Cur addition, suggesting that Cur has a role in enhancing chemotherapeutic effectiveness. 59
Curcumin Derivatives and Cancer
Several Cur analogs can increase their antioxidant ability. The presence of Cu 2+ , Pb 2+ , and Fe 2+ increased the chelating effect of Cur derivatives and O-methoxy substitution also exhibited increased antioxidant activity in comparison to regular Cur. 60 , 61 Pyridine and sulfone derivatives in prostate cancer, glucoside and heterocyclic Cur derivatives in breast cancer, and mono-carbonyl and various methoxy and hydroxy derivatives of Cur in colon cancer have increased its effectiveness when compared to Cur. 62 C7-curcuminoids, which have the same framework as Cur, and C5-curcuminoids, Cur derivatives with a removed ethylene group, were found to be more effective than base Cur against K562 leukemic cells and resulted in ROS upregulation. 63 A novel Cur derivative, 1g, was effective against colon cancer cells. The administration of 1g resulted in ROS production, G1 cell cycle phase arrest, and increased ER-stress which was reversed upon addition of NAC, an ROS scavenging agent. 64 Recently, Liu et al. demonstrated the effectiveness of a series of Cur analogs and showed the effectiveness of a mono-carbonyl analog. Non-small cell lung cancer cell lines showed marked increases in apoptosis and ferroptosis driven by the analogs ability to generate ROS through TrxR inhibition. 65 The analog WZ26 increased ROS and cell death in cholangiocarcinoma via STAT3 inhibition and L48H37 was found to have similar results and induced ER-stress in human lung cancer cells. 66 , 67 An allylated mono-carbonyl Cur analog (CA6) showed effectiveness against gastric cancer cells through TrxR1 inhibition and ROS-dependent apoptotic death. 68 Another Cur analog, WZ37, induced ROS-dependent ER stress and mitochondrial injury, resulting in an increase in cell death and G2/M phase cell cycle arrest along with decreased Akt/mTOR phosphorylation and an upregulation of BAD and PTEN in head and neck squamous cell carcinoma. 69 Continued development of Cur derivatives will hopefully lead to not only increased targeting of tumorigenic factors such as ROS, but also continued improvement over base Cur formulations.
Multiple limitations surround Cur and its analogs usage including poor bioavailability and cellular uptake which decrease the therapeutic potential of the compound. Studies with doses as high as 12 g/day still resulted in small amounts of traceable plasma Cur, mostly due to low absorption in the small intestine and rapid elimination in the body via the gall bladder. 70 – 72 Efforts to improve the pharmacokinetic profile of Cur involve nanoparticle formulation and increased analog development. Cur nanoparticles not only increase its ability to attack many of its targets mentioned above, but also show increased antioxidant potential and exhibit improved distribution and absorption by target cells. 73 – 75
CONCLUSION
The paradoxical nature of ROS made for a difficult target in the hope for its use in cancer therapy. Relying solely on decreasing or increasing ROS in either direction is still a questionable approach for treatment. However, taking advantage of the antioxidant abilities of drugs shows some promise in terms of its inclusion in treatment regimens. Natural compounds like Cur are especially advantageous in this aspect due to their low toxicity towards healthy cells. Its natural antioxidant ability including its targeting of various protein kinases, transcription factors, and growth factors makes Cur an attractive alternative despite its pharmacokinetic limitations. Further studies into Cur’s mechanistic abilities to alter ROS and change antioxidant potential, chemical analogs, and nanoparticle formulation will improve the chances for successful Cur adaptation into cancer treatments.
Utilizing antioxidants in cancer therapy is a delicate balance and the research is still evolving. Since antioxidant activity can protect cancer cells, novel approaches such as modulation of oxidative stress for the implications in therapeutic application is challenging. Rigorous preclinical and clinical studies are essential to ensure safety and efficacy. Clinical testing utilizing antioxidant mechanisms for cancer therapy is ongoing. New discoveries and clinical trials can provide more insights and potential strategies beyond what is currently known.
Financial Disclosure:
This work was partially supported by the National Institutes of Health [Award #: 1S21MD012472-01; Award #: 2U54MD006882-06 and the Cancer Prevention and Research Institute of Texas (Award #: RP210046)
Conflict of Interest: Authors declared no conflict of interest.
