Oxidative stress and dietary phytochemicals: Role in cancer chemoprevention and treatment

Cancer Letters 413 (2018) 122e134

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Oxidative stress and dietary phytochemicals: Role in cancer chemoprevention and treatment Shireen Chikara a, Lokesh Dalasanur Nagaprashantha a, Jyotsana Singhal b, David Horne b, Sanjay Awasthi c, Sharad S. Singhal a, * a

Department of Medical Oncology, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA Department of Molecular Medicine, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA c Department of Medical Oncology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 29 September 2017 Received in revised form 23 October 2017 Accepted 2 November 2017

Several epidemiological observations have shown an inverse relation between consumption of plantbased foods, rich in phytochemicals, and incidence of cancer. Phytochemicals, secondary plant metabolites, via their antioxidant property play a key role in cancer chemoprevention by suppressing oxidative stress-induced DNA damage. In addition, they modulate several oxidative stress-mediated signaling pathways through their anti-oxidant effects, and ultimately protect cells from undergoing molecular changes that trigger carcinogenesis. In several instances, however, the pro-oxidant property of these phytochemicals has been observed with respect to cancer treatment. Further, in vitro and in vivo studies show that several phytochemicals potentiate the efficacy of chemotherapeutic agents by exacerbating oxidative stress in cancer cells. Therefore, we reviewed multiple studies investigating the role of dietary phytochemicals such as, curcumin (turmeric), epigallocatechin gallate (EGCG; green tea), resveratrol (grapes), phenethyl isothiocyanate (PEITC), sulforaphane (cruciferous vegetables), hesperidin, quercetin and 20 -hydroxyflavanone (2HF; citrus fruits) in regulating oxidative stress and associated signaling pathways in the context of cancer chemoprevention and treatment. © 2017 Elsevier B.V. All rights reserved.

Keywords: Carcinogenesis Chemoprevention Chemotherapy Oxidative stress Nrf2 Phytochemicals

1. Introduction Consumption of plant-based foods, such as fruits, vegetables, and whole grains, rich in diverse phytochemicals, secondary plant

metabolites, is associated with positive health outcomes. Several case-control and epidemiological studies have reported an inverse relationship between intake of phytochemical-rich diet and incidence of breast [1,2], colon [3], lung [4,5], pancreas [6], and prostate

Abbreviations used: AKT, protein kinase B; AMPK, AMP-activated protein kinase; ARE, antioxidant response element; ATF-2, activating transcriptional factor; BBN, Nbutyl-N-(4-hydroxybutyl)nitrosamine; CAF, cancer-associated fibroblasts; CDDP, cisplatin; CYPs, cytochrome P450s; COX-2, cyclooxygenase-2; CXCR4, chemokine receptor; DMBA, 7,12-dimethylbenz(a)anthracene; EGCG, epigallocatechin gallate; EMT, epithelial-to-mesenchymal transition; EpRE, electrophile response element; ERK, extracellular signal regulated kinase; gH2AX, phosphorylated H2AX; Glut-1, glucose transporter-1; GPx, glutathione peroxidase; GS-E, glutathione-electrophile conjugate; GSH, reduced glutathione; GS-HNE, GSH-4-hydroxy-t-2,3-nonenal conjugate; GSSG, oxidized glutathione; GST, glutathione-S-transferase; 2HF, 20 -hydroxyflavanone; 4-OHE2, 4hydroxyestradiol; 4HNE, 4-hydroxynonenal; HGF, hepatocyte growth factor; Hh, hedgehog; H2O2, hydrogen peroxide; HMOX-1, heme oxygenase-1; ICAM-1, intercellular adhesion molecule-1; iNOS, inducible nitric oxide synthase; JAK, janus kinase; KEAP, kelch-like erythroid Cap‘n’Collar homologue-associated protein; KRAS, kirsten rat sarcoma; MAOA, monoamine oxidase A; MAPK, mitogen activated protein kinase; MMP, matrix metalloproteinase; NAC, N-acetylcysteine; NFkB, nuclear factor-kappa B; 3NT, 3-nitrotyrosine; NNK, 4-(methylnitosamino)-1-(3-pyridyl)-1-butanone; ND6, NADH dehydrogenase subunit 6; NOX5, NADPH oxidase 5; NQO1, NAD(P)H: quinone oxidoreductase 1; Nrf2, nuclear factor-E2; NUDT1, nucleoside diphosphate linked moiety X-type motif 1; OH$, hydroxyl radicals; 8-OHdG, 8-oxo-20 -deoxyguanosine; O 2 , superoxide anion; OGG1, 8-oxoguanine DNA Glycosylase; PAH, polycyclic aromatic hydrocarbon; PEITC, phenethyl isothiocyanate; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine; PARP, poly (ADP-ribose) polymerase; PI3K, phosphatidylinositol-3 kinase; PKC, protein kinase c; PMBC, peripheral blood mononuclear cells; PRDx, peroxiredoxins; QR, quinine reductase; RLIP76, ral-interacting protein; ROS, reactive oxygen species; siRNA, small-interfering RNA; SOD, superoxide dismutase; STAT, signal transducer and activator of transcription; TP53, tumor suppressor 53; TRXR, thioredoxin reductase; TXN, thioredoxins; uPA, urokinase-type plasminogen activator; UGT, UDPglucuronosyltransferases. * Corresponding author. E-mail address: [email protected] (S.S. Singhal). https://doi.org/10.1016/j.canlet.2017.11.002 0304-3835/© 2017 Elsevier B.V. All rights reserved.

