Cancer Chemo Preventive and Therapeutic Potential

Available online at www.sciencedirect.com

Cancer Letters 269 (2008) 243–261

www.elsevier.com/locate/canlet

Mini-review

Cancer chemopreventive and therapeutic potentialof 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 Koreab 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 therapeuticvalues. Resveratrol (3,5,40-trihydroxystilbene), a naturally occurring polyphenol, exhibits pleiotropic health beneficialeffects including anti-oxidant, anti-inflammatory, cardioprotective and anti-tumor activities. Currently, numerous preclin-ical findings suggest resveratrol as a promising nature’s arsenal for cancer prevention and treatment. A remarkable pro-gress in dissecting the molecular mechanisms underlying anti-cancer properties of resveratrol has been achieved in the pastdecade. As a potential anti-cancer agent, resveratrol has been shown to inhibit or retard the growth of various cancer cellsin culture and implanted tumors in vivo. The compound significantly inhibits experimental tumorigenesis in a wide range ofanimal models. Resveratrol targets many components of intracellular signaling pathways including pro-inflammatorymediators, regulators of cell survival and apoptosis, and tumor angiogenic and metastatic switches by modulating a dis-tinct set of upstream kinases, transcription factors and their regulators. This review summarizes the diverse molecular tar-gets of resveratrol with a special focus on those involved in fine-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 efforts to search for a cure,cancer still remains as a formidable challenge forpublic health. It is expected that the number of can-cer-related deaths may double in the next 50 years[1]. Although chemotherapy has long been practicedto combat cancer, it can only contribute to overall

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E-mail address: [email protected] (Y.-J. Surh).

patient’s survival with compromised quality of life.Moreover, an increasing trend of chemoresistanceand the recurrence of secondary tumors put chemo-therapy at the back foot in the fight against cancer.In this context, the practice of cancer prevention byuse of non-toxic chemical entities, commonlytermed ‘chemoprevention’, is considered to be analternative, but more realistic and fundamentalstrategy for the management of this dread disease.A wide variety of preclinical and human interven-tion studies demonstrate the success of chemopre-vention in reducing the burden of cancer.

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244 J.K. Kundu, Y.-J. Surh / Cancer Letters 269 (2008) 243–261

Accumulating evidence from population-based andlaboratory studies suggests that regular consump-tion of fruits and vegetables is inversely associatedwith the risk of certain malignancies [2]. Besidesanti-oxidant vitamins, numerous non-nutritive sub-stances present in plant-based diet, collectivelytermed phytochemicals, have been identified aspromising chemopreventive agents. Some of thesedietary chemopreventive phytochemicals have beenreported to have chemotherapeutic potential aswell.

One of the promising dietary phytochemicalswith chemopreventive and chemotherapeutic poten-tial is resveratrol (3,5,40-trihydroxystilbene) [3],which has first been isolated from the roots of whitehellebore (Veratrum glandiflorum O. Loes), and sub-sequently identified in various food sources includ-ing red wine, grapes, peanuts, mulberries, etc. andin more than 70 other plant species [4]. There hadbeen little interest in the medicinal value of resvera-trol until 1990s. Due to its broad-spectrum healthbeneficial effects, such as anti-infective, anti-oxi-dant, and cardioprotective functions, resveratrol isconsidered as the state-of-the-art nature’s medicine[4]. This phytoalexin has attracted considerableattention from cancer researchers as well as generalpublic since 1997, when Jang and colleagues [5] pub-lished a seminal article demonstrating its anti-car-cinogenic effects. Shortly thereafter, there has beena rapid progress in uncovering the molecular mech-

Blocking inhibiting

Boosting inducing pdetoxifyinArresting modulatinmachinery

Inducing atransform

Turning oand blocktumor tiss

Suppress

Sensitizinchemothe

Resveratrol

Fig. 1. Biochemical mechanisms responsible for chemoprev

anisms of anti-carcinogenic properties of resveratrol[6]. Fig. 1 illustrates the biochemical basis of cancerchemopreventive and therapeutic potential of resve-ratrol. The chemopreventive property of resveratrolhas been reflected by its ability to block the activa-tion of various carcinogens and/or to stimulate theirdetoxification, to prevent oxidative damage of tar-get cell DNA, to reduce inflammatory responsesand to diminish proliferation of cancer cells[3,6,7]. Blockade of angiogenic and metastatic pro-cesses of tumor progression, and alleviation of che-motherapy resistance indicate the chemotherapeuticpotential of resveratrol [6,8,9]. The induction ofapoptosis in various premalignant or cancerous cellsby resveratrol can contribute to both chemopreven-tive and chemotherapeutic potential of this com-pound (Fig. 1). The biochemistry behind the anti-cancer property of resveratrol has been extensivelystudied over past ten years. Resveratrol was shownto modulate various intracellular signal transduc-tion pathways, which often become awry duringthe course of carcinogenesis. This review is intendedto shed light on multifarious molecular targets ofresveratrol as an anti-cancer agent (Table 1).

2. Chemopreventive and chemotherapeutic potential

of resveratrol

In a pioneering study, John M. Pezzuto and hiscolleagues [5] reported that resveratrol was effective

carcinogen activation by phase I enzymes

antioxidant capacity and hase II carcinogen

g enzymescell proliferation by g cell cycle regulatory

poptosis of damaged or ed cells

ff the angiogenic switches ing neovascularization inues

ing invasion and metastasis

g tumor cells for rapy-induced apoptosis

Che

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entive and chemotherapeutic potential of resveratrol.

Table 1Molecular targets of resveratrol as an anti-cancer agent

Molecular targets Experimental models

AhR and CYP enzymes

;AhR DNA binding; ;expression and activity of CYP 1A1/1B1 TCDD-treated MCF-10A cells [22];Expression and activity of CYP 1A1/1A2 B[a]P-treated HepG2 cells and DMBA-treated MCF-7 cells

[26];CYP 1A activity Hepa1c1c7 cells [25];CYP 1A1 and CYP1B1 activity In vitro study using human liver microsomes [29];Expression of CYP 1A1 B[a]P-treated mouse lung tissue [27];CYP 19 (aromatase) activity MCF-7 cells [30]Direct interaction with CYP 19 Molecular modeling and docking study [31]

Phase II detoxification and antioxidant enzymes

"NQO-1 activity Hepa1c1c7 murine hepatoma cells [25]"Expression of protein and mRNA of NQO-1; "NQO-1 activity Human K562 cells [36]"Gastrointestinal GPx promoter activity HepG2 cells [35]"Expression of protein and mRNA and promoter activity of HO-1 Human aortic smooth muscle cells [34]"Expression of HO-1 protein and mRNA; "GCLC mRNA and GCLC

promoter activityPC12 cells [32]

"Expression of GCL CSE-treated SAEC and A549 cells [37]