REFERENCES
1. Sahoo BM , Banik BK , Borah P , Jain A . Reactive oxygen species (ROS): Key components in cancer therapies . Anticancer Agents Med Chem . 2022 ; 22 ( 2 ): 215 – 222 . 34102991 10.2174/1871520621666210608095512
2. Reczek CR , Chandel NS . ROS Promotes cancer cell survival through calcium signaling . Cancer Cell . 2018 ; 33 ( 6 ): 949 – 951 . 29894695 10.1016/j.ccell.2018.05.010
3. Schafer ZT , Grassian AR , Song L , Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment . Nature . 2009 ; 461 ( 7260 ): 109 – 113 . 19693011 10.1038/nature08268 PMC2931797
4. Weinberg F , Ramnath N , Nagrath D . Reactive oxygen species in the tumor microenvironment: An overview . Cancers (Basel) . 2019 ; 11 ( 8 ). doi: 10.3390/cancers11081191 PMC6721577 31426364
5. Gorrini C , Harris IS , Mak TW . Modulation of oxidative stress as an anticancer strategy . Nat Rev Drug Discov . 2013 ; 12 ( 12 ): 931 – 947 . 24287781 10.1038/nrd4002
6. Zhao RZ , Jiang S , Zhang L , Yu ZB . Mitochondrial electron transport chain, ROS generation and uncoupling (Review) . Int J Mol Med . 2019 ; 44 ( 1 ): 3 – 15 . 31115493 10.3892/ijmm.2019.4188 PMC6559295
7. Perillo B , Di Donato M , Pezone A , ROS in cancer therapy: The bright side of the moon . Exp Mol Med . 2020 ; 52 ( 2 ): 192 – 203 . 32060354 10.1038/s12276-020-0384-2 PMC7062874
8. Sena LA , Chandel NS . Physiological roles of mitochondrial reactive oxygen species . Mol Cell . 2012 ; 48 ( 2 ): 158 – 167 . 23102266 10.1016/j.molcel.2012.09.025 PMC3484374
9. Wiseman H , Halliwell B . Damage to DNA by reactive oxygen and nitrogen species: Role in inflammatory disease and progression to cancer . Biochem J . 1996 ; 313 ( Pt 1 )( Pt 1 ): 17 – 29 . 8546679 10.1042/bj3130017 PMC1216878
10. Okon IS , Zou MH . Mitochondrial ROS and cancer drug resistance: Implications for therapy . Pharmacol Res . 2015 ; 100 : 170 – 174 . 26276086 10.1016/j.phrs.2015.06.013 PMC4893310
11. Nakamura H , Takada K . Reactive oxygen species in cancer: Current findings and future directions . Cancer Sci . 2021 ; 112 ( 10 ): 3945 – 3952 . 34286881 10.1111/cas.15068 PMC8486193
12. Jelic MD , Mandic AD , Maricic SM , Srdjenovic BU . Oxidative stress and its role in cancer . J Cancer Res Ther . 2021 ; 17 ( 1 ): 22 – 28 . 33723127 10.4103/jcrt.JCRT_862_16
13. Ishimoto T , Nagano O , Yae T , CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(−) and thereby promotes tumor growth . Cancer Cell . 2011 ; 19 ( 3 ): 387 – 400 . 21397861 10.1016/j.ccr.2011.01.038
14. Taguchi K , Motohashi H , Yamamoto M . Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution . Genes Cells . 2011 ; 16 ( 2 ): 123 – 140 . 21251164 10.1111/j.1365-2443.2010.01473.x
15. Kansanen E , Kuosmanen SM , Leinonen H , Levonen AL . The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer . Redox Biol . 2013 ; 1 ( 1 ): 45 – 49 . 24024136 10.1016/j.redox.2012.10.001 PMC3757665
16. Ma Q . Role of nrf2 in oxidative stress and toxicity . Annu Rev Pharmacol Toxicol . 2013 ; 53 : 401 – 426 . 23294312 10.1146/annurev-pharmtox-011112-140320 PMC4680839
17. Li W , Kong AN . Molecular mechanisms of Nrf2-mediated antioxidant response . Mol Carcinog . 2009 ; 48 ( 2 ): 91 – 104 . 18618599 10.1002/mc.20465 PMC2631094