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[7,8] cancers. The cellular and molecular events regulated by these chemopreventive phytochemicals include apoptosis, cell cycle, cell proliferation, DNA repair, differentiation, carcinogen activation/ detoxification by xenobiotic metabolizing enzymes, functional inactivation/activation of oncogenes and tumor-suppressor genes, angiogenesis, and metastasis. Along with these, mitigation of oxidative stress-mediated tumorigenesis is one of the mechanisms by which phytochemicals exert their anticancer potential (see Table 1). Oxidative stress results from an imbalance in the production of reactive oxygen species (ROS) and the antioxidant capability of the cells [9]. ROS, such as, superoxide anion (O 2 ), hydrogen peroxide  (H2O2), and hydroxyl radicals (OH ) are constantly produced in aerobic cells by incomplete reduction of molecular O2 to H2O during mitochondrial oxidative phosphorylation [9]. In addition, ROS are generated during a number of processes such as inflammation, infection, mechanical and chemical stresses, and exposure to UVrays and ionizing radiation. Basal levels of ROS act as signaling molecules to activate cell proliferation, survival, apoptosis, differentiation, immune responses, motility, and stress-responsive pathways [10e12]. On the other hand, increased levels of ROS damage DNA, protein, and lipids which, if unrepaired, cause mutations and promote carcinogenesis [13]. However, excessive production of ROS results in extensive irreversible DNA damage, such as single or double-strand breaks, base modifications, and DNA cross links which ultimately leads to cell death [14,15]. Therefore, regulating cellular ROS is critical for maintaining cellular homeostasis. A number of ROS-mediated signaling pathways, deregulation of which favors carcinogenesis, have been shown to be modulated by phytochemicals. In this article, we have primarily reviewed phytochemicals such as curcumin from turmeric, epigallocatechin gallate (EGCG) from green tea, resveratrol from grapes, phenethyl isothiocyanate (PEITC) and sulforaphane from cruciferous vegetables, hesperidin, 20 -hydroxyflavanone (2HF) and quercetin from citrus fruits in cancer chemoprevention. In addition, we have briefly reviewed the pro-oxidant properties of some of these phytochemicals, and their anticancer efficacy as an adjuvant chemotherapeutic agent in the context of cancer treatment. 2. Role of oxidative stress in carcinogenesis Oxidative stress is associated with three stages of cancer development: initiation, promotion, and progression. The oxidative stress mediated mechanisms in carcinogenesis are represented in Fig. 1. During the initiation stage, oxidative stress leads to mutations in oncogenes and tumor-suppressor genes [16,17]. The 8-Hydroxy20 -deoxyguanosine (8-OHdG) is a commonly observed oxidative stress-associated DNA-adduct. Elevated levels of 8-OHdG are noted in precancerous and cancerous tissues or cancer cell lines as compared to adjacent normal tissues or normal cell lines [18e22]. The presence of 8-OHdG results in GC to TA missense mutations, which if unrepaired prior to DNA replication, will produce a transformed cell (22). Interestingly, mutations in tumor suppressor (TP53) and oncogene (KRAS) observed in lungs of smokers exposed to tobacco smoke-induced oxidative stress are often related to the formation of 8-OHdG DNA-adducts [23,24]. The promotion stage, characterized by clonal expansion of transformed/initiated cells, may also be regulated by ROS. Oxidation of cysteine and methionine residues in proteins can affect their structure and enzymatic activities, resulting in deregulation of several signaling pathways, such as RAS-MEK-ERK1/2 [25], PI3K/ AKT [26], Keap1-Nrf2-ARE [27], NFkB [28], and JAK/STAT [29]. An important group of proteins affected by ROS are phosphatases. Upon inactivation by ROS-mediated oxidation of the reactive

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cysteine thiol at their catalytic site, phosphatases are unable to dephosphorylate and thereby cannot inactivate target proteins, such as those belonging to RAS-MEK-ERK and PI3K/AKT signaling pathways, leading to their constitutive signaling and proliferation [30]. Finally, elevated levels of ROS contribute to progression phase of carcinogenesis by generating additional genomic instability that increases the metastatic potential of tumor cells. Cancer cells isolated from circulating blood and secondary tumor sites have been shown to display higher levels of cytoplasmic and mitochondrialderived ROS than those from their primary tumors [31,32]. At the same time, mouse lung carcinoma cells having mutations in mitochondrial gene NADH dehydrogenase subunit 6 (ND6) showed higher ROS levels and increased metastatic potential compared to cells containing wild-type mitochondrial DNA [33]. Further, treatment with N-acetylcysteine (NAC), an antioxidant, abrogated the metastatic potential of these cells [33]. Indeed, a number of studies support the role of ROS in initiating tumor metastasis in animal models of breast [34], bladder [35], colon [36], lung [33], melanoma [37], and prostate [38] cancers. This has been attributed to ROSmediated increased expression of matrix metalloproteinases (MMPs) which, via their proteolytic activities, assist in degradation of the extracellular matrix and basement membrane [35], aid in inhibition of an antioxidant enzyme catalase that detoxifies H2O2 [34], and stabilization of transcriptional factor HIF1a, a master regulator of O2, which up-regulates vascular endothelial growth factor (VEGF) and stimulates angiogenesis [36,38]. In addition to ROS-mediated DNA damage, lipid peroxidation in the presence of high ROS level plays a critical role in carcinogenesis. Generally, the cellular concentration of 4-hydroxynonenal (4HNE), a major end products of lipid peroxidation, ranges from 0.1 to 0.3 mM, however, during oxidative stress, it may increase by several folds [39]. It has been estimated that 1e8% of the 4HNE may form protein adducts [40], of which about 30% are located in mitochondria and are members of electron transport chain [41]. In addition, in liver carcinoma, 4HNE has been shown to form mutagenic DNA-adducts in TP53 [42]. Further, 4HNE protein adducts in renal and colon cancer tissues have been shown to promote growth and progression of kidney and colon cancers [43]. Therefore, production of lipid-derived radicals can interact and modify proteins and DNA to further aggravate oxidative stress and promote carcinogenesis. 3. Oxidative stress and antioxidant defense mechanism 3.1. Nrf2-ARE pathway Nuclear factor-E2 related factor 2 (Nrf2) is a transcription factor that binds to the antioxidant response element (ARE) in the 50 flanking region of antioxidant and detoxification genes in response to oxidative stress [44]. The cancer protective role of Nrf2 is evident in Nrf2-knockout (/) mice which are highly susceptible to carcinogen-induced gastric neoplasia [45], and inflammationinduced colon carcinogenesis [46]. Under normal conditions, a majority of the Nrf2 is sequestered in the cytoplasm by Kelch-like erythroid Cap‘n’Collar homologue-associated protein 1 (Keap 1) [47], and only residual nuclear Nrf2 binds to the ARE, and drives basal expression of target genes. These target genes that neutralize ROS include superoxide dismutases (SODs), catalase, heme oxygenase-1 (HMOX-1), glutathione peroxidase (GPx), thioredoxins (TXN), thioredoxin reductase (TRXR), peroxiredoxins (PRDx), NAD(P)H: quinone oxidoreductase 1 (NQO1), and glutathione-Stransferase (GSTs) (Fig. 2) [48]. For example, SOD converts O 2 to O2 or H2O2 and catalase and GPx convert H2O2 to H2O and O2 [49]. In addition, the endogenous non-enzymatic antioxidants include

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Table 1 Regulation of oxidative stress and associated signaling pathways by Phytochemicals in Cancer Chemoprevention. Phytochemicals

Cell line/tumor model

Molecular Effect

Molecular mechanism

Curcumin

Pancreatic cancer cells (BxPC3 and PANC1)

Suppresses cancer cell migration and invasion Suppresses cancer cell proliferation and invasion

Y ERK1/2 and NFkB [71] Y MMP2 and 9 [71] Y NFkB [72] Y Cyclin D1, CDK4 and MMP1 [72] Y uPA and NFkB [73] Y MMP9, PKCa/Nox2/ROS/ATF2 signaling [74] Y Bcl2 [75] Y MAOA/TOR/HIF-1a signaling [76] Y CXCR4 and IL6 [76] [ Nrf2 and HO-1 [83] [ HO-1 and SOD [84] Y MMPs, VEGF, and PKC [84] [ Phase I CYP1A1 [86] [ GSTs [86] [ Nrf2-mediated expression of HO-1 and SOD-1 [101] [ Cellular GSH [102] Y Aberrant cryptic foci formation [103] [ Nrf2, UGT1A, UGT1A8, and UGT1A10 [103] Y Nrf2-UGT1A10 signaling pathway [107]

