Cancer Chemo Preventive and Therapeutic Potential

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Cancer Letters 269 (2008) 243261 www.elsevier.com/locate/canlet
Mini-review
Cancer chemopreventive and therapeutic potential of resveratrol: Mechanistic perspectives

Joydeb Kumar Kundu a, Young-Joon Surh a,b,*
a
National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Shillim-dong, Kwanak-gu, Seoul 151-742, Republic of Korea b Cancer Research Institute, Seoul National University, Seoul 110-799, Republic of Korea Received 10 February 2008; received in revised form 11 February 2008; accepted 28 March 2008
Abstract A plant kingdom is considered as a gold mine for the discovery of many biologically active substances with therapeutic values. Resveratrol (3,5,40 -trihydroxystilbene), a naturally occurring polyphenol, exhibits pleiotropic health benecial eects including anti-oxidant, anti-inammatory, cardioprotective and anti-tumor activities. Currently, numerous preclinical ndings suggest resveratrol as a promising natures arsenal for cancer prevention and treatment. A remarkable progress in dissecting the molecular mechanisms underlying anti-cancer properties of resveratrol has been achieved in the past decade. As a potential anti-cancer agent, resveratrol has been shown to inhibit or retard the growth of various cancer cells in culture and implanted tumors in vivo. The compound signicantly inhibits experimental tumorigenesis in a wide range of animal models. Resveratrol targets many components of intracellular signaling pathways including pro-inammatory mediators, regulators of cell survival and apoptosis, and tumor angiogenic and metastatic switches by modulating a distinct set of upstream kinases, transcription factors and their regulators. This review summarizes the diverse molecular targets of resveratrol with a special focus on those involved in ne-tuning of orchestrated intracellular signal transduction. 2008 Elsevier Ireland Ltd. All rights reserved.
Keywords: Resveratrol; Chemoprevention; Signal transduction; Phytochemicals; Anti-carcinogenesis
1. Introduction Despite enormous eorts to search for a cure, cancer still remains as a formidable challenge for public health. It is expected that the number of cancer-related deaths may double in the next 50 years [1]. Although chemotherapy has long been practiced to combat cancer, it can only contribute to overall
* Corresponding author. Tel.: +82 2 880 7845; fax: +82 2 874 9775. E-mail address: surh@plaza.snu.ac.kr (Y.-J. Surh).
patients survival with compromised quality of life. Moreover, an increasing trend of chemoresistance and the recurrence of secondary tumors put chemotherapy at the back foot in the ght against cancer. In this context, the practice of cancer prevention by use of non-toxic chemical entities, commonly termed chemoprevention, is considered to be an alternative, but more realistic and fundamental strategy for the management of this dread disease. A wide variety of preclinical and human intervention studies demonstrate the success of chemoprevention in reducing the burden of cancer.
0304-3835/$ - see front matter 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.canlet.2008.03.057
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J.K. Kundu, Y.-J. Surh / Cancer Letters 269 (2008) 243261
Accumulating evidence from population-based and laboratory studies suggests that regular consumption of fruits and vegetables is inversely associated with the risk of certain malignancies [2]. Besides anti-oxidant vitamins, numerous non-nutritive substances present in plant-based diet, collectively termed phytochemicals, have been identied as promising chemopreventive agents. Some of these dietary chemopreventive phytochemicals have been reported to have chemotherapeutic potential as well. One of the promising dietary phytochemicals with chemopreventive and chemotherapeutic potential is resveratrol (3,5,40 -trihydroxystilbene) [3], which has rst been isolated from the roots of white hellebore (Veratrum glandiorum O. Loes), and subsequently identied in various food sources including red wine, grapes, peanuts, mulberries, etc. and in more than 70 other plant species [4]. There had been little interest in the medicinal value of resveratrol until 1990s. Due to its broad-spectrum health benecial eects, such as anti-infective, anti-oxidant, and cardioprotective functions, resveratrol is considered as the state-of-the-art natures medicine [4]. This phytoalexin has attracted considerable attention from cancer researchers as well as general public since 1997, when Jang and colleagues [5] published a seminal article demonstrating its anti-carcinogenic eects. Shortly thereafter, there has been a rapid progress in uncovering the molecular mech-
anisms of anti-carcinogenic properties of resveratrol [6]. Fig. 1 illustrates the biochemical basis of cancer chemopreventive and therapeutic potential of resveratrol. The chemopreventive property of resveratrol has been reected by its ability to block the activation of various carcinogens and/or to stimulate their detoxication, to prevent oxidative damage of target cell DNA, to reduce inammatory responses and to diminish proliferation of cancer cells [3,6,7]. Blockade of angiogenic and metastatic processes of tumor progression, and alleviation of chemotherapy resistance indicate the chemotherapeutic potential of resveratrol [6,8,9]. The induction of apoptosis in various premalignant or cancerous cells by resveratrol can contribute to both chemopreventive and chemotherapeutic potential of this compound (Fig. 1). The biochemistry behind the anticancer property of resveratrol has been extensively studied over past ten years. Resveratrol was shown to modulate various intracellular signal transduction pathways, which often become awry during the course of carcinogenesis. This review is intended to shed light on multifarious molecular targets of resveratrol as an anti-cancer agent (Table 1). 2. Chemopreventive and chemotherapeutic potential of resveratrol In a pioneering study, John M. Pezzuto and his colleagues [5] reported that resveratrol was eective
Boosting antioxidant capacity and inducing phase II carcinogen detoxifying enzymes Arresting cell proliferation by modulating cell cycle regulatory machinery Inducing apoptosis of damaged or transformed cells Resveratrol
Suppressing invasion and metastasis Sensitizing tumor cells for chemotherapy-induced apoptosis
Fig. 1. Biochemical mechanisms responsible for chemopreventive and chemotherapeutic potential of resveratrol.
Chemotherapy
Turning off the angiogenic switches and blocking neovascularization in tumor tissues
Chemoprevention
Blocking carcinogen activation by inhibiting phase I enzymes
J.K. Kundu, Y.-J. Surh / Cancer Letters 269 (2008) 243261 Table 1 Molecular targets of resveratrol as an anti-cancer agent Molecular targets AhR and CYP enzymes ;AhR DNA binding; ;expression and activity of CYP 1A1/1B1 ;Expression and activity of CYP 1A1/1A2 ;CYP 1A activity ;CYP 1A1 and CYP1B1 activity ;Expression of CYP 1A1 ;CYP 19 (aromatase) activity Direct interaction with CYP 19 Phase II detoxication and antioxidant enzymes "NQO-1 activity "Expression of protein and mRNA of NQO-1; "NQO-1 activity "Gastrointestinal GPx promoter activity "Expression of protein and mRNA and promoter activity of HO-1 "Expression of HO-1 protein and mRNA; "GCLC mRNA and GCLC promoter activity "Expression of GCL Pro-inammatory mediators ;Mammary tumorigenesis; ;COX-2 ;Esophageal tumors; ;COX-1 and COX-2; ;PGE2 level ;COX activity; ;expression and activity of ODC ;COX-2 mRNA and protein level; ;PGE2 level; ;cox-2 promoter activity; ;PKC activation; ;AP-1 activity ;Expression of iNOS and COX-2; ;IjBa degradation ;Expression of COX-2, ;IKK activity, ;MAP kinase activation, ;NF-jB and AP-1 DNA binding; ;IjBa phosphorylation and degradation, ;p65 phosphorylation and nuclear translocation, ;p65 and CBP interaction ;NF-jB nuclear translocation; ;NO production ;IL-8 production; ;AP-1 activity ;TNF-a mRNA expression ;Serum levels of IL-6 Components of cell cycle machinery "p21 expression; G1 phase arrest "p21WAF1/CIP1 expression, ;cyclin D1/D2-Cdk6 and ;cyclin D1/D2-Cdk4 complex formation ;Cyclin E-Cdk2 complex formation; ;hyperphosphorylation of Rb; ;free E2F ;Expression of cyclin B1, D1, A1 and b-catenin ;Cyclin D1 and Cdk4 expression; "cyclin E and A expression; shifting of hyperphosphorylated Rb to hypophosphorylated form ;ERK phosphorylation, ; expression of cyclin D1/D2 Causes G1 arrest, ;cyclin A and D1, ;Cdk-6, ;ERK, ;AP-1, "accumulation of hypophosphorylated Rb Induces S phase arrest, "Cdc25c phosphorylation, "Chk1/2 expression, "ATM kinase activity Molecules of the apoptotic signaling pathway "Expression of CD95L, "caspase-mediated PARP cleavage Redistribution of death receptors in membrane lipid rafts; "activation of caspases ;Akt phosphorylation, stimulation of death receptors, "caspase activation "Activation of ERK, p38 and JNK; "p53 phosphorylation "Expression of p53 responsive genes: p53,p21, p300/CBPand Apaf-1 "MAP kinases; " phosphorylation of p53; "p53 DNA binding ;Bcl-2 expression; "Bax expression "Bax expression; "activation of caspase 3 and 9 Experimental models