18. Siegel RL , Miller KD , Wagle NS , Jemal A . Cancer statistics, 2023 . CA Cancer J Clin . 2023 ; 73 ( 1 ): 17 – 48 . 36633525 10.3322/caac.21763
19. Weinstein IB , Joe A . Oncogene addiction . Cancer Res . 2008 ; 68 ( 9 ): 3077 – 3080 . doi: 10.1158/0008-5472.CAN-07-3293 18451130
20. Hanahan D , Weinberg RA . Hallmarks of cancer: The next generation . Cell . 2011 ; 144 ( 5 ): 646 – 674 . doi: 10.1016/j.cell.2011.02.013 21376230
21. Arihara Y , Takada K , Kamihara Y , Small molecule CP-31398 induces reactive oxygen species-dependent apoptosis in human multiple myeloma . Oncotarget . 2017 ; 8 ( 39 ): 65889 – 65899 . 29029480 10.18632/oncotarget.19508 PMC5630380
22. Nakamura H , Takada K , Arihara Y , Six-transmembrane epithelial antigen of the prostate 1 protects against increased oxidative stress via a nuclear erythroid 2-related factor pathway in colorectal cancer . Cancer Gene Ther . 2019 ; 26 ( 9-10 ): 313 – 322 . 30401882 10.1038/s41417-018-0056-8
23. Shiau JP , Chuang YT , Cheng YB , Impacts of oxidative stress and PI3K/AKT/mTOR on metabolism and the future direction of investigating fucoidan-modulated metabolism . Antioxidants (Basel) . 2022 ; 11 ( 5 ). doi: 10.3390/antiox11050911 PMC9137824 35624775
24. Wen C , Wang H , Wu X , ROS-mediated inactivation of the PI3K/AKT pathway is involved in the antigastric cancer effects of thioredoxin reductase-1 inhibitor chaetocin . Cell Death Dis . 2019 ; 10 ( 11 ): 809 . doi: 10.1038/s41419-019-2035-x 31649256 PMC6813365
25. Wang Y , Qi H , Liu Y , The double-edged roles of ROS in cancer prevention and therapy . Theranostics . 2021 ; 11 ( 10 ): 4839 – 4857 . 33754031 10.7150/thno.56747 PMC7978298
26. Assi M . The differential role of reactive oxygen species in early and late stages of cancer . AmJ Physiol Regul Integr Comp Physiol . 2017 ; 313 ( 6 ): R646 – R653 . 28835450 10.1152/ajpregu.00247.2017
27. Zalewska-Ziob M , Adamek B , Kasperczyk J , Activity of antioxidant enzymes in the tumor and adjacent noncancerous tissues of non-small-cell lung cancer . Oxid Med Cell Longev . 2019 ; 2901840 . doi: 10.1155/2019/2901840 31781331 PMC6875225
28. Reczek CRCN . The two faces of reactive oxygen species in cancer . Annu Rev Cancer Biol . 2017 ; 1 : 79 – 98 .
29. Luo J , Solimini NL , Elledge SJ . Principles of cancer therapy: Oncogene and non-oncogene addiction . Cell . 2009 ; 136 ( 5 ): 823 – 837 . 19269363 10.1016/j.cell.2009.02.024 PMC2894612
30. Li Y , Zhang X , Wang Z , Li B , Zhu H . Modulation of redox homeostasis:Astrategy to overcome cancer drug resistance . Front Pharmacol . 2023 ; 14 : 1156538 . doi: 10.3389/fphar.2023.1156538 37033606 PMC10073466
31. Aggarwal V , Tuli HS , Varol A , Role of reactive oxygen species in cancer progression: Molecular mechanisms and recent advancements . Biomolecules . 2019 ; 9 ( 11 ). doi: 10.3390/biom9110735 PMC6920770 31766246
32. Yu G , Sun W , Shen Y , PKM2 functions as a potential oncogene and is a crucial target of miR-148a and miR-326 in thyroid tumorigenesis . Am J Transl Res . 2018 ; 10 ( 6 ): 1793 – 1801 . 30018720 PMC6038060
33. Huang W , Zeng YC . Acandidate for lung cancer treatment: arsenic trioxide . Clin Transl Oncol . 2019 ; 21 ( 9 ): 1115 – 1126 . 30756240 10.1007/s12094-019-02054-6