Breast cancer cells (MDA-MB-231, BT-483, and MCF7)

EGCG

Resveratrol

Lung cancer cells (A549 and H460)

Decreases in vitro metastatic progression, and increased apoptosis

Prostate cancer cells (PC12)

Inhibits cancer cell invasion

UV-induced skin injury model Dalton's lymphoma bearing mice

Reduces UV-induced cytotoxicity Reduces tumor invasiveness

BaP-induced forestomach tumorigenesis

Reduces tumor growth

Mammary epithelial cells (MCF10A)

Enhances antioxidant defense capacity

Liver cancer cells (HepG2) Orthotropic mouse model of colon cancer

Reduces exogenous oxidative stress Reduces primary tumor growth and its metastasis to liver and lungs

Carcinogen-induced mouse model of colon carcinogenesis Immortalized human keratinocyte (HaCaT)

Protective role against colon carcinogenesis

Breast epithelial cells (MCF10A) Pancreatic cancer cells (BxPC3 and PANC1)

Prostate cancer cells (PC12) Estrogen induced breast carcinogenesis

Hesperedin 20 -hydroxyflavanone

Rat model of hepatocarcinogenesis Azoxymethane induced Liver carcinogenesis Renal cancer Breast cancer

Quercetin

Lung cancer Liver cancer

Protects skin against ionizing-radiation against DNA damage Protects against (4-OHE2)- induced migration and transformation Inhibits ROS-induced proliferation and migration Protects from H2O2-induced cytotoxicity and oxidative stress Protects from oxidative stress and its associated DNA damage Suppresses oxidative stress Inhibits burden of Hepatic tumors Inhibits survival of cancer cells in vitro and tumors in vivo Inhibits cancer cell survival, cell cycle in vitro, and tumor progression in vivo Inhibits breast cancer cell survival Inhibits liver cancer cell survival

[ HMOX-1 and SOD2 [108] Y gH2AX [108] Y pERK, pAKT, and pNFkB [116] Y ERK, NFkB and p38MAPK/NFkB signaling [117] Y uPA, E-cadherin, and Glut-1 [117] Y Hedgehog signaling HIF1a, uPA, and MMP2 [118] [ HO-1 via Nrf2 pathway [119] [ NQO1, SOD3, and OGG1 [121] [ Nrf2 [127] Y Lipid peroxidation, OH radicals [176] Y NFkB and COX-2 [176] Y Angiogenesis [179,180] Y GSTp activity [179,180] Y RLIP76 [181] Y Angiogenesis [181] [ AURKB, a negative regulator of p53 [183] [ GST and GPx [182] [ Apoptosis [182]

Fig. 1. Link between oxidative stress and carcinogenesis: Chemical carcinogens and radiation induce DNA damage (single-strand break, double-strand breaks and DNA adducts) and lipid peroxidation in normal cell. This leads to increased oxidative stress and stimulates their carcinogenic transformation, resulting in an initiated cell which further undergoes dedifferentiation and clonal expansion as a result of increased genetic instability, mutations in critical tumor suppressor genes and oncogenes, increased cell proliferation, evasion of apoptosis, and increased angiogenesis.

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Fig. 2. Activation of Nrf2 in response to mild oxidative stress: Exposure to UV-rays and/or carcinogens results in a rapid increase in ROS. This acute oxidative stress environment leads to dissociation of Nrf2 from Keap1. The dissociated Keap1 is ubiquitinated for proteasomal degradation, while, Nrf2 translocates to the nucleus and binds to MAF to initiate transcription of antioxidant/detoxification genes such as superoxide dismutase (SOD), heme oxygenase-1 (HMOX-1), NAD(P)H: quinone oxidoreductase 1 (NQO1), and glutathione-stransferases (GSTs). These genes also suppress chronic oxidative stress and prevent DNA, protein, and lipid damage leading to carcinogenesis.

proteins and metabolites produced by cells, such as glutathione (GSH), and nicotinamide adenine dinucleotide phosphate (NADPH), as well as dietary components, such as vitamins A, C, and E, selenium, and b-carotene [49]. They are re-generated from their oxidized, disulfide forms, using NADPH as an electron donor. Furthermore, it has been shown that Nrf2 suppressed cancer metastasis as Nrf2-deficient mice implanted with Lewis lung carcinoma cell line were susceptible to lung and bone metastasis as comparted to wild-type mice [50]. This was attributed to elevated levels of ROS myeloid-derived suppressor cells, a potent population of immunosuppressive cells [50]. Therefore, the cancer protective role of Nrf2 pathway stems from its ability to efficiently detoxify and eliminate ROS, and consequently prevents DNA from oxidative damage (Fig. 2) [50]. 3.2. Phase I, II, and III detoxifying enzymes A key component in understanding the initial events of carcinogenesis was the recognition by James and Elizabeth Miller that many chemical carcinogens are not chemically reactive per se and must undergo metabolic activation via phase I enzymes such as cytochrome P450s (CYPs) to form highly reactive electrophilic carcinogens [51]. These can then interact with nucleophilic groups in DNA resulting in mutagenic lesions. However, the products of phase I metabolism are detoxified by phase II enzymes such as GSTs, NQO1, UDP-glucuronosyltransferases (UGTs), and HO-1, and readily excreted from the body [52]. Detoxification of carcinogens and inactivation of ROS via phase II enzymes is one of the contributing factors towards the chemopreventive potential of several phytochemicals [53,54]. The induction of phase II enzymes is under the control of Nrf2 transcription factor [52]. Compared to wild-type mice, loss of expression of Nrf2 significantly enhances susceptibility of mice to chemical carcinogens, such as benzo(a) pyrene induced gastric neoplasia [45], and 7,12-dimethylbenz(a) anthracene (DMBA) or 12-O-tetradecanoylphorbol-13-acetate induced skin tumors [55] due to decreased expression of phase II detoxification enzymes. The mechanism by which Nrf2 protects