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TCDD-treated MCF-10A cells [22] B[a]P-treated HepG2 cells and DMBA-treated MCF-7 cells [26] Hepa1c1c7 cells [25] In vitro study using human liver microsomes [29] B[a]P-treated mouse lung tissue [27] MCF-7 cells [30] Molecular modeling and docking study [31] Hepa1c1c7 murine hepatoma cells [25] Human K562 cells [36] HepG2 cells [35] Human aortic smooth muscle cells [34] PC12 cells [32] CSE-treated SAEC and A549 cells [37] DMBA-induced rat mammary tumor and MCF-7 cells [152] NMBA-treated F344 male rats [49] UVB-irradiated SKH hairless mouse skin [153] Human mammary and oral epithelial cells [52,147] LPS- or IFN-c-stimulated Raw 264.7 cells [47] Female ICR mouse skin treated with TPA [48,154]
Raw 264.7 and J774.2 cells treated with LPS [139] TPA-treated Myeloid (U937) cells [57] LPS-treated J774.2 macrophages [54] Mice transplanted with L1210 cells [56] HepG2 cells [82] A431 cells [63] A431 cells [64] SW480 cells [69] Caco2 and HCT-116 cells [70] UVB-irradiated SKH-1 hairless mouse skin [65] A-431 cells [119] OVCAR-3 cells [71]
HL-60 and T47D cells [75] SW480 cells [76,77] PC-3 and DU-145 cells [79] JB6 cells [86,87] LNCaP cells [85] DU-145 cells [115] Human esophageal cancer cells [155] HCT-116 cells [84] (continued on next page)
246 Table 1 (continued) Molecular targets
Experimental models Human pancreatic cancer cells [156] HCT-116 cells [88] MCF-7 and MDA-MB-231 cells [91] MCF-7 cells [90] HCT-116 cells [81]
"Cytochrome c release; activation of caspase-3 "Caspase 2, "mitochondrial translocation of Bid, "AIF, "caspase-3 and -9 "Nuclear co-localization of COX-2, p53 and CBP, "phosphorylation of p53 Direct binding to integrinaVb3, "p53-dependent apoptosis "Mitochondrial ROS, "phosphorylation of ERK and p38 MAP kinases, "p53 phosphorylation, "p21, "pChk1, "ATM kinase, "senescence-like growth arrest "Caspase-6-mediated cleavage of lamin A "Cytochrome c release, "cleavage of caspase-9 and-3, and PARP, "expression of p53, "Bax expression, "APAF-1, ;Bcl-2 Molecular switches of angiogenic and metastatic progression ;Secretion of VEGF ;Phosphorylation of ERK, ;Expression of MMP-9 ;Expression of MMP-9 ;Expression and activity of MMP-2 and -9 ;HIF-1a protein expression, ;VEGF expression ;Extracellular levels of VEGF ;Expression of protein and mRNA of HIF-1a and VEGF ;HIF-1a and VEGF expression
HCT-116 (Bax+/) cells [89] DMBA-TPA-induced mouse skin papillomas [74]
Human leukemia U937 cells [157] Heregulin-b1-treated MCF-7 cells [104] DMBA-induced mouse mammary tumors [152] Multiple myeloma cells [103] A2780/CP70 and OVCAR-3 cells [72] MDA-MB-231 cells [12] Human tongue squamous cell carcinomas and hepatoma cells [100] LPA-treated ovarian cancer cells [101]
in blocking all three stages (i.e., initiation, promotion and progression) of carcinogenesis. According to this study, topically applied resveratrol signicantly reduced 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and 12-O-teradecanoylphorbol13-acetate (TPA)-promoted skin tumors in female CD-1 mice. Subsequent studies demonstrated that resveratrol exhibited strong chemopreventive eects in various experimentally induced tumor models [3, references therein]. Resveratrol inhibited transformation of mouse epidermal JB6 C141 cells stimulated with epidermal growth factor (EGF) or TPA [10,11]. The compound also inhibited proliferation and induced apoptosis of various cancerous or transformed cells, sensitized chemoresistant or radioresistant cancer cells to apoptosis, and repressed metastasis [3,6,9]. Several recent studies reported that intratumoral, peritumoral or intraperitoneal administration of resveratrol signicantly arrested tumor growth in vivo and induced apoptosis in xenografted tumors in athymic nude mice [12,13]. Administration of resveratrol by gavage reduced the formation of aberrant crypt foci and tumors in the colon of rats treated with 1,2-dimethylhydrazine (DMH) [14]. Resveratrol (0.1%) administered in drinking water caused 70% reduction in intestinal tumorigenesis in APCMin/+ mice [15]. Moreover, dietary administration of resveratrol signicantly reduced the incidence of poorly dierentiated prostatic adenocarcinoma by 7.7-fold in the TRansgenic Adenocar-
cinoma Mouse Prostate (TRAMP) model [16]. In contrast, dietary administration of resveratrol failed to inhibit intestinal tumorigenesis in ApcMin/+ mice [17], pulmonary tumorigenesis induced by benzo[a]pyrene (B[a]P) and 4-(methyl-nitrosamino)-1-(3pyridyl)-1-butanone in female A/J mice [18], and the growth of human melanoma xenograft in vivo [19]. While resveratrol attenuated growth of cultured 4T1 breast cancer cells, the compound given intraperitoneally exhibited no inhibitory eect on the growth and the metastatic potential of the same cells inoculated into female Balb/c mice [20]. These notable dierences in the ecacy of resveratrol treatment may be due to variations in the dosage, the route of administration, the tumor origin, and the presence of other dietary components. 2.1. Inhibition of metabolic activation and stimulation of detoxication of carcinogens One of the mechanisms by which resveratrol exerts chemopreventive eects is the modulation of carcinogen activating and detoxifying enzymes [3,4]. Many chemical carcinogens undergo oxidative metabolism by phase I enzymes, especially those that belong to the cytochrome P450 (CYP) superfamily, to get converted into polar intermediates, which are subsequently eliminated via conjugation reactions catalyzed by phase II enzymes. In the absence of adequate phase II enzymes, the metabolically active carcinogens are more likely to attack
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cellular DNA, thereby initiating tumorigenesis. Besides undergoing metabolic activation to electrophilic species, some carcinogens produce excessive amounts of reactive oxygen species (ROS), through either enzymatic or non-enzymatic reactions, which can also contribute to tumor initiation as corroborated by genotoxic 8-oxo-deoxyguanosine formation [21]. Thus, targeted inhibition of metabolic activation and induction of carcinogen detoxifying enzymes has been considered as a fundamental strategy for blocking the early stage of multi-step carcinogenesis. 2.1.1. Inhibition of carcinogen activation Several studies have demonstrated that resveratrol impairs the carcinogenic activity of polyaromatic hydrocarbons (PAHs), which undergo metabolic activation predominantly by CYP enzymes. The transactivation of CYP1A1, which encodes an enzyme frequently involved in metabolic activation of a wide spectrum of PAHs, requires the binding of activated arylhydrocarbon receptor (AhR) to the promoter segment of the gene. We have reported that resveratrol strongly inhibited 2,3,7,8-tetrachlorodibenzo-p-dioxin-(TCDD)-induced AhR DNA-binding activity in human mammary epithelial (MCF-10A) cells [22]. Moreover, resveratrol inhibited induction of CYP1A1 expression in rat primary hepatocytes, suggesting that the compound acts as an AhR antagonist [23]. Plausible mechanisms by which resveratrol can target AhR include: (i) the blockade of the conversion of ligand-bound cytosolic AhR into its nuclear DNA-binding form, and (ii) the suppression of the interaction between the AhR and the transcription initiation complex at the CYP1A1 gene promoter [24]. Besides blocking the transcriptional activation of CYP enzymes, resveratrol has been shown to inhibit the activity of CYP1A1, CYP1B1 and CYP1A2 in murine hepatoma (Hepa1c1c7) cells [25], TCDDstimulated mammary epithelial (MCF-10A) cells [22], DMBA-treated human breast cancer (MCF7) cells [26], and B[a]P-treated human hepatoma (HepG2) cells [26]. In addition, resveratrol abrogated the B[a]P-diol epoxide-DNA adduct formation in mouse lung tissue by down-regulating the expression of CYP1A1 [27]. Boyce et al. [28] reported that resveratrol inhibited genotoxicity induced by N-hydroxy-2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (N-hydroxy-PhIP) in CYP1A2 overexpressing Chinese hamster lung