Pro-inflammatory mediators

;Mammary tumorigenesis; ;COX-2 DMBA-induced rat mammary tumor and MCF-7 cells [152];Esophageal tumors; ;COX-1 and COX-2; ;PGE2 level NMBA-treated F344 male rats [49];COX activity; ;expression and activity of ODC UVB-irradiated SKH hairless mouse skin [153];COX-2 mRNA and protein level; ;PGE2 level; Human mammary and oral epithelial cells [52,147];cox-2 promoter activity; ;PKC activation; ;AP-1 activity;Expression of iNOS and COX-2; ;IjBa degradation LPS- or IFN-c-stimulated Raw 264.7 cells [47];Expression of COX-2, ;IKK activity, ;MAP kinase activation, ;NF-jB

and AP-1 DNA binding; ;IjBa phosphorylation and degradation, ;p65phosphorylation and nuclear translocation, ;p65 and CBP interaction

Female ICR mouse skin treated with TPA [48,154]

;NF-jB nuclear translocation; ;NO production Raw 264.7 and J774.2 cells treated with LPS [139];IL-8 production; ;AP-1 activity TPA-treated Myeloid (U937) cells [57];TNF-a mRNA expression LPS-treated J774.2 macrophages [54];Serum levels of IL-6 Mice transplanted with L1210 cells [56]

Components of cell cycle machinery

"p21 expression; G1 phase arrest HepG2 cells [82]"p21WAF1/CIP1 expression, ;cyclin D1/D2-Cdk6 and ;cyclin D1/D2-Cdk4

complex formationA431 cells [63]

;Cyclin E-Cdk2 complex formation; ;hyperphosphorylation of Rb; ;freeE2F

A431 cells [64]

;Expression of cyclin B1, D1, A1 and b-catenin SW480 cells [69];Cyclin D1 and Cdk4 expression; "cyclin E and A expression; shifting of

hyperphosphorylated Rb to hypophosphorylated formCaco2 and HCT-116 cells [70]

;ERK phosphorylation, ; expression of cyclin D1/D2 UVB-irradiated SKH-1 hairless mouse skin [65]Causes G1 arrest, ;cyclin A and D1, ;Cdk-6, ;ERK, ;AP-1, "accumulation

of hypophosphorylated RbA-431 cells [119]

Induces S phase arrest, "Cdc25c phosphorylation, OVCAR-3 cells [71]"Chk1/2 expression, "ATM kinase activity

Molecules of the apoptotic signaling pathway

"Expression of CD95L, "caspase-mediated PARP cleavage HL-60 and T47D cells [75]Redistribution of death receptors in membrane lipid rafts; "activation of

caspasesSW480 cells [76,77]

;Akt phosphorylation, stimulation of death receptors, "caspase activation PC-3 and DU-145 cells [79]"Activation of ERK, p38 and JNK; "p53 phosphorylation JB6 cells [86,87]"Expression of p53 responsive genes: p53,p21, p300/CBPand Apaf-1 LNCaP cells [85]"MAP kinases; " phosphorylation of p53; "p53 DNA binding DU-145 cells [115];Bcl-2 expression; "Bax expression Human esophageal cancer cells [155]"Bax expression; "activation of caspase 3 and 9 HCT-116 cells [84]

(continued on next page)

J.K. Kundu, Y.-J. Surh / Cancer Letters 269 (2008) 243–261 245

Table 1 (continued)

Molecular targets Experimental models

"Cytochrome c release; activation of caspase-3 Human pancreatic cancer cells [156]"Caspase 2, "mitochondrial translocation of Bid, "AIF, "caspase-3 and -9 HCT-116 cells [88]"Nuclear co-localization of COX-2, p53 and CBP, "phosphorylation of p53 MCF-7 and MDA-MB-231 cells [91]Direct binding to integrinaVb3, "p53-dependent apoptosis MCF-7 cells [90]"Mitochondrial ROS, "phosphorylation of ERK and p38 MAP kinases,"p53 phosphorylation, "p21, "pChk1, "ATM kinase, "senescence-likegrowth arrest

HCT-116 cells [81]

"Caspase-6-mediated cleavage of lamin A HCT-116 (Bax+/�) cells [89]"Cytochrome c release, "cleavage of caspase-9 and-3, and PARP,"expression of p53, "Bax expression, "APAF-1, ;Bcl-2

DMBA-TPA-induced mouse skin papillomas [74]

Molecular switches of angiogenic and metastatic progression

;Secretion of VEGF Human leukemia U937 cells [157];Phosphorylation of ERK, ;Expression of MMP-9 Heregulin-b1-treated MCF-7 cells [104];Expression of MMP-9 DMBA-induced mouse mammary tumors [152];Expression and activity of MMP-2 and -9 Multiple myeloma cells [103];HIF-1a protein expression, ;VEGF expression A2780/CP70 and OVCAR-3 cells [72];Extracellular levels of VEGF MDA-MB-231 cells [12];Expression of protein and mRNA of HIF-1a and VEGF Human tongue squamous cell carcinomas and hepatoma

cells [100];HIF-1a and VEGF expression LPA-treated ovarian cancer cells [101]


in blocking all three stages (i.e., initiation, promo-tion and progression) of carcinogenesis. Accordingto this study, topically applied resveratrol signifi-cantly reduced 7,12-dimethylbenz[a]anthracene(DMBA)-initiated and 12-O-teradecanoylphorbol-13-acetate (TPA)-promoted skin tumors in femaleCD-1 mice. Subsequent studies demonstrated thatresveratrol exhibited strong chemopreventive effectsin various experimentally induced tumor models [3,references therein]. Resveratrol inhibited transfor-mation of mouse epidermal JB6 C141 cells stimu-lated with epidermal growth factor (EGF) or TPA[10,11]. The compound also inhibited proliferationand induced apoptosis of various cancerous ortransformed cells, sensitized chemoresistant or radi-oresistant cancer cells to apoptosis, and repressedmetastasis [3,6,9].

Several recent studies reported that intratumoral,peritumoral or intraperitoneal administration ofresveratrol significantly arrested tumor growthin vivo and induced apoptosis in xenografted tumorsin athymic nude mice [12,13]. Administration of res-veratrol by gavage reduced the formation of aber-rant crypt foci and tumors in the colon of ratstreated with 1,2-dimethylhydrazine (DMH) [14].Resveratrol (0.1%) administered in drinking watercaused 70% reduction in intestinal tumorigenesisin APCMin/+ mice [15]. Moreover, dietary adminis-tration of resveratrol significantly reduced theincidence of poorly differentiated prostatic adeno-carcinoma by 7.7-fold in the TRansgenic Adenocar-

cinoma Mouse Prostate (TRAMP) model [16]. Incontrast, dietary administration of resveratrol failedto inhibit intestinal tumorigenesis in ApcMin/+ mice[17], pulmonary tumorigenesis induced by benzo[a]-pyrene (B[a]P) and 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone in female A/J mice [18], andthe growth of human melanoma xenograft in vivo

[19]. While resveratrol attenuated growth of cul-tured 4T1 breast cancer cells, the compound givenintraperitoneally exhibited no inhibitory effect onthe growth and the metastatic potential of the samecells inoculated into female Balb/c mice [20]. Thesenotable differences in the efficacy of resveratroltreatment may be due to variations in the dosage,the route of administration, the tumor origin, andthe presence of other dietary components.