34. Massaro RR , Faiao-Flores F , Rebecca VW , Inhibition of proliferation and invasion in 2D and 3D models by 2-methoxyestradiol in human melanoma cells . Pharmacol Res . 2017 ; 119 : 242 – 250 . 28212889 10.1016/j.phrs.2017.02.013 PMC5642284
35. Karlsson JO , Kurz T , Flechsig S , Nasstrom J , Andersson RG . Superior therapeutic index of calmangafodipir in comparison to mangafodipir as a chemotherapy adjunct . Transl Oncol . 2012 ; 5 ( 6 ): 492 – 502 . 23323161 10.1593/tlo.12238 PMC3542842
36. Coriat R , Alexandre J , Nicco C , Treatment of oxaliplatininduced peripheral neuropathy by intravenous mangafodipir . J Clin Invest . 2014 ; 124 ( 1 ): 262 – 272 . 24355920 10.1172/JCI68730 PMC3871222
37. Wang J , Ren XR , Piao H , Niclosamide-induced Wnt signaling inhibition in colorectal cancer is mediated by autophagy . Biochem J . 2019 ; 476 ( 3 ): 535 – 546 . 30635359 10.1042/BCJ20180385 PMC6643999
38. Disoma C , Zhou Y , Li S , Peng J , Xia Z . Wnt/beta-catenin signaling in colorectal cancer: Is therapeutic targeting even possible? Biochimie . 2022 ; 195 : 39 – 53 . 35066101 10.1016/j.biochi.2022.01.009
39. Lotfi N , Yousefi Z , Golabi M , The potential anti-cancer effects of quercetin on blood, prostate and lung cancers: An update . Front Immunol . 2023 ; 14 : 1077531 . doi: 10.3389/fimmu.2023.1077531 36926328 PMC10011078
40. Shafer D , Tombes MB , Shrader E , Phase I trial of dimethyl fumarate, temozolomide, and radiation therapy in glioblastoma . Neurooncol Adv . 2020 ; 2 ( 1 ): vdz052 . doi: 10.1093/noajnl/vdz052 32642720 PMC7212848
41. Howells LM , Iwuji COO , Irving GRB , Curcumin combined with FOLFOX chemotherapy is safe and tolerable in patients with metastatic colorectal cancer in a randomized phase IIa trial . JNutr . 2019 ; 149 ( 7 ): 1133 – 1139 . 31132111 10.1093/jn/nxz029 PMC6602900
42. Talib WH , Alsalahat I , Daoud S , Abutayeh RF , Mahmod AI . Plant-derived natural products in cancer research: extraction, mechanism of action, and drug formulation . Molecules . 2020 ; 25 ( 22 ). doi: 10.3390/molecules25225319 PMC7696819 33202681
43. Hashem S , Ali TA , Akhtar S , Targeting cancer signaling pathways by natural products: Exploring promising anti-cancer agents . Biomed Pharmacother . 2022 ; 150 : 113054 . doi: 10.1016/j.biopha.2022.113054 35658225
44. Hatcher H , Planalp R , Cho J , Torti FM , Torti SV . Curcumin: From ancient medicine to current clinical trials . Cell Mol Life Sci . 2008 ; 65 ( 11 ): 1631 – 1652 . 18324353 10.1007/s00018-008-7452-4 PMC4686230
45. Choudhari AS , Mandave PC , Deshpande M , Ranjekar P , Prakash O . Phytochemicals in cancer treatment: From preclinical studies to clinical practice . Front Pharmacol . 2019 ; 10 : 1614 . doi: 10.3389/fphar.2019.01614 32116665 PMC7025531
46. Singh S , Aggarwal BB . Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane) . J Biol Chem . 1995 ; 270 ( 42 ): 24995 – 5000 . 7559628 10.1074/jbc.270.42.24995
47. Marin YE , Wall BA , Wang S , Curcumin downregulates the constitutive activity of NF-kappaB and induces apoptosis in novel mouse melanoma cells . Melanoma Res . 2007 ; 17 ( 5 ): 274 – 283 . 17885582 10.1097/CMR.0b013e3282ed3d0e