broblast V79 cells, possibly by blocking the activity of CYP1A2 responsible for metabolic activation of this heterocyclic amine. According to Chang et al. [29], resveratrol exhibited direct inhibitory eects on the activities of CYP1A1 and CYP1B1, but it inactivated CYP1A2 indirectly. Another member of CYP family is CYP19, alternatively known as aromatase, which is a rate-limiting enzyme in the biosynthesis of estrogen. Since estrogens play a crucial role in the development of breast cancer, the inhibitory eect of resveratrol on the aromatase/CYP19 activity in MCF-7 cells [30] suggests that the chemopreventive eects of this stilbene compound on mammary carcinogenesis are attributed partly to its anti-estrogenic property. However, several other studies have demonstrated a weak estrogenic eect of resveratrol [24]. Recent computational study revealed that resveratrol docks within the active site of aromatase [31]. Although, the inhibition by resveratrol of CYP enzymes is considered as a mechanism for an anti-tumor initiating eect of the compound, it is noticeable that some carcinogens are metabolized by the same CYP enzymes before they are processed further for being excreted. Therefore, inhibition of CYPs may not necessarily provide the benecial eects on chemically induced carcinogenesis. 2.1.2. Induction of carcinogen detoxifying/antioxidant enzymes Resveratrol enhances the expression and/or the activity of phase II anti-oxidant/detoxication enzymes including glutathione S-transferase (GST), glutathione peroxidase (GPx), UDP glucuronosyl transferase (UGT)-1A, NADPH:quinone oxidoreductase (NQO), heme oxygenase-1 (HO-1), glutamate cysteine ligase (GCL), etc. [3235]. Treatment of mouse hepatoma cells with resveratrol has resulted in the activation of NQO-1 [5,25]. Resveratrol also induced the activity as well as the expression of NQO-1 at both protein and mRNA levels in human K562 cells [36]. Kluth et al. [35] reported that resveratrol induced gastrointestinal GPx promoter activity in HepG2 cells. Several recent studies also demonstrated that the compound induced the protein and mRNA expression of HO-1 in human aortic smooth muscle [34] and rat pheochoromocytoma (PC12) cells [32]. According to the former study, resveratrol suppressed the transcription factor nuclear factor-jB (NF-jB) at a concentration higher than 20 lM, accounting for its anti-inammatory eect, but enhanced NF-jB activation and
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subsequently increased expression and promoter activity of HO-1 at a lower concentration range (110 lM) [34]. Moreover, resveratrol restored the cellular glutathione (GSH), which is prone to be depleted by cigarette smoke extract (CSE), by inducing GCL-catalyzed GSH synthesis in human primary small airway epithelial cells (SAEC) and human alveolar epithelial cells (A549) [37]. By upregulating GCL, resveratrol may have rescued these cells from CSE-induced oxidative stress. 2.2. Anti-inammatory eects: implications for suppression of tumor promotion and progression Chronic inammation is causally linked to multistage carcinogenesis. Mediators of inammation, such as cyclooxygenase-2 (COX-2), prostaglandins, inducible nitric oxide synthase (iNOS), NO, and pro-inammatory cytokines have been involved in carcinogenesis, especially in the promotion and progression stages [21,38]. The elevated expression and/ or activity of COX-2 and production of certain prostaglandins in various cancers [38], the increased susceptibility of cox-2 transgenic mice to chemically induced carcinogenesis [39], the abrogation of experimental tumorigenesis in cox-2 knock out animals [40] and the enhanced skin tumorigenesis after topical administration of a COX-2 product 15deoxy-D12,14-prostaglandin J2 (15d-PGJ2) [41] support the roles of COX-2 and prostanoids in carcinogenesis. Likewise, the inhibition of chemically induced skin papillomas in mice topically treated with an iNOS inhibitor aminoguanidine [42], the enhancement of iNOS expression in PhIPor azoxymethane (AOM)-initiated and dextran sulfate sodium (DSS)-promoted mouse colon carcinogenesis [43,44], and the suppression of DSSinduced mouse colon adenocarcinoma formation by an iNOS inhibitor ONO-1714 [45] strongly support the contribution of iNOS and NO to tumorigenesis. In addition, pro-inammatory cytokines, such as interleukin 1 (IL-1), IL-6, IL-8 and tumor necrosis factor-a (TNF-a), have also been known to be involved directly or indirectly in carcinogenesis [21]. Thus, components of the inammatory signaling pathways are recognized as potential targets for chemoprevention. Resveratrol exhibited anti-tumor promoting eects by blocking the expression of various components of pro-inammatory signaling. The compound signicantly inhibited the expression of COX-2 in lipopolysachaaride (LPS)-, TPA- or
H2O2-stimulated mouse peritoneal macrophages [46], LPS plus interferon-c (IFN-c)-treated RAW 264.7 macrophages [47], and TPA-stimulated mouse skin [48]. Resveratrol also down-regulated the expression of cox-2 mRNA transcript in N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumors in F344 rats [49]. Mutoh and colleagues [50] suggested that the inhibition of COX-2 promoter activity in both unstimulated and transforming growth factor-a-stimulated colon cancer (DLD-1) cells by resveratrol was partly attributed to the resorcin moiety present in the molecule. Resveratrol diminished the COX-2 activity and reduced the production of PGE2 in peripheral blood leukocytes stimulated with LPS plus IFN-c [51] and human mammary epithelial cells treated with TPA [52]. Resveratrol also suppressed the expression and activity of iNOS [47,53]. The expression of iNOS protein and its mRNA transcript, and subsequent NO generation in LPS-activated RAW 264.7 cells were attenuated by resveratrol [53]. The expression of pro-inammatory cytokines appears to be dierentially aected by resveratrol. While the compound signicantly decreased the expression of TNF-a mRNA in LPS-activated J774.2 macrophage cells [54] and peripheral blood leukocytes [51], it failed to suppress IL-1b gene expression in J774.2 cells [54]. However, the inhibition of proliferation and induction of apoptosis in human multiple myeloma (MM) cells by resveratrol were found to be associated with its interference with signaling pathways initiated by IL-1b [55]. Resveratrol signicantly reduced the serum IL-6 level in mice transplanted with lymphocytic leukemia L1210 cells [56]. The expression of IL-8 protein and/or its mRNA in human monocytic leukemia (U937) cells [57] and human peripheral blood leukocytes [51] was also attenuated by resveratrol. 2.3. Modulation of cell survival and apoptosis 2.3.1. Induction of cancer cell cycle arrest The growth of various cancer cells in culture is arrested by treatment with resveratrol at dierent phases of the cell cycle [3, references therein]. The inhibition of ornithine decarboxylase (ODC), a biochemical hall mark of tumor promotion, accounted for the anti-proliferative and anti-tumor eects of resveratrol [58]. Recently, Ulrich and colleagues [59] have demonstrated that resveratrol suppresses ODC activity via de novo synthesis of ceramides in human colon cancer (Caco-2) cells.