2.1. Inhibition of metabolic activation and stimulation

of detoxification of carcinogens

One of the mechanisms by which resveratrolexerts chemopreventive effects is the modulation ofcarcinogen activating and detoxifying enzymes[3,4]. Many chemical carcinogens undergo oxidativemetabolism by phase I enzymes, especially thosethat belong to the cytochrome P450 (CYP) super-family, to get converted into polar intermediates,which are subsequently eliminated via conjugationreactions catalyzed by phase II enzymes. In theabsence of adequate phase II enzymes, the metabol-ically active carcinogens are more likely to attack


cellular DNA, thereby initiating tumorigenesis.Besides undergoing metabolic activation to electro-philic species, some carcinogens produce excessiveamounts of reactive oxygen species (ROS), througheither enzymatic or non-enzymatic reactions, whichcan also contribute to tumor initiation as corrobo-rated by genotoxic 8-oxo-deoxyguanosine forma-tion [21]. Thus, targeted inhibition of metabolicactivation and induction of carcinogen detoxifyingenzymes has been considered as a fundamentalstrategy for blocking the early stage of multi-stepcarcinogenesis.

2.1.1. Inhibition of carcinogen activation

Several studies have demonstrated that resvera-trol impairs the carcinogenic activity of polyaro-matic hydrocarbons (PAHs), which undergometabolic activation predominantly by CYPenzymes. The transactivation of CYP1A1, whichencodes an enzyme frequently involved in metabolicactivation of a wide spectrum of PAHs, requires thebinding of activated arylhydrocarbon receptor(AhR) to the promoter segment of the gene. Wehave reported that resveratrol strongly inhibited2,3,7,8-tetrachlorodibenzo-p-dioxin-(TCDD)-inducedAhR DNA-binding activity in human mammaryepithelial (MCF-10A) cells [22]. Moreover, resvera-trol inhibited induction of CYP1A1 expression inrat primary hepatocytes, suggesting that the com-pound acts as an AhR antagonist [23]. Plausiblemechanisms by which resveratrol can target AhRinclude: (i) the blockade of the conversion ofligand-bound cytosolic AhR into its nuclearDNA-binding form, and (ii) the suppression of theinteraction between the AhR and the transcriptioninitiation complex at the CYP1A1 gene promoter[24].

Besides blocking the transcriptional activation ofCYP enzymes, resveratrol has been shown to inhibitthe activity of CYP1A1, CYP1B1 and CYP1A2 inmurine hepatoma (Hepa1c1c7) cells [25], TCDD-stimulated mammary epithelial (MCF-10A) cells[22], DMBA-treated human breast cancer (MCF-7) cells [26], and B[a]P-treated human hepatoma(HepG2) cells [26]. In addition, resveratrol abro-gated the B[a]P-diol epoxide-DNA adduct forma-tion in mouse lung tissue by down-regulating theexpression of CYP1A1 [27]. Boyce et al. [28]reported that resveratrol inhibited genotoxicityinduced by N-hydroxy-2-amino-1-methyl-6-pheny-limidazo-[4,5-b]pyridine (N-hydroxy-PhIP) inCYP1A2 overexpressing Chinese hamster lung

fibroblast V79 cells, possibly by blocking the activ-ity of CYP1A2 responsible for metabolic activationof this heterocyclic amine. According to Changet al. [29], resveratrol exhibited direct inhibitoryeffects on the activities of CYP1A1 and CYP1B1,but it inactivated CYP1A2 indirectly. Anothermember of CYP family is CYP19, alternativelyknown as aromatase, which is a rate-limitingenzyme in the biosynthesis of estrogen. Since estro-gens play a crucial role in the development of breastcancer, the inhibitory effect of resveratrol on thearomatase/CYP19 activity in MCF-7 cells [30] sug-gests that the chemopreventive effects of this stil-bene compound on mammary carcinogenesis areattributed partly to its anti-estrogenic property.However, several other studies have demonstrateda weak estrogenic effect of resveratrol [24]. Recentcomputational study revealed that resveratrol dockswithin the active site of aromatase [31]. Although,the inhibition by resveratrol of CYP enzymes is con-sidered as a mechanism for an anti-tumor initiatingeffect of the compound, it is noticeable that somecarcinogens are metabolized by the same CYPenzymes before they are processed further for beingexcreted. Therefore, inhibition of CYPs may notnecessarily provide the beneficial effects on chemi-cally induced carcinogenesis.

2.1.2. Induction of carcinogen detoxifying/anti-

oxidant enzymes

Resveratrol enhances the expression and/or theactivity of phase II anti-oxidant/detoxificationenzymes including glutathione S-transferase(GST), glutathione peroxidase (GPx), UDP glucur-onosyl transferase (UGT)-1A, NADPH:quinoneoxidoreductase (NQO), heme oxygenase-1 (HO-1),glutamate cysteine ligase (GCL), etc. [32–35]. Treat-ment of mouse hepatoma cells with resveratrol hasresulted in the activation of NQO-1 [5,25]. Resvera-trol also induced the activity as well as the expres-sion of NQO-1 at both protein and mRNA levelsin human K562 cells [36]. Kluth et al. [35] reportedthat resveratrol induced gastrointestinal GPx pro-moter activity in HepG2 cells. Several recent studiesalso demonstrated that the compound induced theprotein and mRNA expression of HO-1 in humanaortic smooth muscle [34] and rat pheochoromocy-toma (PC12) cells [32]. According to the formerstudy, resveratrol suppressed the transcription fac-tor nuclear factor-jB (NF-jB) at a concentrationhigher than 20 lM, accounting for its anti-inflam-matory effect, but enhanced NF-jB activation and


subsequently increased expression and promoteractivity of HO-1 at a lower concentration range(1–10 lM) [34]. Moreover, resveratrol restored thecellular glutathione (GSH), which is prone to bedepleted by cigarette smoke extract (CSE), byinducing GCL-catalyzed GSH synthesis in humanprimary small airway epithelial cells (SAEC) andhuman alveolar epithelial cells (A549) [37]. By up-regulating GCL, resveratrol may have rescued thesecells from CSE-induced oxidative stress.