against chemical-induced carcinogenesis may also be partly due to its ability to reduce carcinogen-induced ROS related DNA damage in cell. The phase II enzymes, in particular GSTs catalyze the conjugation of electrophiles including xenobiotics and the endogenous products of oxidative stress-induced lipid peroxidation. The GSHelectrophile conjugates (GS-E) are then removed from the cells by phase III transporters to prevent cellular toxicity [56]. The major GS-E transporters in human cells are the ATP binding cassette transporters such as those of multidrug resistance protein family, and the noneATP binding cassette transporter RLIP76 (Ralbp1) [56]. RLIP76, accounting for up to 80% of the GS-E efflux, catalyzes ATP-dependent transport and extrusion of GSH-conjugates, such as GSH-4-hydroxy-t-2, 3-nonenal (GS-HNE) from the cell and thereby reduces oxidative stress [57e59]. On the contrary, RLIP76 is overexpressed in multiple cancers, such as kidney [60], lung [61], and pancreatic [62] and skin [63] carcinomas, and its inhibition regresses tumor growth in non-small cell lung and colon carcinomas [64], prostate cancer [65] and B16 melanomas [66] in mice due to accumulation of oxidative stress-induced 4HNE resulting in cancer cell death. Therefore, the ability of RLIP76 to modulate intracellular ROS contributes towards its cancer chemoprevention and treatment potential. 4. Antioxidant potential of phytochemicals in cancer chemoprevention and treatment Oxidative stress contributes to all phases of tumorigenesis either by a direct mechanism involving DNA damage or indirectly by modulating cell signal transduction. Therefore, reducing oxidative stress may play a critical role in chemoprevention. Diet-derived phytochemicals via their antioxidant property have shown promising chemopreventive effects in a wide variety of cancer types. In addition, these phytochemicals display minimal or no toxicity towards healthy tissue, thus making them ideal chemopreventive agents. At the same time, several phytochemicals exert antiproliferative, anti-migratory and anti-invasive effects on cancer

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cells and may be considered as adjuvant therapy in cancer, discussed in subsequent paragraphs (Fig. 3).

4.1. Curcumin Curcumin, responsible for the yellow color of a common Indian spice turmeric, is classified under bioactive compounds known as curcuminoids [67]. Curcumin, comprising of 2e5% of turmeric, has been shown to suppress ROS-induced tumorigenesis, and simultaneously protect normal tissues from ROS-mediated DNA damage [67]. The varied biologic properties of curcumin and lack of toxicity to healthy tissue, even when administered at doses as high as 8 g/ d [68], makes it an attractive anticancer agent. The in vitro anticancer potential of curcumin lies in its ability to reduce oxidative stress by modulating a number of downstream signaling pathways in cancer cells. For instance, ERK1/2 is an important signaling cascade downstream of ROS and is involved in tumor migration and invasion [69]. In addition, ERK pathway has been shown to induce aberrant activation of NFkB transcription factor [70], suggesting that ERK1/2 acts upstream of NFkB. In BxPC3 and PANC1 pancreatic cancer cell lines, curcumin suppressed migration and invasion by inhibiting ROS-mediated activation of ERK1/2 and NFkB leading to decreased expression of invasionrelated genes MMP2 and 9 [71]. Studies have also reported that curcumin inhibits in vitro growth of MDA-MB-231 and BT483 breast cancer cells by inhibiting mRNA expression levels of cell cycle-related gene cyclin D1, and MMP1 [72], and protein levels of urokinase-type plasminogen activator (uPA) [73] via suppressing

NFkB signaling pathway [72,73]. Curcumin has been shown to inhibit in vitro invasive ability of A549 lung cancer cell lines by decreasing expression of MMP9 by suppressing PKCa/Nox-2/ROS/ ATF-2 signaling [74]. In H460 lung cancer cells curcumin has been shown to initiate anoikis-induced apoptosis by down-regulating expression of anti-apoptotic Bcl2 protein [75]. These observed effects were inhibited upon treatment with a superoxide anion scavenger, indicating that curcumin mediated pro-apoptotic effects were through generation of ROS [75]. Curcumin suppressed cancerassociated fibroblasts (CAFs)-induced prostate cancer cell invasion by targeting ROS-induced monoamine oxidase A (MAOA)/mTOR/ HIF1a signaling [76]. Increased expression of chemokine receptor (CXCR4) and interleukin-6 (IL6) have been shown to promote EMTmediated migration and invasion in pancreatic [77] and colon [78] cancers. Inhibition of MAOA/mTOR/HIF1a signaling by curcumin decreased CAF-induced epithelial-to-mesenchymal transition (EMT), a prerequisite for metastasis, by upregulating expression of E-cadherin and suppressing vimentin, cell surface adhesion molecules, and suppressing expression of CXCR4 and IL6 [76]. The findings from these studies highlight the anti-proliferative and anti-migratory potential of curcumin as a chemotherapeutic agent in cancer treatment. The chemopreventive potential of curcumin has also been documented in chemical-induced animal models of skin [79], forestomach [80], colon [81], and liver [82] cancers. Curcumin has been shown to modulate Keap/Nrf2 signaling pathway, the master transcriptional regulator in detoxification of ROS and induce expression of HO-1 phase II enzyme in UV rays-induced skin injury

Fig. 3. The antioxidant and pro-oxidant role of phytochemicals: The cancer preventive role of phytochemicals is seen in their ability to suppress radiation and/or carcinogeninduced ROS levels in normal cells. Phytochemicals via their antioxidant potential mitigate oxidative stress by activating cellular antioxidant defense mechanism, preventing ROSinduced DNA damage, enhancing DNA repair machinery, and inhibiting aberrant cell proliferation. On the other hand, in the context of cancer treatment, phytochemicals in combination with chemotherapeutic agents increase oxidant stress in cancer cells by inhibiting ROS-scavenging system, inactivating pro-survival signals such as NFkB, activating apoptosis-related signals, inducing DNA damage, and inhibiting signaling pathways favoring cancer cell growth.