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The inhibition of abnormal cell proliferation via modulation of cell cycle progression is one of the important strategies for chemoprevention as well as chemotherapy. Intracellular signaling pathways, comprised of various cyclins, cyclin-dependent kinases (Cdk), Cdk inhibitors, and check point kinases (Chk 1 and Chk 2), are involved in ne-tuning of homeostatic maintenance of cell growth and dierentiation [60,61]. Therefore, the suppression of abnormal cell proliferation by down-regulating cyclin-Cdks and/or upregulating Cdk inhibitors may provide an ample scope to intervene in the multistage carcinogenesis by dietary phytochemicals. Resveratrol has been reported to inhibit inappropriate proliferation and growth of various cancer cells in culture, tissues from animals exposed to carcinogenic insults and xenografted tumors in vivo by targeting aforementioned signaling molecules involved in regulating cell cycle progression [3, vide infra]. The anti-proliferative and growth inhibitory eects of resveratrol have been attributed to its ability to block DNA synthesis [62] and interference with various stages of cell cycle progression [24]. Resveratrol arrested the growth of human epidermoid carcinoma (A431) cells via down-regulation of the expression of some cyclins (D1, D2 and E), inhibition of the expression and/or activities of Cdk (-2, -4 and -6) and upregulation of p21WAF1/CIP1 [63]. In addition, the anti-proliferative eect of resveratrol in A431 cells was associated with a decrease in the expression of E2F transcription factor as well as the reduced level of the hyperphosphorylated form of Rb protein [64]. Resveratrol suppressed the expression of Cdks (-2, -4 and -6) and cyclins (D1 and D2), and elevated the expression of p21WAF1/CIP1 and p53 in SKH-1 hairless mouse skin stimulated with UV irradiation [65]. Likewise, resveratrol elicited an anti-proliferative eect by targeting cyclin D1 and Cdk4 in human prostate (DU145) [66] and breast (MCF-7) [67] cancer cells, which was associated with the induction of p53 and p21WAF1/CIP1. Moreover, resveratrol blocked the formation of the cyclin E-Cdk2 complex in DU-145 cells without altering the protein levels [66]. Treatment of A549 cells with resveratrol resulted in the S-phase arrest, inhibition of Rb phosphorylation and induction of p21WAF1/CIP1 and p53 proteins [68]. In addition to its common inhibitory eect on cyclin B1 expression in a series of human cancer (MCF-7, SW480, HCE7, Seg-1, Bic-1 and HL-60) cells, resveratrol diminished the expression of cyclin A and cyclin D1 in human colon cancer
(SW480) cells [69]. Although resveratrol attenuated the expression of cyclin D1 in SW480 cells, it failed to inhibit the cyclin D1 promoter activity [69]. According to Wolter et al. [70], resveratrol inhibited the expression of cyclin D1 and its complex formation with Cdk4, but increased the expression of cyclin E and cyclin A in human colon cancer (Caco-2 and HCT-116) cells. Likewise, resveratrol activated ataxia telangiectasia mutated (ATM)/ ataxia telangiectasia-Rad3-related (ATR)-Chk1/2, phosphorylated cell division cycle (Cdc)-25C, Cdc2 and histone 2AX, and induced S phase arrest in human ovarian cancer (OVCAR-3) cells, while it caused only marginal S phase arrest in normal human foreskin broblasts [71]. Besides the modulation of cell cycle regulatory proteins, resveratrol inhibits tumor growth by targeting several components of protein translation machinery. Resveratrol attenuated insulin-like growth factor-1-induced phosphorylation of protein translation regulators, such as 4E-BP1, eIF4E and 70S6K1, and expression of S6 ribosomal kinase in ovarian cancer (A2780/CP70 and OVCAR-3) cells [72]. Moreover, resveratrol-induced growth inhibition in human breast cancer (MDA-MB-231) cells was partly associated with a reduced expression of pS6 ribosomal protein [73]. 2.3.2. Induction of apoptosis The induction of apoptosis selectively in cancer cells is regarded as an important strategy for cancer prevention as well as therapy. Resveratrol has been reported to induce apoptosis in various cancerous or transformed cells in culture, chemically induced mouse skin tumors, and in transplanted tumors in nude mice by activating both extrinsic and intrinsic pathways of cell death machinery [3,12,74]. Multiple lines of evidence suggest that resveratrol induces apoptosis by activating pro-apoptotic signaling molecules as well as inhibiting anti-apoptotic molecules of the intracellular signal transduction pathways. The induction of apoptosis in human promyelocytic leukemia (HL-60) and breast cancer (T47D) cells by resveratrol was mediated via activation of the CD95CD95L signaling [75]. Most notably, resveratrol did not aect the survival of normal peripheral blood lymphocytes up to 72 h, suggesting that the compound induced apoptosis selectively in cancer cells [75]. Resveratrol failed to alter the expression level of FAS or FAS-L in human colon cancer (SW480) cells, but rather redistributed cell surface receptors such as CD95, death receptor
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(DR)-4 and DR5 in membrane lipid rafts, thereby inducing a caspase-dependent, but Bcl-2-independent apoptosis [76,77]. Co-incubation of these cancer cells with nystatin, a cholesterol sequestering agent, attenuated resveratrol-induced redistribution of death receptors into membrane lipid rafts and death receptor-mediated cell death [77]. In another study, resveratrol was shown to sensitize various cancer cells to TNF-related apoptosis-inducing ligand (TRAIL)-dependent cell death via stimulation of both death receptor and mitochondrial apoptotic signaling pathways [78]. Likewise, pretreatment of human prostate cancer (PC-3 and DU-145) cells with resveratrol resulted in TRAIL-, FAS- or TNF-a-mediated cells death by multiple mechanisms involving down-regulation of inhibitor of apoptotic protein (IAPs), suppression of Akt phosphorylation, and subsequent activation of caspases [79]. Resveratrol inhibited mitochondrial F1F0-ATPase, an enzyme involved in cellular ATP synthesis, providing a possible explanation for resveratrolinduced dysfunction of mitochondria and induction of apoptosis [80]. By targeting the mitochondriadependent (intrinsic) pathway, resveratrol activated p53 and caspases, stimulated cytochrome c release from mitochondria, upregulated pro-apoptotic Bax, downregulated anti-apoptotic Bcl-2, and induced DNA fragmentation [13,24,67]. Resveratrol induced apoptosis in various cancer cells in a cell type-specic manner, being p53-dependent in certain cells [81,82], while p53-independent in others [83,84]. The upregulation of p53-responsive genes such as p21WAF1/CIP1, p300/CBP and Apaf1 by resveratrol predisposed human prostate cancer (LNCaP) cells to undergo apoptosis [85]. Similarly, resveratrol-induced apoptosis in HepG2 cells which was accompanied by a p53-dependent increase in Bax and p21 [82]. Resveratrol increased the mitogen-activated protein (MAP) kinase-mediated phosphorylation of p53 at serine 15 residue, thereby inducing apoptosis in JB6 Cl41 cells [86,87]. In addition to its role in cancer cell death, resveratrol induced apoptosis in chemically induced mouse skin papillomas via induction of p53, release of cytochrome c, activation of Bax, inhibition of Bcl-2, and processing of caspases, such as caspase 9, caspase 3 and cleavage of poly-(ADP)ribosylpolymerase (PARP) [74]. Resveratrol also activated caspase-2 and -8, resulting in the processing of down-stream caspases and cell death in a death receptor or mitochondria-independent manner