2.2. Anti-inflammatory effects: implications forsuppression of tumor promotion and progression

Chronic inflammation is causally linked to multi-stage carcinogenesis. Mediators of inflammation,such as cyclooxygenase-2 (COX-2), prostaglandins,inducible nitric oxide synthase (iNOS), NO, andpro-inflammatory cytokines have been involved incarcinogenesis, especially in the promotion and pro-gression stages [21,38]. The elevated expression and/or activity of COX-2 and production of certainprostaglandins in various cancers [38], the increasedsusceptibility of cox-2 transgenic mice to chemicallyinduced carcinogenesis [39], the abrogation ofexperimental tumorigenesis in cox-2 knock out ani-mals [40] and the enhanced skin tumorigenesis aftertopical administration of a COX-2 product 15-deoxy-D12,14-prostaglandin J2 (15d-PGJ2) [41]support the roles of COX-2 and prostanoids incarcinogenesis. Likewise, the inhibition of chemi-cally induced skin papillomas in mice topicallytreated with an iNOS inhibitor aminoguanidine[42], the enhancement of iNOS expression in PhIP-or azoxymethane (AOM)-initiated and dextransulfate sodium (DSS)-promoted mouse colon carci-nogenesis [43,44], and the suppression of DSS-induced mouse colon adenocarcinoma formationby an iNOS inhibitor ONO-1714 [45] strongly sup-port the contribution of iNOS and NO to tumori-genesis. In addition, pro-inflammatory cytokines,such as interleukin 1 (IL-1), IL-6, IL-8 and tumornecrosis factor-a (TNF-a), have also been knownto be involved directly or indirectly in carcinogene-sis [21]. Thus, components of the inflammatorysignaling pathways are recognized as potentialtargets for chemoprevention.

Resveratrol exhibited anti-tumor promotingeffects by blocking the expression of various compo-nents of pro-inflammatory signaling. The com-pound significantly inhibited the expression ofCOX-2 in lipopolysachaaride (LPS)-, TPA- or

H2O2-stimulated mouse peritoneal macrophages[46], LPS plus interferon-c (IFN-c)-treated RAW264.7 macrophages [47], and TPA-stimulated mouseskin [48]. Resveratrol also down-regulated theexpression of cox-2 mRNA transcript in N-nitro-somethylbenzylamine (NMBA)-induced esophagealtumors in F344 rats [49]. Mutoh and colleagues[50] suggested that the inhibition of COX-2promoter activity in both unstimulated and trans-forming growth factor-a-stimulated colon cancer(DLD-1) cells by resveratrol was partly attributedto the resorcin moiety present in the molecule.Resveratrol diminished the COX-2 activity andreduced the production of PGE2 in peripheral bloodleukocytes stimulated with LPS plus IFN-c [51] andhuman mammary epithelial cells treated with TPA[52]. Resveratrol also suppressed the expressionand activity of iNOS [47,53]. The expression ofiNOS protein and its mRNA transcript, and sub-sequent NO generation in LPS-activated RAW264.7 cells were attenuated by resveratrol [53].

The expression of pro-inflammatory cytokinesappears to be differentially affected by resveratrol.While the compound significantly decreased theexpression of TNF-a mRNA in LPS-activatedJ774.2 macrophage cells [54] and peripheral bloodleukocytes [51], it failed to suppress IL-1b geneexpression in J774.2 cells [54]. However, the inhibi-tion of proliferation and induction of apoptosis inhuman multiple myeloma (MM) cells by resveratrolwere found to be associated with its interferencewith signaling pathways initiated by IL-1b [55]. Res-veratrol significantly reduced the serum IL-6 level inmice transplanted with lymphocytic leukemia L1210cells [56]. The expression of IL-8 protein and/or itsmRNA 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 isarrested by treatment with resveratrol at differentphases of the cell cycle [3, references therein]. Theinhibition of ornithine decarboxylase (ODC), a bio-chemical hall mark of tumor promotion, accountedfor the anti-proliferative and anti-tumor effects ofresveratrol [58]. Recently, Ulrich and colleagues[59] have demonstrated that resveratrol suppressesODC activity via de novo synthesis of ceramides inhuman colon cancer (Caco-2) cells.


The inhibition of abnormal cell proliferation viamodulation of cell cycle progression is one of theimportant strategies for chemoprevention as wellas chemotherapy. Intracellular signaling pathways,comprised of various cyclins, cyclin-dependentkinases (Cdk), Cdk inhibitors, and check pointkinases (Chk 1 and Chk 2), are involved in fine-tun-ing of homeostatic maintenance of cell growth anddifferentiation [60,61]. Therefore, the suppressionof abnormal cell proliferation by down-regulatingcyclin-Cdks and/or upregulating Cdk inhibitorsmay provide an ample scope to intervene in the mul-tistage carcinogenesis by dietary phytochemicals.Resveratrol has been reported to inhibit inappropri-ate proliferation and growth of various cancer cellsin culture, tissues from animals exposed to carcino-genic insults and xenografted tumors in vivo by tar-geting aforementioned signaling molecules involvedin regulating cell cycle progression [3, vide infra].

The anti-proliferative and growth inhibitoryeffects of resveratrol have been attributed to its abil-ity to block DNA synthesis [62] and interferencewith various stages of cell cycle progression [24].Resveratrol arrested the growth of human epider-moid carcinoma (A431) cells via down-regulationof the expression of some cyclins (D1, D2 and E),inhibition of the expression and/or activities ofCdk (-2, -4 and -6) and upregulation of p21WAF1/CIP1

[63]. In addition, the anti-proliferative effect of res-veratrol in A431 cells was associated with a decreasein the expression of E2F transcription factor as wellas the reduced level of the hyperphosphorylatedform of Rb protein [64]. Resveratrol suppressedthe expression of Cdks (-2, -4 and -6) and cyclins(D1 and D2), and elevated the expression ofp21WAF1/CIP1 and p53 in SKH-1 hairless mouse skinstimulated with UV irradiation [65]. Likewise,resveratrol elicited an anti-proliferative effect by tar-geting cyclin D1 and Cdk4 in human prostate (DU-145) [66] and breast (MCF-7) [67] cancer cells,which was associated with the induction of p53and p21WAF1/CIP1. Moreover, resveratrol blockedthe formation of the cyclin E-Cdk2 complex inDU-145 cells without altering the protein levels[66]. Treatment of A549 cells with resveratrolresulted in the S-phase arrest, inhibition of Rb phos-phorylation and induction of p21WAF1/CIP1 and p53proteins [68]. In addition to its common inhibitoryeffect on cyclin B1 expression in a series of humancancer (MCF-7, SW480, HCE7, Seg-1, Bic-1 andHL-60) cells, resveratrol diminished the expressionof cyclin A and cyclin D1 in human colon cancer

(SW480) cells [69]. Although resveratrol attenuatedthe expression of cyclin D1 in SW480 cells, it failedto inhibit the cyclin D1 promoter activity [69].According to Wolter et al. [70], resveratrol inhibitedthe expression of cyclin D1 and its complex forma-tion with Cdk4, but increased the expression ofcyclin E and cyclin A in human colon cancer(Caco-2 and HCT-116) cells. Likewise, resveratrolactivated ataxia telangiectasia mutated (ATM)/ataxia telangiectasia-Rad3-related (ATR)-Chk1/2,phosphorylated cell division cycle (Cdc)-25C, Cdc-2 and histone 2AX, and induced S phase arrest inhuman ovarian cancer (OVCAR-3) cells, while itcaused only marginal S phase arrest in normalhuman foreskin fibroblasts [71].