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model [83]. Curcumin has also demonstrated protective effects in liver, a major metabolic and detoxifying organ of the body, in Dalton's lymphoma bearing mice (a murine transplantable nonhodgkin's T-cell lymphoma) by decreasing ROS levels [84]. Curcumin treatment led to activation of endogenous antioxidant enzymes such as HO-1 and SOD, inhibition of ROS producing enzyme NADPH:oxidase in the liver, and reduced tumor invasiveness and decreased liver metastases by down-regulating MMPs, VEGF and PKC levels [84]. Curcumin has been shown to alleviate radiationinduced ROS in non-malignant primary cells derived from murine lung tissues by upregulating HO-1 expression [85]. This suggests that curcumin protects normal cells from radiation-induced damage. Inhibition of phase I CYP1A1 and simultaneously induction of hepatic phase II GSTs by curcumin has been shown to protect against bezo[a]pyrene (BaP)-induced forestomach tumorigenesis by suppressing DNA damage [86]. Suppression of oxidative-stress induced DNA damage has also been observed in curcumin treated mouse fibroblast cells [87]. Dietary curcumin has demonstrated little or no effect on 4-(methylnitosamino)-1-(3-pyridyl)-1butanone (NNK)-induced lung carcinogenesis and DMBA-induced breast carcinogenesis in mice [88]. In these studies, poor circulating bioavailability of curcumin may account for the lack of lung and breast carcinogenesis inhibition. Regarding clinical studies, several phase I and phase II trials indicate that curcumin is quite safe and may exhibit therapeutic efficacy against cancer [68]. Consumption of increasing doses of curcumin (500e8000 mg/d) for 3 months led to histologic improvement in precancerous lesions in patients with recently resected bladder cancer, oral leucoplakia, intestinal metaplasia, and uterine cervical intraepithelial neoplasms [68]. Similarly, advanced pancreatic patients receiving 8 g curcumin showed decreased levels of NFkB and its downstream target cyclooxygenase-2 (COX2), which is overexpressed in many tumors, including pancreatic cancer [89]. 4.2. EGCG Epidemiological studies have suggested that consumption of green tea may reduce the risk of a variety of cancers. In addition, an inverse association between green tea consumption and DNA damage has been observed in several case-control studies. In chronic smokers consumption of green tea led to a significant reduction in smoking-induced micronuclei, an indicator of DNA damage, in peripheral white blood cells [90]. In a randomized control study, supplementation of diet of smokers with 4 cups of decaffeinated green tea (73.5 mg of catechins/cup) for 4 months reduced urinary 8-OHdG levels by 31% [91]. Similarly, consumption of 150 g of tea per month (an equivalent of 2e3 cups of tea per day) has been reported to have protective effect against oesophageal cancer in women [92]. In addition, consumption of green tea has been shown to play modest protective role against breast [93e95], colon [96e98], and prostate [99] cancers. EGCG, a natural chemotherapeutic agent and a major active catechin in green tea, is known to possess antioxidant and antiinflammatory properties [100]. EGCG has been shown to increase Nrf-2-mediated protein expression levels of HO-1 and SOD1 in MCF10A human mammary epithelial cells in vitro, the levels of which were reduced by small-interfering RNA (siRNA)-mediated disruption of Nrf2 [101]. In addition, it was observed that activation of ERK1/2 and AKT by EGCG may be needed for subsequent activation of Nrf2 and its mediated expression of endogenous antioxidant enzymes [101]. In HepG2 liver carcinoma cells, EGCG has been reported to suppress H2O2-mediated cytotoxicity by enhancing levels of cellular GSH [102]. Further, EGCG has been shown to inhibit the growth of colon tumors, as well as their metastasis to

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liver or lungs, in an orthotropic mouse model. This has been postulated to be partly due to activation of Nrf2eUGT1A signal pathway [103]. The chemopreventive potential of green tea polyphenols by virtue of its antioxidant properties has also been demonstrated in several in vivo studies. Rats fed green tea polyphenol extract equivalent to a human dose of 500 mL of green tea/day for 5 days exhibited less DNA damage in lymphocytes, colonocytes, and hepatocytes as compared to control rats [104]. In the pancreas of hamsters, consumption of green tea polyphenols (0.1% in drinking water) inhibited carcinogen induced-lipid peroxidation and oxidative DNA damage [105]. Exposure of Wistar rats to cooking oil fumes, an important environmental toxicant associated with lung diseases including cancer, for 30 min increased ROS levels in the blood, and also increased levels of ROS and 4HNE in the alveolar lavage fluid [106]. Pre-treatment with green tea extracts for two weeks significantly reduced their levels in the lavage fluid [106]. EGCG has been shown to protect against carcinogen-induced aberrant cryptic foci formation, a preneoplastic lesion in mice colon via activation of Nrf2-UGT1A10 signaling pathway [107]. Suppression of radiation-induced mitochondrial DNA damage, as seen by decreased phosphorylated H2AX (gH2AX), a robust marker of DNA double-strand breaks, was observed in skin cells treated with EGCG. This protection against radiation was due to upregulation in mRNA levels of HMOX-1 and SOD2 in response to EGCG treatment [108]. EGCG has also demonstrated remarkable success in clinical trials for cancer prevention and cancer treatment. It has been clinically demonstrated that three out of four patients having low grade Bcell malignancies showed partial response after oral ingestion of EGCG [109]. A phase II clinical trial in Italy showed that consumption of green tea catechins significantly delayed the appearance of prostate cancer in men with high-grade prostatic intraepithelial neoplasia [110]. In another phase II clinical trial men with prostate cancer who consumed green tea catechins (1.3 g/day) for 6 weeks showed a reduction in serum levels of hepatocyte growth factor (HGF), VEGF, and tissue levels of the phosphorylated/active forms of c-Met and AKT [111]. Stimulation of c-Met leads to aberrant activation of ERK1/2, PI3K-AKT, and STAT signaling pathways promoting unrestricted cell proliferation [112]. In a phase II clinical trial, patients with high-risk oral premalignant lesions receiving 500e1000 mg/m2 of green tea extract for 12 weeks exhibited reduced VEGF levels, an angiogenic stimulus for tumors [113]. The findings from these clinical trials bolster the role of green tea in cancer prevention and treatment. 4.3. Resveratrol The cancer chemopreventive properties of resveratrol were first appreciated in 1997, when Jang and colleagues found that resveratrol possess chemopreventive activity against all the three stages of carcinogenesis [114]. Resveratrol, a natural polyphenol found in blueberries, cranberries, nuts, red grapes, and wine, exerts anticancer effects via its antioxidant and anti-inflammatory properties. Epidemiologic study showed a 50% or greater reductions in breast cancer risk in women consuming grapes rich in resveratrol [115]. The chemotherapeutic efficacy of resveratrol via its antioxidant potential has been studied in vitro in the context of breast, pancreatic, and prostate cancers. In breast epithelial cells resveratrol has been shown to suppress 4-hydroxyestradiol (4-OHE2)induced-ROS production. This was followed by inhibition in phosphorylation/activation of ERK, AKT, and NFkB signaling pathways and suppression in migration and transformation of MCF10A cells [116]. Resveratrol has been shown to suppress hyperglycemiainduced migration and invasion of PANC1 pancreatic cancer cells