48. Paul S , Sa G . Curcumin as an adjuvant to cancer immunotherapy . Front Oncol . 2021 ; 11 : 675923 . doi: 10.3389/fonc.2021.675923 34485117 PMC8415504
49. Kim GY , Kim KH , Lee SH , Curcumin inhibits immunostimulatory function of dendritic cells: MAPKs and translocation of NF-kappa B as potential targets . J Immunol . 2005 ; 174 ( 12 ): 8116 – 8124 . 15944320 10.4049/jimmunol.174.12.8116
50. Giordano A , Tommonaro G . Curcumin and cancer . Nutrients . 2019 ; 11 ( 10 ). doi: 10.3390/nu11102376 PMC6835707 31590362
51. Wang H , Zhang K , Liu J , Curcumin regulates cancer progression: Focus on ncRNAs and molecular signaling pathways . Front Oncol . 2021 ; 11 : 660712 . doi: 10.3389/fonc.2021.660712 33912467 PMC8072122
52. Sadatsharifi M , Purgel M . Radical scavenger competition of alizarin and curcumin: A mechanistic DFT study on antioxidant activity . J Mol Model . 2021 ; 27 ( 6 ): 166 . doi: 10.1007/s00894-021-04778-1 33987710 PMC8119285
53. Jakubczyk K , Druzga A , Katarzyna J , Skonieczna-Zydecka K . Antioxidant Potential of curcumin-a meta-analysis of randomized clinical trials . Antioxidants (Basel) . 2020 ; 9 ( 11 ). doi: 10.3390/antiox9111092 PMC7694612 33172016
54. Wang T , Wu X , Al Rudaisat M , Song Y , Cheng H . Curcumin induces G2/M arrest and triggers autophagy, ROS generation and cell senescence in cervical cancer cells . J Cancer . 2020 ; 11 ( 22 ): 6704 – 6715 . 33046993 10.7150/jca.45176 PMC7545669
55. Larasati YA , Yoneda-Kato N , Nakamae I , Yokoyama T , Meiyanto E , Kato JY . Curcumin targets multiple enzymes involved in the ROS metabolic pathway to suppress tumor cell growth . Sci Rep . 2018 ; 8 ( 1 ): 2039 . doi: 10.1038/s41598-018-20179-6 29391517 PMC5794879
56. Liu C , Rokavec M , Huang Z , Hermeking H . Curcumin activates a ROS/KEAP1/NRF2/miR-34a/b/c cascade to suppress colorectal cancer metastasis . Cell Death Differ . 2023 ; 30 ( 7 ): 1771 – 1785 . 37210578 10.1038/s41418-023-01178-1 PMC10307888
57. Gabr SA , Elsaed WM , Eladl MA , Curcumin modulates oxidative stress, fibrosis, and apoptosis in drug-resistant cancer cell lines . Life (Basel) . 2022 ; 12 ( 9 ). doi: 10.3390/life12091427 PMC9504331 36143462
58. Wang G , Duan P , Wei Z , Liu F . Curcumin sensitizes carboplatin treatment in triple negative breast cancer through reactive oxygen species induced DNA repair pathway . Mol Biol Rep . 2022 ; 49 ( 4 ): 3259 – 3270 . 35076853 10.1007/s11033-022-07162-1
59. Wu MF , Huang YH , Chiu LY , Cherng SH , Sheu GT , Yang TY . Curcumin induces apoptosis of chemoresistant lung cancer cells via ROS-Regulated p38 MAPK phosphorylation . Int J Mol Sci . 2022 ; 23 ( 15 ). doi: 10.3390/ijms23158248 PMC9367815 35897820
60. Dairam A , Limson JL , Watkins GM , Antunes E , Daya S . Curcuminoids, curcumin, and demethoxycurcumin reduce lead-induced memory deficits in male Wistar rats . J Agric Food Chem . 2007 ; 55 ( 3 ): 1039 – 1044 . 17263510 10.1021/jf063446t
61. Ravindran J , Subbaraju GV , Ramani MV , Sung B , Aggarwal BB . Bisdemethylcurcumin and structurally related hispolon analogues of curcumin exhibit enhanced prooxidant, anti-proliferative and anti-inflammatory activities in vitro . Biochem Pharmacol . 2010 ; 79 ( 11 ): 1658 – 1666 . 20138025 10.1016/j.bcp.2010.01.033 PMC2846970