Besides the modulation of cell cycle regulatoryproteins, resveratrol inhibits tumor growth by tar-geting several components of protein translationmachinery. Resveratrol attenuated insulin-likegrowth factor-1-induced phosphorylation of proteintranslation regulators, such as 4E-BP1, eIF4E and70S6K1, and expression of S6 ribosomal kinase inovarian cancer (A2780/CP70 and OVCAR-3) cells[72]. Moreover, resveratrol-induced growth inhibi-tion in human breast cancer (MDA-MB-231) cellswas partly associated with a reduced expression ofpS6 ribosomal protein [73].

2.3.2. Induction of apoptosis

The induction of apoptosis selectively in cancercells is regarded as an important strategy for cancerprevention as well as therapy. Resveratrol has beenreported to induce apoptosis in various cancerousor transformed cells in culture, chemically inducedmouse skin tumors, and in transplanted tumors innude mice by activating both extrinsic and intrinsicpathways of cell death machinery [3,12,74]. Multiplelines of evidence suggest that resveratrol inducesapoptosis by activating pro-apoptotic signalingmolecules as well as inhibiting anti-apoptotic mole-cules of the intracellular signal transduction path-ways. The induction of apoptosis in humanpromyelocytic leukemia (HL-60) and breast cancer(T47D) cells by resveratrol was mediated via activa-tion of the CD95–CD95L signaling [75]. Most nota-bly, resveratrol did not affect the survival of normalperipheral blood lymphocytes up to 72 h, suggestingthat the compound induced apoptosis selectively incancer cells [75]. Resveratrol failed to alter theexpression level of FAS or FAS-L in human coloncancer (SW480) cells, but rather redistributed cellsurface receptors such as CD95, death receptor


(DR)-4 and DR5 in membrane lipid rafts, therebyinducing a caspase-dependent, but Bcl-2-indepen-dent apoptosis [76,77]. Co-incubation of these can-cer cells with nystatin, a cholesterol sequesteringagent, attenuated resveratrol-induced redistributionof death receptors into membrane lipid rafts anddeath receptor-mediated cell death [77]. In anotherstudy, resveratrol was shown to sensitize variouscancer cells to TNF-related apoptosis-inducingligand (TRAIL)-dependent cell death via stimula-tion of both death receptor and mitochondrialapoptotic signaling pathways [78]. Likewise, pre-treatment of human prostate cancer (PC-3 andDU-145) cells with resveratrol resulted in TRAIL-,FAS- or TNF-a-mediated cells death by multiplemechanisms involving down-regulation of inhibitorof apoptotic protein (IAPs), suppression of Aktphosphorylation, and subsequent activation ofcaspases [79].

Resveratrol inhibited mitochondrial F1F0-ATP-ase, an enzyme involved in cellular ATP synthesis,providing a possible explanation for resveratrol-induced dysfunction of mitochondria and inductionof apoptosis [80]. By targeting the mitochondria-dependent (intrinsic) pathway, resveratrol activatedp53 and caspases, stimulated cytochrome c releasefrom mitochondria, upregulated pro-apoptoticBax, downregulated anti-apoptotic Bcl-2, andinduced DNA fragmentation [13,24,67]. Resveratrolinduced apoptosis in various cancer cells in a celltype-specific manner, being p53-dependent in cer-tain cells [81,82], while p53-independent in others[83,84]. The upregulation of p53-responsive genessuch as p21WAF1/CIP1, p300/CBP and Apaf1 by res-veratrol predisposed human prostate cancer(LNCaP) cells to undergo apoptosis [85]. Similarly,resveratrol-induced apoptosis in HepG2 cells whichwas accompanied by a p53-dependent increase inBax and p21 [82]. Resveratrol increased the mito-gen-activated protein (MAP) kinase-mediated phos-phorylation of p53 at serine 15 residue, therebyinducing apoptosis in JB6 Cl41 cells [86,87]. In addi-tion to its role in cancer cell death, resveratrolinduced apoptosis in chemically induced mouse skinpapillomas via induction of p53, release of cyto-chrome c, activation of Bax, inhibition of Bcl-2,and processing of caspases, such as caspase 9, cas-pase 3 and cleavage of poly-(ADP)ribosylpolymer-ase (PARP) [74]. Resveratrol also activatedcaspase-2 and -8, resulting in the processing ofdown-stream caspases and cell death in a deathreceptor or mitochondria-independent manner

[88]. The induction of apoptosis in HCT-116(Bax+/�) cells by resveratrol was mediated via acti-vation of caspase 6 and subsequent degradation ofnuclear coat protein lamin A [89].

Although resveratrol is a well known anti-oxi-dant, the compound was shown to impose bothredox and replication stress in cells, resulting insenescence-like growth arrest. Heiss et al. [81] dem-onstrated that resveratrol generated mitochondria-derived ROS in HCT-116 cells and inducedsenescence-like growth arrest by increasing phos-phorylation of p53 and elevation of the p21 levelvia activation of p38 MAP kinase and ATM kinase.Preincubation of cells with the anti-oxidant N-ace-tylcysteine abrogated resveratrol-induced ROSgeneration and apoptosis in these cells [81]. In con-trast, a p53-independent mechanism for resveratrol-induced apoptosis of HCT-116 cells was reported[83,84].

Lin et al. [90] reported that resveratrol, by actingas a ligand capable of binding to b3 domain of a cellsurface receptor integrin-aVb3, transduced activat-ing signals to extracellular signal-regulated proteinkinase (ERK) and p53, and induced apoptosis inMCF-7 cells. Another interesting mechanisminvolved in p53-dependent apoptosis was observedin MCF-7 and MDA-MB-231 cells treated with res-veratrol [91]. According to this study, resveratrol-induced apoptosis was mediated via enhanced intra-nuclear colocalization of COX-2, phosphorylatedp53 (at serine 15 residue), and transcriptional co-activator p300. The interaction of COX-2, p53 andp300 was blunted by treatment of MCF-7 cells witha MAP kinase inhibitor PD98059. Moreover, block-ing the COX-2 function with a pharmacologicinhibitor or small interfering RNA reduced resvera-trol-induced p53 phosphorylation and apoptosis inthe MCF-7 cells [91]. The inhibition of casein kinase2 was associated with resveratrol-induced apoptosisin prostate cancer cells [92]. Furthermore, the inhi-bition of Akt, activation of glycogen synthasekinase (GSK)-3b and attenuation of cell survivalsignal-mediated via notch partly accounted for res-veratrol induced apoptosis in T-cell acute lympho-blastic leukemia cells [93].