[88]. The induction of apoptosis in HCT-116 (Bax+/) cells by resveratrol was mediated via activation of caspase 6 and subsequent degradation of nuclear coat protein lamin A [89]. Although resveratrol is a well known anti-oxidant, the compound was shown to impose both redox and replication stress in cells, resulting in senescence-like growth arrest. Heiss et al. [81] demonstrated that resveratrol generated mitochondriaderived ROS in HCT-116 cells and induced senescence-like growth arrest by increasing phosphorylation of p53 and elevation of the p21 level via activation of p38 MAP kinase and ATM kinase. Preincubation of cells with the anti-oxidant N-acetylcysteine abrogated resveratrol-induced ROS generation and apoptosis in these cells [81]. In contrast, a p53-independent mechanism for resveratrolinduced apoptosis of HCT-116 cells was reported [83,84]. Lin et al. [90] reported that resveratrol, by acting as a ligand capable of binding to b3 domain of a cell surface receptor integrin-aVb3, transduced activating signals to extracellular signal-regulated protein kinase (ERK) and p53, and induced apoptosis in MCF-7 cells. Another interesting mechanism involved in p53-dependent apoptosis was observed in MCF-7 and MDA-MB-231 cells treated with resveratrol [91]. According to this study, resveratrolinduced apoptosis was mediated via enhanced intranuclear colocalization of COX-2, phosphorylated p53 (at serine 15 residue), and transcriptional coactivator p300. The interaction of COX-2, p53 and p300 was blunted by treatment of MCF-7 cells with a MAP kinase inhibitor PD98059. Moreover, blocking the COX-2 function with a pharmacologic inhibitor or small interfering RNA reduced resveratrol-induced p53 phosphorylation and apoptosis in the MCF-7 cells [91]. The inhibition of casein kinase 2 was associated with resveratrol-induced apoptosis in prostate cancer cells [92]. Furthermore, the inhibition of Akt, activation of glycogen synthase kinase (GSK)-3b and attenuation of cell survival signal-mediated via notch partly accounted for resveratrol induced apoptosis in T-cell acute lymphoblastic leukemia cells [93]. 2.4. Inhibition of angiogenesis Since the pioneering study by Judah Folkman, the molecular mechanisms of tumor angiogenesis have been thoroughly investigated. The disruption of angiogenic signaling cascades appeared as a front
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line of attack by various anti-cancer agents. There has been paramount information in the literature, suggesting anti-angiogenic eects of resveratrol. Due to increased metabolic activities and oxygen consumption by rapidly proliferating cells, solid tumors are likely to maintain an intratumoral hypoxic environment [94,95], which enforces tumor cells to adapt by inducing hypoxia responsive genes [96,97]. Hypoxia inducible factor (HIF) acts as a master regulator of cellular oxygen homeostasis by regulating expression of hypoxia-responsive genes [98]. Some of well-dened HIF-regulated angiogenic factors include vascular endothelial growth factor (VEGF), basic broblast growth factor (bFGF), VEGF receptor (VEGFR), IL-8, iNOS and angiopoietins [96,99]. Resveratrol has been reported to inhibit the expression of HIF-1a and VEGF in OVCAR-3 cells through multiple mechanisms, such as inhibition of Akt and MAP kinases, inhibition of protein translational regulators, and enhancement of proteasomal degradation of HIF-1a protein [72]. Moreover, resveratrol signicantly reduced hypoxia-induced HIF1a protein accumulation and VEGF expression in human tongue squamous cell carcinomas (SCC-9) and HepG2 cells, without aecting HIF-1a mRNA expression, partly by inhibiting activation of ERK and Akt, and promoting proteasomal degradation of HIF-1a [100]. According to a recent study, resveratrol retarded tumor growth and angiogenesis in ERa/ERb (+) MDA-MB-231 breast tumor xenografts in nude mice and reduced extracellular levels of VEGF in vitro [12]. 2.5. Anti-invasive and anti-metastatic eects The invasion of tumor cells through tumor-associated stroma and subsequent metastasis are the central events in neoplastic progression. One of the mediators of tumor invasion and metastasis is lysophosphatidic acid (LPA), which has been reported to enhance migration of human ovarian cancer cells through upregulation of HIF-1a and VEGF [101]. Resveratrol signicantly attenuated LPA-induced expression of HIF-1a and VEGF, and subsequent migration of ovarian cancer cells by blocking activation of upstream ERK1/2 and p70S6 kinase [101]. Busquets et al. [102] demonstrated protection against lung metastasis by resveratrol in mice intramuscularly transplanted with Lewis lung carcinoma cells. Resveratrol inhibited invasion of various cancer cells by reducing the
expression and activity of matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) [103105]. The inhibition of endogenous peroxide levels and down-regulation of hepatocyte growth factor (HGF), a well known cell motility factor, by resveratrol in ROS-stimulated rat ascites hepatoma (AH109A) cells suggests that the anti-oxidant property of this compound accounts for its anti-invasive and anti-metastatic eects [106]. Moreover, resveratrol decreased the chemotactic response of metastatic MDA-MB-231 cells by reducing the focal adhesion kinase activity [107].
2.6. Chemosensitizing eects Currently, the emergence of resistance to chemotherapy is a growing challenge in reducing cancerrelated deaths worldwide. The use of cancer chemopreventive phytochemicals as adjuvants in combination with chemotherapeutic agents has been shown to be a pragmatic approach to sensitize chemoresistant cancer cells to apoptosis or growth arrest, while minimizing the side eects arising from the conventional therapy [9]. As an example, resveratrol enhanced the apoptotic eects of bortezomib and thalidomide in multiple myeloma cells [108]. Resveratrol, used as a combination therapy with etoposide, inhibited growth and induced apoptosis of human colon cancer (HT-29) cells by a ROS-dependent activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) [109]. Treatment of OVCAR-3 and uterine (Ishikawa) cells with resveratrol in combination with cisplatin or doxorubicin elicited an additive growth inhibitory eect with a left shift of the therapeutically eective range of these chemotherapeutic agents in a doseresponse curve, while resveratrol enhanced viability of neonatal rat cardiac myocytes and reduced bradycardia in mice treated with doxorubicin [110]. These ndings suggest that resveratrol, as an adjuvant to chemotherapy, can enhance chemosensitvity of cancer cells, while it alleviates unavoidable chemotherapy-associated adverse eects. P-Glycoprotein, a product of multi drug resistant (MDR)-1 gene, has been considered as a key player in developing chemoresistance. By actively euxing drugs from cells, P-glycoprotein reduces intratumoral concentrations of chemotherapeutic drugs and hence lowers their ecacy. Resveratrol was shown to inhibit the P-glycoprotein function and increase accumulation of daunorubicin
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CARCINOGEN DETOXIFICATION Cancer cells APOPTOSIS
in multidrug resistant KB-C2 cells, thereby sensitizing these cells to apoptosis [111].
Normal cells
3. Upstream kinases and transcription factors as molecular targets of resveratrol The multistage carcinogenesis involves a breaking of the chain-of-command in the normal intracellular signaling network. A panel of receptor proteins, linkers, upstream kinases, DNA-interacting proteins, and transcriptionally regulated gene products function abnormally during the course of carcinogenesis. In response to carcinogenic insults, the microenvironment of intracellular signaling network becomes disrupted, thereby favoring premalignant and malignant transformation of damaged cells [38]. Mounting data from pre-clinical studies conducted in cultured cells and experimental animals indicate that resveratrol can modulate abnormal turning on or switching o various upstream kinases and transcription factors (Fig. 2). 3.1. Modulation of inappropriate signaling via upstream kinases A wide array of plasma membrane-bound or cytosolic protein kinases, such as proline-directed serine threonine kinases, tyrosine kinases, and different isoforms of protein kinase C, function as important components of various intracellular signaling pathways to translate extracellular signals into biological responses. Many of these signaling enzymes are aberrantly activated in response to diverse external stimuli including radiation, chemical carcinogens, growth factors, bacterial toxins, etc., and actively participate in oncogenic signal transduction. Signals transmitted via one or more of these upstream kinases converge on down-stream transcription factors, thereby transactivating a vast variety of target genes. Resveratrol has been shown to modulate signal transduction mediated by many of these upstream kinases. 3.1.1. MAP kinases MAP kinases comprise several distinct sets of serinethreonine kinases with ERK, p38 MAP kinase and C-Jun-N-terminal kinase (JNK) as representative members [2,38]. Signaling through MAP kinase can both enhance proliferation and cause growth arrest [112,113]. While the activation of some MAP kinases has been reported to be associated with resveratrol-induced inhibition of proliferation