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by inhibiting ROS-induced activation of ERK/NFkB and p38MAPK/ NFkB signaling pathways [117]. Further, high glucose-modulated mRNA and protein expression levels of uPA, E-cadherin, and glucose transporter-1 (Glut-1) were inhibited by treatment with resveratrol [117]. In addition, resveratrol has been shown to suppress hypoxia-driven ROS-induced invasive and migratory abilities of pancreatic cancer cells (BxPC3 and PANC1). In these cells, inhibition in mRNA and protein expression levels of HIF1a, uPA, and MMP2 was achieved by suppressing Hedgehog signaling pathway [118]. In PC12 prostate cancer cells, resveratrol has been shown to exert protective effects against H2O2-induced cytotoxicity and oxidative stress by upregulating the mRNA and protein levels of HO-1, a major antioxidant enzyme, via the ARE-mediated transcriptional activation of Nrf2 [119]. A number of studies have evaluated the chemopreventive potential of resveratrol. It has been shown to exhibit anticancer effects in several carcinogen-induced tumor models of breast [120,121], liver [122], esophagus [123], and colon [124,125] cancers. Resveratrol has also been shown to inhibit estrogen-induced breast carcinogenesis via induction of Nrf2-mediated expression of antioxidant genes NQO1 and SOD3, and DNA damage repair gene 8oxoguanine DNA glycosylase 1 (OGG1) that provide protection against oxidative DNA damage [121]. The efficacy of low daily doses of resveratrol (200 mg/kg b.w.) in animals with induced colon carcinogenesis suggests that even low concentrations of the compound, such as those obtained by the intake of red wine, could be therapeutic in some cases. Resveratrol has been shown to inhibit the formation of preneoplastic ductal lesions induced by DMBA in mammary gland [120] and reduce N-methyl-N-nitrosoureainduced mammary tumorigenesis in female Sprague Dawley rats [126]. It was observed that resveratrol mediates suppression of DMBA-induced NFkB and reduces expression levels COX2 and MMP9 proteins in the breast tumor tissue [120]. In a rat model of hepatocarcinogenesis, resveratrol has been found to upregulate hepatic Nrf2 [127]. Resveratrol has been shown to suppress hepatic inducible nitric oxide synthase (iNOS), an inflammatory marker, and decrease presence of 3-nitrotyrosine (3-NT)-containing proteins, biomarkers of oxidative damage [127]. In lung epithelial cells, resveratrol attenuates cigarette smoke-mediated oxidative stressinduced apoptosis by inducing GSH biosynthesis via activation of Nrf2 [128]. It also quenches cigarette smoke-induced release of ROS and protects these cells from ROS-induced DNA damage [128]. Taken together, the findings from these studies suggest that resveratrol exhibits chemopreventive effects which are mediated by activation of Nrf2. A clinical phase I study has demonstrated that consumption of grapes (0.15e0.45 kg/day) for 2 weeks reduces mucosal proliferation and Wnt signaling, a pathway constitutively activated in over 85% of colon cancer [129]. Findings from another clinical phase I study has shown that intake of resveratrol-containing freeze-dried grape powder (80 g/day) suppresses target genes involved in Wnt signaling, in normal colonic mucosa [130]. A randomized doubleblind phase I study investigated the potential of micronized resveratrol (SRT501) in patients with hepatic metastases. Compared to placebo-treated patients, daily in take of 5 g of SRT501 for 14 days by patients with colorectal cancer and hepatic metastases has been shown to increase expression of cleaved caspase-3, a marker of apoptosis by 39% in hepatic tissue [131]. While, phase I/II clinical trials have shown that administration of resveratrol correlates with a 5% reduction of tumor growth in patients with confirmed colon cancer [132]. Therefore, these studies indicate the potential of resveratrol as a chemopreventive and chemotherapeutic phytochemical.

4.4. PEITC Cruciferous vegetables such as broccoli, brussels sprouts, cabbage, and cauliflower are rich in glucosinolates that can endogenously be converted into isothiocyanates such as phenethyl isothiocyanate (PEITC) [133]. Epidemiological evidence suggests an inverse relationship between the intake of cruciferous vegetables and risk of breast [134,135], bladder [136,137], colorectal [138], gastric [139], kidney [140,141], lung [142], pancreatic [6,143], and prostate [144] cancers. Furthermore, consumption of broccoli (200e250 g) for 10 days has been shown to decrease tobacco smoke-induced DNA damage in smokers [145,146]. Broccoli consumption by smokers led to decrease in DNA damage in lymphocytes by 41% and increase in resistance to ex vivo H2O2-induced DNA strand breaks in peripheral blood mononuclear cells (PBMCs) by 23% [145,146]. In addition, increase in mRNA expression levels of DNA repair and antioxidant genes such as, OGG1, nucleoside diphosphate linked moiety X-type motif 1 (NUDT1) and HMOX-1 suggest that broccoli consumption improved overall antioxidant status in PMBCs of smokers [146]. Others have shown that dietary administration of broccoli sprout extract in rats leads to a significant, dose-dependent inhibition of bladder cancer development in an N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced rat bladder cancer model [147]. Broccoli sprout extract was found to inhibit the incidence, multiplicity, size, and progression of bladder tumors [147]. These chemopreventive effects of broccoli sprout extract were mediated by induction of GSTs and NQO1, phase II detoxification enzymes [147]. Phytochemicals such as PEITC and sulforaphane derived from consuming cruciferous vegetables such as broccoli have been studied for their potential chemotherapeutic and chemoprevention role in a variety of cancer types [148,149]. PEITC is a well-known phytochemical found in its glucosinolate precursor form in cruciferous vegetables [148,150]. Although watercress and broccoli are known to be the richest source, PEITC can also be obtained from turnips and radish. PEITC has demonstrated chemopreventive potential in animal models of colon [151], prostate [152], and lung [153,154] cancers. Numerous studies have shown that PEITC induces phase II detoxification and antioxidant enzymes in vitro and in vivo. In an experiment to determine the chemopreventive effect of PEITC against 2-amino-1-methyl-6phenylimidazo [4,5-b]pyridine (PhIP), a heterocyclic amine that is responsible for cooked meat-induced genotoxicity, it was found that PEITC induced one or more hepatic phase II enzymes, such as GSTs, UGTs, and quinone reductase (QR), and led to significantly decreased PhIP-DNA adduct levels in all tissues examined [155]. In PC-12 prostate cancer cells, PEITC has been shown to increase phosphorylation/activation of ERK1/2 and JNK signaling pathway which leads to release of Nrf2 from sequestration by keap 1. Translocation of NRf2 then mediates mRNA expression of the HMOX-1 [156]. In addition to ERK1/2 and JNK, PEITC has also been shown to activate Nrf2 via the MAPK signaling pathway possibly via electrophilic-mediated stress response [157]. The activation of MAPK pathway is coupled with activation of Nrf2 and its dimerization with Mafs. The Nrf2eMafs complex subsequently binds to the antioxidant/electrophile response element (ARE/EpRE) that is found in the promoters of many phase II/antioxidant genes [157]. The anticancer activity of PEITC has also been reported to be due to reduction in the activation of carcinogens and their enhanced detoxification via activation of phase II enzymes. A number of clinical trials also support the anticancer potential of PEITC. An oral dose of 40 mg PEITC has been shown to result in a plasma concentration in the micromolar range within 3e8 h [158]. Therefore, the effective concentration of PEITC is achievable by oral supplementation in humans. A Phase I trial has shown that consumption of PEITC 40 and 80 mg/d for 30 days was well-tolerated,

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and patients that consumed high doses of PEITC (120 and 160 mg daily for 30 days) show only minor toxicity with low-grade diarrhea [159]. The b-phenethyl isothiocyanate (PEITC) is being investigated in phase 2 clinical trials for lung and oral cancer prevention (NCI clinical trial data base access numbers: NCT00005883, NCT00691132, and NCT01790204).

carcinoma cells [182]. In addition, quercetin treatment inhibits Aurora kinase B, an inhibitor of p53 [183], and regressed lung tumors in mice xenografts model of lung cancer via p53-mediated ROS pathway [184]. Thus, citrus flavonoids exert potent regulatory effects on oxidative stress pathways both in cancer chemoprevention and treatment.