2.4. Inhibition of angiogenesis

Since the pioneering study by Judah Folkman,the molecular mechanisms of tumor angiogenesishave been thoroughly investigated. The disruptionof angiogenic signaling cascades appeared as a front


line of attack by various anti-cancer agents. Therehas been paramount information in the literature,suggesting anti-angiogenic effects of resveratrol.Due to increased metabolic activities and oxygenconsumption by rapidly proliferating cells, solidtumors are likely to maintain an intratumoral hyp-oxic environment [94,95], which enforces tumor cellsto adapt by inducing hypoxia responsive genes[96,97]. Hypoxia inducible factor (HIF) acts as amaster regulator of cellular oxygen homeostasis byregulating expression of hypoxia-responsive genes[98]. Some of well-defined HIF-regulated angiogenicfactors include vascular endothelial growth factor(VEGF), basic fibroblast growth factor (bFGF),VEGF receptor (VEGFR), IL-8, iNOS and angio-poietins [96,99].

Resveratrol has been reported to inhibit theexpression of HIF-1a and VEGF in OVCAR-3 cellsthrough multiple mechanisms, such as inhibition ofAkt and MAP kinases, inhibition of protein transla-tional regulators, and enhancement of proteasomaldegradation of HIF-1a protein [72]. Moreover, res-veratrol significantly reduced hypoxia-induced HIF-1a protein accumulation and VEGF expression inhuman tongue squamous cell carcinomas (SCC-9)and HepG2 cells, without affecting HIF-1a mRNAexpression, partly by inhibiting activation of ERKand Akt, and promoting proteasomal degradationof HIF-1a [100]. According to a recent study, resve-ratrol retarded tumor growth and angiogenesis inERa/ERb (+) MDA-MB-231 breast tumor xeno-grafts in nude mice and reduced extracellular levelsof VEGF in vitro [12].

2.5. Anti-invasive and anti-metastatic effects

The invasion of tumor cells through tumor-asso-ciated stroma and subsequent metastasis are thecentral events in neoplastic progression. One ofthe mediators of tumor invasion and metastasis islysophosphatidic acid (LPA), which has beenreported to enhance migration of human ovariancancer cells through upregulation of HIF-1a andVEGF [101]. Resveratrol significantly attenuatedLPA-induced expression of HIF-1a and VEGF,and subsequent migration of ovarian cancer cellsby blocking activation of upstream ERK1/2 andp70S6 kinase [101]. Busquets et al. [102] demon-strated protection against lung metastasis by resve-ratrol in mice intramuscularly transplanted withLewis lung carcinoma cells. Resveratrol inhibitedinvasion of various cancer cells by reducing the

expression and activity of matrix metalloprotein-ase-2 (MMP-2) and -9 (MMP-9) [103–105]. Theinhibition of endogenous peroxide levels anddown-regulation of hepatocyte growth factor(HGF), a well known cell motility factor, by resve-ratrol in ROS-stimulated rat ascites hepatoma(AH109A) cells suggests that the anti-oxidant prop-erty of this compound accounts for its anti-invasiveand anti-metastatic effects [106]. Moreover, resvera-trol decreased the chemotactic response of meta-static MDA-MB-231 cells by reducing the focaladhesion kinase activity [107].

2.6. Chemosensitizing effects

Currently, the emergence of resistance to chemo-therapy is a growing challenge in reducing cancer-related deaths worldwide. The use of cancer chemo-preventive phytochemicals as adjuvants in combina-tion with chemotherapeutic agents has been shownto be a pragmatic approach to sensitize chemoresis-tant cancer cells to apoptosis or growth arrest, whileminimizing the side effects arising from the conven-tional therapy [9]. As an example, resveratrolenhanced the apoptotic effects of bortezomib andthalidomide in multiple myeloma cells [108]. Resve-ratrol, used as a combination therapy with etopo-side, inhibited growth and induced apoptosis ofhuman colon cancer (HT-29) cells by a ROS-depen-dent activation of adenosine monophosphate(AMP)-activated protein kinase (AMPK) [109].Treatment of OVCAR-3 and uterine (Ishikawa)cells with resveratrol in combination with cisplatinor doxorubicin elicited an additive growth inhibi-tory effect with a left shift of the therapeuticallyeffective range of these chemotherapeutic agents ina dose–response curve, while resveratrol enhancedviability of neonatal rat cardiac myocytes andreduced bradycardia in mice treated with doxorubi-cin [110]. These findings suggest that resveratrol, asan adjuvant to chemotherapy, can enhancechemosensitvity of cancer cells, while it alleviatesunavoidable chemotherapy-associated adverseeffects. P-Glycoprotein, a product of multi drugresistant (MDR)-1 gene, has been considered as akey player in developing chemoresistance. Byactively effluxing drugs from cells, P-glycoproteinreduces intratumoral concentrations of chemothera-peutic drugs and hence lowers their efficacy.Resveratrol was shown to inhibit the P-glycoproteinfunction and increase accumulation of daunorubicin

MAP Kinases

PI3K

/Akt

Nrf2 p53

MAP Kinases, IKK, PKC

NF-κB AP-1

PI3K

/Akt

APOPTOSIS

GROWTH ARREST ANTIINFLAMMATIONANTIANGIOGENESIS ANTIMETASTASIS

CARCINOGENDETOXIFICATION

NF-κB/AP-1

STAT3HIF-1αN

orm

al c

ells

Cells/tissues stimulated with oncogenic stimuli

MAP KinasesNF-κB/AP-1

Cancer cells

Resveratrol

Fig. 2. Upstream kinases and transcription factors in theintracellular signaling network as potential targets of resveratrolin normal and cancer cells. These signal transducers are subject tofine-tuning in normal cells to maintain homeostasis, while manyof them are constitutively overactivated or deregulated incancerous or transformed cells. Some external stimuli (e.g.,carcinogens, tumor promoters, growth factors, UV, ROS,inflammatory cytokines, bacterial toxins, etc.) cause abnormalfunctioning of some of transcription factors or their regulators innormal cells. Depending on the cell types and stimuli, resveratroleither suppresses the abnormal expression/activation of particu-lar signal pathways or restores the activities of others whosefunction is suppressed or not properly working.


in multidrug resistant KB-C2 cells, thereby sensitiz-ing these cells to apoptosis [111].

3. Upstream kinases and transcription factors asmolecular targets of resveratrol

The multistage carcinogenesis involves a break-ing of the ‘chain-of-command’ in the normal intracel-lular signaling network. A panel of receptorproteins, linkers, upstream kinases, DNA-interact-ing proteins, and transcriptionally regulated geneproducts function abnormally during the course ofcarcinogenesis. In response to carcinogenic insults,the microenvironment of intracellular signaling net-work becomes disrupted, thereby favoring premalig-nant and malignant transformation of damagedcells [38]. Mounting data from pre-clinical studiesconducted in cultured cells and experimental ani-mals indicate that resveratrol can modulate abnor-mal turning on or switching off various upstreamkinases and transcription factors (Fig. 2).