Nrf2
p53
MAP Kinases
NF-B/AP-1
MAP Kinases
PI3K/Akt
Resveratrol
PI3K/Akt
MAP Kinases, IKK, PKC
NF-B/AP-1
HIF-1
STAT3
NF-B
AP-1
GROWTH ARREST ANTIINFLAMMATION ANTIANGIOGENESIS ANTIMETASTASIS Cells/tissues stimulated with oncogenic stimuli
Fig. 2. Upstream kinases and transcription factors in the intracellular signaling network as potential targets of resveratrol in normal and cancer cells. These signal transducers are subject to ne-tuning in normal cells to maintain homeostasis, while many of them are constitutively overactivated or deregulated in cancerous or transformed cells. Some external stimuli (e.g., carcinogens, tumor promoters, growth factors, UV, ROS, inammatory cytokines, bacterial toxins, etc.) cause abnormal functioning of some of transcription factors or their regulators in normal cells. Depending on the cell types and stimuli, resveratrol either suppresses the abnormal expression/activation of particular signal pathways or restores the activities of others whose function is suppressed or not properly working.
and induction of apoptosis in various cancer cells [73,86,114116], signicant down-regulation of stimulus-induced phosphorylation of MAP kinases by resveratrol has been attributed to the anti-inammatory and anti-tumor promoting eect of this phytochemical [48,65,104,117,118]. Resveratrol suppressed TPA-induced phosphorylation of all three representative MAP kinases, such as ERK1/ 2, p38 MAP kinase and JNK in HeLa cells [118] and mouse skin in vivo [48,117]. Moreover, resveratrol inhibited UV-induced expression of MAP kinase kinase (MEK), but not ERK1/2, in SKH-1 hairless mouse skin [65]. Resveratrol down-regu-
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lated the phosphorylation of ERK1/2 in human breast cancer cells treated with a growth factor heregulin-b1 [104] and also in human epidermoid carcinoma (A431) cells [119]. In addition, TPAinduced growth of androgen-independent human prostate cancer cells was suppressed by resveratrol through inhibition of phosphorylation of ERK1/2 [120]. 3.1.2. PKC Resveratrol exerts inhibitory eects on PKCmediated signaling. Subbaramaiah and colleagues reported that resveratrol inhibited TPA-induced PKC expression in human mammary and oral epithelial cells [52]. The inhibition of TPA-induced growth of human prostate cancer (PC3) cells by resveratrol was partly dependent on the translocation of cytosolic PKCa to the plasma membrane as well as autophosphorylation of both cytosolic and membrane bound PKCa [120]. Resveratrol diminished TPA-induced PKCd expression and reduced the metastatic potential of human cervical cancer (Cisaki) cells [121]. Storz et al. [122] also demonstrated that resveratrol inhibited H2O2-induced NF-jB activation in HeLa cells partly by blocking activation of PKCl, which is alternatively known as protein kinase D (PKD). However, an in vitro study revealed that resveratrol inhibited TPA-induced autophosphorylation of PKD, but not that of other isoforms of PKC [123]. On the other hand, resveratrol attenuated the proliferation of human gastric adenoma cells by blocking PKC activity, without inuencing the phosphorylation of ERK1/2 [124]. 3.1.3. PI3K/Akt The phosphorylation of another upstream kinase Akt in MCF-7 cells was abrogated by resveratrol [125]. Resveratrol induced apoptosis in human T cell acute lymphoblastic leukemia cells by inhibiting phosphorylation of Akt and subsequent activation of GSK3b [93]. The induction of apoptosis by resveratrol in ovarian [126], breast [127], uterine [128], and prostate [129,130] cancer cells and multiple myeloma cells [108] was associated with the inhibition of Akt phosphorylation. 3.2. Targeting transcription factors Transcription factors are DNA-interacting proteins, which transcriptionally regulate the expression of various target genes. Signaling pathways mediated via upstream kinases converge on diver-
gent classes of transcription factors, which act independently or co-ordinately to regulate expression of critical genes involved in various physiological processes [2]. Abnormal activation or inactivation of various transcription factors results in disrupted cellular protein repertoire, thereby facilitating cell transformation and malignancy. Enhanced activation of NF-jB or activator protein-1 (AP-1) contributes to tumorigenesis either by transactivating pro-inammatory (e.g., cox-2, iNOS), anti-apoptotic (e.g., cIAP1, cIAP2, XIAP, Bcl-2, Bcl-3 and Bcl-XL), and the cell cycle regulatory genes (e.g., cyclin D1) or by transcriptional repression of apoptosis-inducing genes (e.g., p53) [131133]. Genes contributing to angiogenesis harbors hypoxia response elements (HRE) located on their promoter region, and improper activation of HIF-1a turns on various angiogenic switches, such as VEGF and HO-1. Accumulating data from a wide range of in vitro and in vivo studies suggest that resveratrol suppresses inducible or constitutive activation of major transcription factors such as NF-jB [48,108], AP-1 [117,119], and signal transducer of activated transcription (STAT)-3 [108,134]. Complementary to its inhibitory eect on the activation of aforementioned transcription factors, which are mostly involved in upregulating inammatory gene expression, resveratrol has been reported to activate nuclear factor E2 related factor-2 (Nrf2) thereby elevating the expression of Nrf2-regulated anti-oxidant and detoxication enzymes [32,36,37]. Moreover, resveratrol has been reported to act as a ligand of nuclear receptor transcription factor peroxisome proliferating activated receptor-c (PPARc) [135]. 3.2.1. Nrf2 Resveratrol up-regulates anti-oxidant and phase II detoxifying enzymes largely by activating Nrf2. As a basic-region leucine zipper (bZIP) transcription factor, Nrf2 preferentially binds to the anti-oxidant response element (ARE, alternatively known as electrophile response element or EpRE) located in the promoter region of many genes encoding phase II enzymes, thereby regulating their transcriptional activation [136]. In unstimulated cells, Nrf2 is sequestered in cytoplasm by binding with an inhibitory protein called Keap1 [136]. Activation of upstream kinases such as Akt, ERK and JNK leads to the dissociation of Nrf2 from keap1, thereby facilitating nuclear translocation and ARE binding of Nrf2 [2,136,137]. Several recent studies have