4.5. Sulforaphane

5. Pro-oxidant role of phytochemicals in combination with chemotherapeutic agents in cancer treatment

Sulforaphane, a potent antioxidant phytochemical from broccoli and broccoli sprouts has been shown to inhibit or retard tumor incidence and progression in carcinogenesis models of breast [160], colon [161], stomach [162], and lung [163]. Previously, these anticancer effects were attributed to modulation of carcinogen metabolism through inhibition of metabolic activation of phase I enzymes including CYP450, and induction of phase II detoxification enzymes [164,165]. It has been reported that sulforaphane inhibit cytochrome P450 (CYP)1A1 and CYP1A2 enzymes induced by polycyclic aromatic hydrocarbons (PAHs) in HepG2 and MCF7 cancer cells [166], inhibits CYP1B1 in MCF10A cells [167], inhibits CYP3A4 in human hepatocytes [168]; however, sulforaphane upregulated CYP1A2 in MCF10A cells [167]. The underlying mechanisms of the actions of sulforaphane on cytochrome P450 expression is unclear, but is suggested to relate in part to cross-talk between the Nrf2 and Aryl hydrocarbon receptor (Ahr) pathway [169]. Sulforaphane has also been shown to inhibit breast cancer stem cells by downregulating Wnt/b-catenin self-renewal pathway [170]. Cancer stem cells have the capacity to drive tumor resistance and relapse/recurrence. Therefore, the preferential killing of cancer stem cells by sulforaphane may be significant for cancer chemoprevention. Sulforaphane has been shown to modulate estrogenDNA adducts partially via the Nrf2-Keap1 pathway in MCF10A breast cells [171]. In liver of C57BL/6J mice sulforaphane has been shown to induce Nrf2-dependent expression of detoxification phase I, II drug metabolizing enzymes and phase III transporters, and provide protection against ROS-induced DNA and/or protein damage [172]. In addition, in a carcinogen-induced mouse model of skin tumorigenesis, sulforaphane treatment reduced tumor incidence and size in Nrf2 wild-type (þ/þ) mice and not in Nrf2 knockout (/) mice [55]. A number of additional studies have shown that majority of the chemopreventive effects of sulforaphane are due to Nrf2-mediated activation of antioxidant enzymes [173e175]. 4.6. Citrus flavonoids Citrus fruits and peels are a rich source of flavonoids such as hesperedin, nobiletin, 20 -hydroxyflavanone (2HF), and quercetin which possess anticancer effects. Hesperidin has been shown to protect from carcinogen-induced hepatocarcinogenesis by activating Nrf2/ARE/HO-1 pathway and increasing GSH levels in liver tissues [176]. In azoxymethane-induced colon carcinogenesis, hesperedin has been shown to decrease the number of colon cancer foci, attenuate levels of lipid peroxidation products, hydroxyl radicals, and decrease activation of NFkB and COX2 [176]. In skin gradiation model, hesperedin has been shown to increase protein levels of GSH, SOD, GPx, and decrease levels of lipid peroxidation products [177]. Nobiletin has been shown to inhibit inflammationinduced colon carcinogenesis by increasing HO-1 and NQO1 levels [178]. The citrus flavonoid 2HF has been shown to exhibit strong anticancer effects in renal cancer by decreasing protein expression and activity of GSTs [179,180]. In addition, 2HF regressed in vitro and in vivo growth of breast cancer cells by inhibiting expression of RLIP76, a phase III drug transporter both in vitro and in vivo [181]. Quercetin has been shown to transiently activate Nrf2 which then leads to increase in GST and GPx expression in HepG2 liver

ROS-induced oxidative stress plays a key role in cancer development and progression. Suppression of ROS using phytochemicals is crucial for cancer chemoprevention, however, at the same time, these have also been recognized as ROS-inducing agents in a wide variety of cancers. As compared to normal cells, cancer cells have heightened ROS levels [185]. However, high levels of ROS are also detrimental to cancer cells and so, they rely on a robust endogenous antioxidant system that attenuates oxidative stress in order to proliferate [186]. A number of phytochemicals have been shown to enhance the anticancer properties of chemotherapeutic agents by elevating ROS levels (Fig. 3). We have discussed a few of those phytochemicals in the sections below. Chemo-resistance to paclitaxel in breast cancer cells has been attributed to paclitaxel-induced activation of NFkB [187]. Increased NFkB expression induces chemo-resistance via increased expression of antioxidant enzymes. In this study, curcumin suppressed paclitaxel-induced NFkB expression and thereby, potentiated the growth inhibitory effect of paclitaxel in MDA-MB-231 breast cancer cells [187]. In addition, in a nude mouse model of breast cancer, combined treatment of paclitaxel and curcumin has been shown to significantly reduce tumor cell proliferation and size, increase apoptosis, decrease expression MMP9, and decrease incidence of breast cancer metastasis to the lung compared to either agent alone [188]. The decrease in NFkB expression and simultaneous decrease in expression of antioxidant enzymes may have led to increased oxidative stress associated growth inhibitory effects in these instances. Further, curcumin analog 2a has been shown to inhibit the growth of cisplatin-resistant A549 (A549/CDDP) lung cancer cells much more effectively than that of A549 cells [189]. By inhibiting TRXR, a component of thioredoxin system regulating redoxdependent signaling pathways, 2a upregulated intracellular ROS levels, depleted GSH, reduced the GSH/GSSG ratio, and therefore, shifted the redox balance to a more oxidative state in A549/CDDP cells [189]. Curcumin has been shown to induce apoptosis in cisplatin resistant ovarian cancer cells by down-regulating antiapoptotic AKT and/or also by activating the pro-apoptotic p38 MAPK in conjunction with the generation of superoxide radicals [190]. In bladder cancer cell lines, co-treatment with cisplatin and curcumin significantly increased apoptosis by caspase-3 activation, increased protein levels of p53 and p21, and decreased protein levels of pSTAT3 [191]. In addition, pre-treatment of cells with a ROS scavenger (NAC) and U0126 (ERK1/2 inhibitor) inhibited combination treatment-induced cell death, suggesting that ROSinduced ERK1/2 phosphorylation enhance apoptosis in these cells [191]. Recently, curcumin has been shown to enhance the anticancer effects of irinotecan, a derivative of natural camptothecin, by inducing ROS generation and activation of endoplasmic reticulum stress pathway in colon cancer cells [192]. In gliobastoma, curcumin potentiated the apoptotic effect of temozolomide on U87MG gliobastoma cell line by increasing the production of ROS which then decreased phosphorylation/activation of AKT/mTOR signaling [193]. A number of studies have shown that resveratrol sensitizes cancer cells to chemotherapeutic agents by increasing oxidative stress. In lung cancer cells, resveratrol synergistically enhanced