3.1. Modulation of inappropriate signaling via

upstream kinases

A wide array of plasma membrane-bound orcytosolic protein kinases, such as proline-directedserine threonine kinases, tyrosine kinases, and dif-ferent isoforms of protein kinase C, function asimportant components of various intracellular sig-naling pathways to translate extracellular signalsinto biological responses. Many of these signalingenzymes are aberrantly activated in response todiverse external stimuli including radiation, chemi-cal carcinogens, growth factors, bacterial toxins,etc., and actively participate in oncogenic signaltransduction. Signals transmitted via one or moreof these upstream kinases converge on down-streamtranscription factors, thereby transactivating a vastvariety of target genes. Resveratrol has been shownto modulate signal transduction mediated by manyof these upstream kinases.

3.1.1. MAP kinasesMAP kinases comprise several distinct sets of ser-

ine–threonine kinases with ERK, p38 MAP kinaseand C-Jun-N-terminal kinase (JNK) as representa-tive members [2,38]. Signaling through MAP kinasecan both enhance proliferation and cause growtharrest [112,113]. While the activation of someMAP kinases has been reported to be associatedwith resveratrol-induced inhibition of proliferation

and induction of apoptosis in various cancer cells[73,86,114–116], significant down-regulation ofstimulus-induced phosphorylation of MAP kinasesby resveratrol has been attributed to the anti-inflam-matory and anti-tumor promoting effect of this phy-tochemical [48,65,104,117,118]. Resveratrolsuppressed TPA-induced phosphorylation of allthree representative MAP kinases, such as ERK1/2, p38 MAP kinase and JNK in HeLa cells [118]and mouse skin in vivo [48,117]. Moreover, resvera-trol inhibited UV-induced expression of MAPkinase kinase (MEK), but not ERK1/2, in SKH-1hairless mouse skin [65]. Resveratrol down-regu-


lated the phosphorylation of ERK1/2 in humanbreast cancer cells treated with a growth factorheregulin-b1 [104] and also in human epidermoidcarcinoma (A431) cells [119]. In addition, TPA-induced growth of androgen-independent humanprostate cancer cells was suppressed by resveratrolthrough inhibition of phosphorylation of ERK1/2[120].

3.1.2. PKC

Resveratrol exerts inhibitory effects on PKC-mediated signaling. Subbaramaiah and colleaguesreported that resveratrol inhibited TPA-inducedPKC expression in human mammary and oral epi-thelial cells [52]. The inhibition of TPA-inducedgrowth of human prostate cancer (PC3) cells by res-veratrol was partly dependent on the translocationof cytosolic PKCa to the plasma membrane as wellas autophosphorylation of both cytosolic and mem-brane bound PKCa [120]. Resveratrol diminishedTPA-induced PKCd expression and reduced themetastatic potential of human cervical cancer (Cisa-ki) cells [121]. Storz et al. [122] also demonstratedthat resveratrol inhibited H2O2-induced NF-jBactivation in HeLa cells partly by blocking activa-tion of PKCl, which is alternatively known as pro-tein kinase D (PKD). However, an in vitro studyrevealed that resveratrol inhibited TPA-inducedautophosphorylation of PKD, but not that of otherisoforms of PKC [123]. On the other hand, resvera-trol attenuated the proliferation of human gastricadenoma cells by blocking PKC activity, withoutinfluencing the phosphorylation of ERK1/2 [124].

3.1.3. PI3K/Akt

The phosphorylation of another upstream kinaseAkt in MCF-7 cells was abrogated by resveratrol[125]. Resveratrol induced apoptosis in human Tcell acute lymphoblastic leukemia cells by inhibitingphosphorylation of Akt and subsequent activationof GSK3b [93]. The induction of apoptosis by resve-ratrol in ovarian [126], breast [127], uterine [128],and prostate [129,130] cancer cells and multiplemyeloma cells [108] was associated with the inhibi-tion of Akt phosphorylation.

3.2. Targeting transcription factors

Transcription factors are DNA-interacting pro-teins, which transcriptionally regulate the expres-sion of various target genes. Signaling pathwaysmediated via upstream kinases converge on diver-

gent classes of transcription factors, which act inde-pendently or co-ordinately to regulate expression ofcritical genes involved in various physiological pro-cesses [2]. Abnormal activation or inactivation ofvarious transcription factors results in disrupted cel-lular protein repertoire, thereby facilitating celltransformation and malignancy. Enhanced activa-tion of NF-jB or activator protein-1 (AP-1) con-tributes to tumorigenesis either by transactivatingpro-inflammatory (e.g., cox-2, iNOS), anti-apopto-tic (e.g., cIAP1, cIAP2, XIAP, Bcl-2, Bcl-3 andBcl-XL), and the cell cycle regulatory genes (e.g.,cyclin D1) or by transcriptional repression of apop-tosis-inducing genes (e.g., p53) [131–133]. Genescontributing to angiogenesis harbors hypoxiaresponse elements (HRE) located on their promoterregion, and improper activation of HIF-1a turns onvarious angiogenic switches, such as VEGF andHO-1.

Accumulating data from a wide range of in vitroand in vivo studies suggest that resveratrol sup-presses inducible or constitutive activation of majortranscription factors such as NF-jB [48,108], AP-1[117,119], and signal transducer of activated tran-scription (STAT)-3 [108,134]. Complementary toits inhibitory effect on the activation of aforemen-tioned transcription factors, which are mostlyinvolved in upregulating inflammatory gene expres-sion, resveratrol has been reported to activatenuclear factor E2 related factor-2 (Nrf2) thereby ele-vating the expression of Nrf2-regulated anti-oxidantand detoxification enzymes [32,36,37]. Moreover,resveratrol has been reported to act as a ligand ofnuclear receptor transcription factor peroxisomeproliferating activated receptor-c (PPARc) [135].

3.2.1. Nrf2

Resveratrol up-regulates anti-oxidant and phaseII detoxifying enzymes largely by activating Nrf2.As a basic-region leucine zipper (bZIP) transcrip-tion factor, Nrf2 preferentially binds to the anti-oxi-dant response element (ARE, alternatively knownas electrophile response element or EpRE) locatedin the promoter region of many genes encodingphase II enzymes, thereby regulating their transcrip-tional activation [136]. In unstimulated cells, Nrf2 issequestered in cytoplasm by binding with an inhib-itory protein called Keap1 [136]. Activation ofupstream kinases such as Akt, ERK and JNK leadsto the dissociation of Nrf2 from keap1, therebyfacilitating nuclear translocation and ARE bindingof Nrf2 [2,136,137]. Several recent studies have


demonstrated that the compound can induce theexpression and activity of phase II detoxification/anti-oxidant enzymes in rat pheochoromocytoma(PC12) [32] and human leukemia (K562) cells [36]by promoting nuclear translocation and subsequentARE binding of Nrf2. Reportedly, resveratrolenhanced Nrf2 signaling via mechanisms involvingthe activation of upstream kinases, such as Aktand ERK1/2 [32]. Since resveratrol contains a resor-cin moiety that can chelate metal ions, and the Nrf2inhibitory protein Keap1 is a zinc metalloprotein[138], Nrf2 activation by resveratrol may alterna-tively be mediated through inactivation of Keap1as a consequence of chelation with zinc ion. More-over, resveratrol-induced Nrf2-driven GCL expres-sion and subsequently GSH biosynthesis in humanlung epithelial cells by reversing CSE-inducedpost-translational modifications of Nrf2 [37].