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demonstrated that the compound can induce the expression and activity of phase II detoxication/ anti-oxidant enzymes in rat pheochoromocytoma (PC12) [32] and human leukemia (K562) cells [36] by promoting nuclear translocation and subsequent ARE binding of Nrf2. Reportedly, resveratrol enhanced Nrf2 signaling via mechanisms involving the activation of upstream kinases, such as Akt and ERK1/2 [32]. Since resveratrol contains a resorcin moiety that can chelate metal ions, and the Nrf2 inhibitory protein Keap1 is a zinc metalloprotein [138], Nrf2 activation by resveratrol may alternatively be mediated through inactivation of Keap1 as a consequence of chelation with zinc ion. Moreover, resveratrol-induced Nrf2-driven GCL expression and subsequently GSH biosynthesis in human lung epithelial cells by reversing CSE-induced post-translational modications of Nrf2 [37]. 3.2.2. NF-jB Resveratrol attenuated nuclear translocation and DNA binding of NF-jB in LPS-stimulated Raw 264.7 cells by blocking phosphorylation and degradation of IjBa [53,139]. Manna et al. [140] demonstrated that resveratrol inhibited the activation of NF-jB in Jurkat-T, HeLa and glioma cells treated with dierent stimuli, such as TPA, LPS, H2O2, okadaic acid, and ceramide. Likewise, resveratrol suppressed the activation of NF-jB in IL-1b- and Cr (VI)-stimulated acute myeloid leukemia (OCIM2) cells [55] and mouse epidermal (JB6) cells [141], respectively. While resveratrol diminished TNF-a-induced activation of NF-jB in U937 cells by suppressing phosphorylation and nuclear translocation of p65 without aecting IjBa degradation [140], the compound inhibited UVB-induced activation of NF-jB in normal human epidermal keratinocytes by blocking the activation of upstream IKKa as well as phosphorylation and degradation of IjBa [142]. Resveratrol suppressed LPS-induced activation of NF-jB by inhibiting phosphorylation and transactivation potential of p65, but failed to inhibit nuclear translocation of NF-jB/Rel proteins [143]. In contrast, the constitutive nuclear accumulation of p65 protein in human multiple myeloma cells was diminished by resveratrol [144]. Topical application of resveratrol attenuated TPA-induced NF-jB activation in mouse skin in vivo by blocking the activation of IKK, phosphorylation of IjBa and p65, nuclear translocation of p65 and interaction of p65 with a transcriptional co-activator cyclic AMPresponse element binding protein-binding protein
(CBP) [48]. Resveratrol also suppressed proliferation and induced apoptosis in human multiple myeloma cells by inhibiting the constitutive activation of NF-jB via blockade of IKK activity and subsequent phosphorylation of IjBa [108]. Alternatively, resveratrol exerted epigenetic control on NF-jB activation by inducing SIRT1 activation [145,146]. It was reported that SIRT1, a nicotinamide adenosine dinucleotide-dependent histone deacetylase, interacted physically with the RelA/p65 and negated NF-jB-driven gene transcription by deacetylating RelA/p65 at lysine 310 [146]. Resveratrol inhibited CSE-induced NF-jB activation and NFjB-regulated pro-inammatory gene expression by activating SIRT1 in monocyte-macrophage (MonoMac6) cells, bronchoalveolar lavage uid, and rat lungs [145]. 3.2.3. AP-1 Resveratrol diminished TPA-induced activation of AP-1 in human mammary epithelial cells [52,147], human leukemia cells U937 [148] and mouse skin in vivo [117], but the compound failed to suppress AP-1-driven transcriptional activity in LPS-stimulated human monocytic (THP-1) cells [143]. By inactivating AP-1, resveratrol suppressed proliferation of human epidermoid carcinoma (A431) cells [119]. Resveratrol attenuated the AP-1 reporter gene activation in HeLa cells stimulated with UVC or TPA by blocking activation of MAP kinases and PKC [118]. It also diminished TNF-ainduced AP-1 DNA binding in U937 cells [140]. 3.2.4. Other transcription factors The hypoxia- or growth factor-induced expression of HIF-1a, a transcription factor that regulates the induction of hypoxia-responsive genes, in human tongue squamous cell carcinoma, hepatoma [100] and ovarian carcinoma cells [72], was inhibited by resveratrol. According to Urlich et al. [135], resveratrol induced transcriptional activation of PPARc, but not its protein expression, and increased the expression of a PPAR-c target gene cytokeratin 20 in Caco-2 cells by acting as a PPAR-c ligand. Resveratrol-induced activation of PPARc resulted in elevated expression of spermine/spermidine acetyltransferase, an enzyme involved in polyamine metabolism, thereby inhibiting proliferation of colorectal cancer cells [135]. The induction of apoptosis and growth arrest in SW480 cells by resveratrol was associated with a diminished expression of b-catenin and its target
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gene product cyclin D1 [69]. The phosphorylation of STAT3, an immediate early step in STAT3 nuclear translocation and its DNA binding, was suppressed by resveratrol in IL-6-stimulated human multiple myeloma cells [108] and in some other malignant cells constitutively expressing STAT3 [134]. Treatment of human epidermoid carcinoma (A431) cells with resveratrol resulted in diminished expression of all E2F family members of transcription factors involved in controlling the progression of cell cycle at and near G1-S phase transition [64]. 4. Conclusion Fighting cancer with naturally occurring substances, especially those derived from plant-based diet, appears to be a fascinating strategy. We are currently passing an accelerated phase of developing dietary phytochemicals as potential chemopreventive/chemotherapeutic agents. Due to extreme heterogeneity of cancer cells, it is hard to nd a specic molecular target for the prevention or treatment of cancer. Thus, a cancer preventive/therapeutic agent should target multiple biochemical pathways involved in the process leading to malignancy, while limiting any undesired toxicity or side eects in normal tissues. Among the ever-increasing list of naturally occurring anti-carcinogenic agents, resveratrol has been extensively investigated with regards to its underlying molecular and cellular mechanisms. As discussed in previous sections of this article, resveratrol has been reported to target diverse molecular switches involved in carcinogen metabolism (both activation and detoxication), inammation, cell proliferation, cell cycle, apoptosis, angiogenesis, tumor metastasis, etc. Considering its multifarious molecular targets, John Pezzuto has asserted very timely that resveratrol induces biologically specic tsunami [149]. While numerous studies are coming up with multiple molecular targets of resveratrol to prevent cancer, Baur and Sinclair [4] have recently proposed that resveratrol might follow the same pathway as does calorie restriction. Although the mechanism of calorie restriction as an anti-cancer regimen has been addressed [150], how exactly resveratrol can follow these mechanisms is yet to be investigated. Despite substantial progress in the understanding of the molecular basis of anti-carcinogenic activities of resveratrol, there have been very few clinical studies commensurate with its preclinical ndings. A recent phase I clinical trial demonstrates that
consumption of resveratrol (5 g) does not cause any serious adverse eects in healthy volunteers, but the peak plasma level (2.4 lmol/L) remains much below the minimum required concentration (5 lmol/L) of the compound to exert the chemopreventive eect in cultured cells [151]. The study also indicates the presence of several fold higher plasma levels of resveratrol monoglucuronides and resveratrol-3-sulfate. A phase-I clinical trial for evaluating the safety and the pharmacokinetic prole of repeated administration of resveratrol has recently been launched [4]. Another phase-I colon cancer prevention trial is currently underway at the University of California, Irvine, USA [4]. Results of these phase I trials will provide important background information useful in designing large scale clinical trials to ascertain the chemopreventive and chemotherapeutic ecacy of resveratrol. Pharmacokinetic data from studies with murine models suggest a poor bioavailability of resveratrol. Thus, further studies are necessary to enhance the bioavailability of resveratrol by modulating its metabolism, devising an appropriate formulation, identifying possible interactions with other dietary factors, and developing more bioavailable analogues of the compound. Nevertheless, currently available preclinical and mechanistic data suggest that resveratrol might be a promising candidate to be applied for the molecular target-based cancer prevention and adjuvant therapy. Acknowledgements This work was supported by the National Research Laboratory Fund from the Ministry of Science and Technology and the Grant (B050007) from the Ministry of Health and Welfare, Republic of Korea. References
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Cancer Letters 269 (2008) 243261 www.elsevier.com/locate/canlet