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erlotinib-induced apoptosis via increased ROS-dependent DNA damage, repressed expression of anti-apoptotic proteins, such as survivin and Mcl-1, and increased protein levels of p53, PUMA, and cleaved caspase-3 [194]. In addition, resveratrol has been shown to enhance the anticancer effects of gemcitabine possibly via suppressing NFkB activation and down-regulating protein expression levels of cyclin D1, COX2, ICAM1, MMP9, and survivin in tumor tissues [195]. Resveratrol induces DNA damage as measured by increased formation of gH2AX. This was mediated by increased expression NADPH oxidase 5 (NOX55), that generates superoxide and other ROS [196]. In breast cancer cells resveratrol has been shown to enhance the efficacy of sorafenib (a multi-kinase inhibitor) mediated apoptosis by causing ROS-induced cell cycle inhibition, activation of caspase 3 and 9, and poly (ADP-Ribose) polymerase (PARP) cleavage [197]. In malignant mesothelioma, characterized by poor responsiveness to chemotherapeutic drugs, combined treatment of cisplatin and resveratrol synergistically has been shown to induce apoptosis through increased ROS production [198]. In gliobastoma, co-treatment with temozolomide and resveratrol decreased in vitro proliferation of cancer cells and in vivo tumor growth in orthotopic xenograft mouse model. The inhibition in in-vitro cell growth was due to increase in ROS-mediated activation of AMP-activated protein kinase (AMPK) signaling, which led to subsequent downregulation of anti-apoptosis protein Bcl2 [199]. Several studies have shown that PEITC enhances the cytotoxic effect of cisplatin in cancer cells [200,201]. This cytotoxic effects PEITC has been shown to potentiate the anticancer effects of cisplatin in biliary tract cancer cells. Co-treatment of these cells with cisplatin and PEITC increased apoptosis by decreasing GSH/ GSSG ratio and thereby inducing oxidative stress [202]. PEITC conjugates with GSH, leading to its exportation, and therefore depletion of cellular GSH which then leads to oxidative stress due to ROS accumulation. This effective depletion of cellular GSH by PEITC also proved beneficial in overcoming drug resistance to platinum-based chemotherapy [201]. EGCG has been shown to enhance the cytotoxic potential of cisplatin on in vitro growth of ovarian cancer cell lines by increasing intracellular H2O2 levels [203]. In chemo-resistant colon cancer, resveratrol potentiated the anticancer effects of etoposide by ROS induced AMPK activation [204]. The serum and tissue levels of copper are elevated in multiple malignancies [205,206]. Copper ions interact with both DNA phosphates and the bases through coordination binding [207]. Further, copper is present in chromatin and is closely associated with DNA bases, particularly guanine [207]. It has been observed that copper transporters mediate resistance to cisplatin [208]. Many phytochemicals switch from antioxidant to pro-oxidant role in the presence of copper. The pro-oxidant properties of dietary antioxidants such as ascorbic acid [209], plumbagin [210], resveratrol [211], and genistein [212] have been studied in cancer cells in the presence of copper. Direct interaction of dietary antioxidants with the DNA bound copper ions in a ternary complex and consequent localized generation of non-diffusible hydroxyl radicals has been implicated as a likely mechanism in the pro-oxidant mechanism mediated anticancer properties of these phytochemicals [209]. Plumbagin, a phytochemical from Plumbago zeylanica, causes copper-dependent ROS mediated cell death which is decreased by co-treatment with the copper chelator neocuproine [210]. Similarly, resveratrol exerts pro-oxidant effect by mobilizing endogenous copper [211]. The COX2 is overexpressed in multiple cancers and regulates the metabolism of arachidonic acid to prostaglandins which in turn modulate cancer cell adhesion, migration and invasion [213]. The LOX enzymes mediate the synthesis of leukotriene metabolites of arachidonic acid and regulate the cellular levels of oxidative stress

and inflammation [214]. The phytochemicals which can mobilize endogenous copper and inhibit cyclooxygenase (COX) and lipoxygenase (LOX) may have strong pro-oxidant anticancer effects in cancers [211,215,216]. Resveratrol, which can mobilize endogenous copper to exert pro-oxidant effects, is also known to enhance the nuclear fraction of COX2 which can in turn facilitate p53-mediated apoptosis in breast cancer cells [211,217]. Curcumin, EGCG, and hesperetin are known COX2 inhibitors [218e220]. Curcumin is a dual LOX and COX inhibitor [221]. The COX2 inhibitor celecoxib is known to enhance cisplatin toxicity by ROS-mediated mechanism in cervical cancer cells [222]. The LOX and COX inhibitors like phenidone are known to increase the response to cisplatin in lung cancer [215,216]. The phytochemicals curcumin and EGCG, known to inhibit LOX and COX2, are known to increase cisplatin sensitivity in lung and cervical cancers, respectively [223,224]. The inhibition of COX and LOX pathways represents one of the mechanisms that can enhance the pro-oxidant anticancer effects of phytochemicals in combination with chemotherapy drugs.

6. Conclusions Oxidative stress contributes to tumor development and growth. Therefore, reducing oxidative stress may protect normal cells from undergoing carcinogenic transformation. On the other hand, cancer cells having heightened ROS levels are under increased intrinsic oxidative stress, and rely on antioxidants for their survival. Therefore, increasing oxidative insults using ROS-generating agents [225] and/or by compounds that abrogate the key antioxidant systems [189,201,202] may make these cells vulnerable to cell death. Hence, enhancing endogenous antioxidant capacity is an attractive strategy to prevent carcinogenesis, while, increasing ROS levels beyond a threshold that results in cancer cell death appears as a promising strategy for cancer treatment. As discussed in this review, a number of the phytochemicals exhibit both antioxidant and pro-oxidant effects to target cancer cells. What determines the antioxidant vs. pro-oxidant of a compound depends on a number of factors. First, this may be due to the change in cancer cell milieu. For example, EGCG acts as an antioxidant at pH 7, while it displays pro-oxidant behavior at acidic pH [226]. Second, in many instances, several phytochemicals induce p53 activation which may then produce ROS [227]. Third, the antioxidant and pro-oxidant property of the phytochemicals may also depend on their concentration. To summarize, the antioxidant and pro-oxidant effects of phytochemicals target different stages of carcinogenesis and also modulate anticancer response to chemotherapy, respectively. The mechanistic spectrum and specificity of the action of phytochemicals represents a complex and evolving field of research. In summary, phytochemicals provide strong anticancer benefits which may be integrated into multiple phases of cancer prevention and treatment based on well-designed and carefully conducted set of pre-clinical and clinical investigations.

Conflict of interest The authors have no conflict of interest to disclose.

Acknowledgements This work was supported in part by the Department of Defense grant (W81XWH-16-1-0641) and funds from the Perricone Family Foundation, Los Angeles, CA. Funding from the Beckman Research Institute of City of Hope is also acknowledged.

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