62. Mbese Z , Khwaza V , Aderibigbe BA . Curcumin and its derivatives as potential therapeutic agents in prostate, colon and breast cancers . Molecules . 2019 ; 24 ( 23 ). doi: 10.3390/molecules24234386 PMC6930580 31801262
63. Nakamae I , Morimoto T , Shima H , Curcumin derivatives verify the essentiality of ROS upregulation in tumor suppression . Molecules . 2019 ; 24 ( 22 ). doi: 10.3390/molecules24224067 PMC6891586 31717651
64. Wang H , Xu Y , Sun J , Sui Z . The novel curcumin derivative 1g induces mitochondrial and ER-stress-dependent apoptosis in colon cancer cells by induction of ROS production . Front Oncol . 2021 ; 11 : 644197 . doi: 10.3389/fonc.2021.644197 34195069 PMC8236884
65. Liu X , Cui H , Li M , Tumor killing by a dietary curcumin mono-carbonyl analog that works as a selective ROS generator via TrxR inhibition . Eur J Med Chem . 2023 ; 250 : 115191 . doi: 10.1016/j.ejmech.2023.115191 36758308
66. Chen M , Qian C , Jin B , Curcumin analog WZ26 induces ROS and cell death via inhibition of STAT3 in cholangiocarcinoma . Cancer Biol Ther . 2023 ; 24 ( 1 ): 2162807 . doi: 10.1080/15384047.2022.2162807 36647192 PMC9851268
67. Feng C , Xia Y , Zou P , Curcumin analog L48H37 induces apoptosis through ROS-mediated endoplasmic reticulum stress and STAT3 pathways in human lung cancer cells . Mol Carcinog . 2017 ; 56 ( 7 ): 1765 – 1777 . 28218464 10.1002/mc.22633
68. Rajamanickam V , Yan T , Wu L , Allylated curcumin analog CA6 inhibits TrxR1 and leads to ROS-dependent apoptotic cell death in gastric cancer through Akt-FoxO3a . Cancer Manag Res . 2020 ; 12 : 247 – 263 . 32021440 10.2147/CMAR.S227415 PMC6968823
69. Zhang Z , Lin R , Liu Z , Curcumin analog, WZ37, promotes G2/M arrest and apoptosis of HNSCC cells through Akt/mTOR inhibition . Toxicol In Vitro . 2020 ; 65 : 104754 . doi: 10.1016/j.tiv.2019.104754 31863822
70. Anand P , Kunnumakkara AB , Newman RA , Aggarwal BB . Bioavailability of curcumin: Problems and promises . Mol Pharm . 2007 ; 4 ( 6 ): 807 – 818 . 17999464 10.1021/mp700113r
71. Heger M , van Golen RF , Broekgaarden M , Michel MC . The molecular basis for the pharmacokinetics and pharmacodynamics of curcumin and its metabolites in relation to cancer . Pharmacol Rev . 2014 ; 66 ( 1 ): 222 – 307 . 24368738 10.1124/pr.110.004044
72. Lao CD , Ruffin MTt , Normolle D , Dose escalation of a curcuminoid formulation . BMC Complement Altern Med . 2006 ; 6 : 10 . doi: 10.1186/1472-6882-6-10 16545122 PMC1434783
73. Sandhiutami NMD , Arozal W , Louisa M , Rahmat D , Wuyung PE . Curcumin nanoparticle enhances the anticancer effect of cisplatin by inhibiting PI3K/AKT and JAK/STAT3 pathway in rat ovarian carcinoma induced by DMBA . Front Pharmacol . 2020 ; 11 : 603235 . doi: 10.3389/fphar.2020.603235 33536913 PMC7848208
74. Adahoun MA , Al-Akhras MH , Jaafar MS , Bououdina M . Enhanced anti-cancer and antimicrobial activities of curcumin nanoparticles . Artif Cells Nanomed Biotechnol . 2017 ; 45 ( 1 ): 98 – 107 . 26747522 10.3109/21691401.2015.1129628
75. Basniwal RK , Khosla R , Jain N . Improving the anticancer activity of curcumin using nanocurcumin dispersion in water . Nutr Cancer . 2014 ; 66 ( 6 ): 1015 – 1022 . 25068616 10.1080/01635581.2014.936948