Cancer chemopreventive and therapeutic potential of resveratrol: Mechanistic perspectives

J.K. Kundu, Y.-J. Surh / Cancer Letters 269 (2008) 243261

Blocking carcinogen activation by inhibiting phase I enzymes

246 Table 1 (continued) Molecular targets

J.K. Kundu, Y.-J. Surh / Cancer Letters 269 (2008) 243261

HCT-116 (Bax+/) cells [89] DMBA-TPA-induced mouse skin papillomas [74]

J.K. Kundu, Y.-J. Surh / Cancer Letters 269 (2008) 243261

J.K. Kundu, Y.-J. Surh / Cancer Letters 269 (2008) 243261

J.K. Kundu, Y.-J. Surh / Cancer Letters 269 (2008) 243261

J.K. Kundu, Y.-J. Surh / Cancer Letters 269 (2008) 243261

J.K. Kundu, Y.-J. Surh / Cancer Letters 269 (2008) 243261

J.K. Kundu, Y.-J. Surh / Cancer Letters 269 (2008) 243261

MAP Kinases, IKK, PKC

J.K. Kundu, Y.-J. Surh / Cancer Letters 269 (2008) 243261

J.K. Kundu, Y.-J. Surh / Cancer Letters 269 (2008) 243261

J.K. Kundu, Y.-J. Surh / Cancer Letters 269 (2008) 243261

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