3.2.2. NF-jBResveratrol attenuated nuclear translocation and

DNA binding of NF-jB in LPS-stimulated Raw264.7 cells by blocking phosphorylation and degra-dation of IjBa [53,139]. Manna et al. [140] demon-strated that resveratrol inhibited the activation ofNF-jB in Jurkat-T, HeLa and glioma cells treatedwith different stimuli, such as TPA, LPS, H2O2,okadaic acid, and ceramide. Likewise, resveratrolsuppressed the activation of NF-jB in IL-1b- andCr (VI)-stimulated acute myeloid leukemia(OCIM2) cells [55] and mouse epidermal (JB6) cells[141], respectively. While resveratrol diminishedTNF-a-induced activation of NF-jB in U937 cellsby suppressing phosphorylation and nuclear trans-location of p65 without affecting IjBa degradation[140], the compound inhibited UVB-induced activa-tion of NF-jB in normal human epidermal kerati-nocytes by blocking the activation of upstreamIKKa as well as phosphorylation and degradationof IjBa [142]. Resveratrol suppressed LPS-inducedactivation of NF-jB by inhibiting phosphorylationand transactivation potential of p65, but failed toinhibit nuclear translocation of NF-jB/Rel proteins[143]. In contrast, the constitutive nuclear accumu-lation of p65 protein in human multiple myelomacells was diminished by resveratrol [144]. Topicalapplication of resveratrol attenuated TPA-inducedNF-jB activation in mouse skin in vivo by blockingthe activation of IKK, phosphorylation of IjBa andp65, nuclear translocation of p65 and interaction ofp65 with a transcriptional co-activator cyclic AMP-response element binding protein-binding protein

(CBP) [48]. Resveratrol also suppressed prolifera-tion and induced apoptosis in human multiple mye-loma cells by inhibiting the constitutive activationof NF-jB via blockade of IKK activity and subse-quent phosphorylation of IjBa [108]. Alternatively,resveratrol exerted epigenetic control on NF-jBactivation by inducing SIRT1 activation [145,146].It was reported that SIRT1, a nicotinamide adeno-sine dinucleotide-dependent histone deacetylase,interacted physically with the RelA/p65 andnegated NF-jB-driven gene transcription by deacet-ylating RelA/p65 at lysine 310 [146]. Resveratrolinhibited CSE-induced NF-jB activation and NF-jB-regulated pro-inflammatory gene expression byactivating SIRT1 in monocyte-macrophage (Mono-Mac6) cells, bronchoalveolar lavage fluid, and ratlungs [145].

3.2.3. AP-1

Resveratrol diminished TPA-induced activationof AP-1 in human mammary epithelial cells[52,147], human leukemia cells U937 [148] andmouse skin in vivo [117], but the compound failedto suppress AP-1-driven transcriptional activity inLPS-stimulated human monocytic (THP-1) cells[143]. By inactivating AP-1, resveratrol suppressedproliferation of human epidermoid carcinoma(A431) cells [119]. Resveratrol attenuated the AP-1reporter gene activation in HeLa cells stimulatedwith UVC or TPA by blocking activation of MAPkinases and PKC [118]. It also diminished TNF-a-induced AP-1 DNA binding in U937 cells [140].

3.2.4. Other transcription factors

The hypoxia- or growth factor-induced expres-sion of HIF-1a, a transcription factor that regulatesthe induction of hypoxia-responsive genes, inhuman tongue squamous cell carcinoma, hepatoma[100] and ovarian carcinoma cells [72], was inhibitedby resveratrol. According to Urlich et al. [135], res-veratrol induced transcriptional activation ofPPARc, but not its protein expression, andincreased the expression of a PPAR-c target genecytokeratin 20 in Caco-2 cells by acting as aPPAR-c ligand. Resveratrol-induced activation ofPPARc resulted in elevated expression of sperm-ine/spermidine acetyltransferase, an enzymeinvolved in polyamine metabolism, thereby inhibit-ing proliferation of colorectal cancer cells [135].The induction of apoptosis and growth arrest inSW480 cells by resveratrol was associated with adiminished expression of b-catenin and its target


gene product cyclin D1 [69]. The phosphorylation ofSTAT3, an immediate early step in STAT3 nucleartranslocation and its DNA binding, was suppressedby resveratrol in IL-6-stimulated human multiplemyeloma cells [108] and in some other malignantcells constitutively expressing STAT3 [134]. Treat-ment of human epidermoid carcinoma (A431) cellswith resveratrol resulted in diminished expressionof all E2F family members of transcription factorsinvolved in controlling the progression of cell cycleat and near G1-S phase transition [64].

4. Conclusion

Fighting cancer with naturally occurring sub-stances, especially those derived from plant-baseddiet, appears to be a fascinating strategy. We arecurrently passing an accelerated phase of developingdietary phytochemicals as potential chemopreven-tive/chemotherapeutic agents. Due to extreme het-erogeneity of cancer cells, it is hard to find aspecific molecular target for the prevention or treat-ment of cancer. Thus, a cancer preventive/therapeu-tic agent should target multiple biochemicalpathways involved in the process leading to malig-nancy, while limiting any undesired toxicity or sideeffects in normal tissues. Among the ever-increasinglist of naturally occurring anti-carcinogenic agents,resveratrol has been extensively investigated withregards to its underlying molecular and cellularmechanisms. As discussed in previous sections ofthis article, resveratrol has been reported to targetdiverse molecular switches involved in carcinogenmetabolism (both activation and detoxification),inflammation, cell proliferation, cell cycle, apopto-sis, angiogenesis, tumor metastasis, etc. Consideringits multifarious molecular targets, John Pezzuto hasasserted very timely that resveratrol induces ‘biolog-ically specific tsunami’ [149]. While numerous stud-ies are coming up with multiple molecular targets ofresveratrol to prevent cancer, Baur and Sinclair [4]have recently proposed that resveratrol might fol-low the same pathway as does calorie restriction.Although the mechanism of calorie restriction asan anti-cancer regimen has been addressed [150],how exactly resveratrol can follow these mecha-nisms is yet to be investigated.

Despite substantial progress in the understandingof the molecular basis of anti-carcinogenic activitiesof resveratrol, there have been very few clinicalstudies commensurate with its preclinical findings.A recent phase I clinical trial demonstrates that

consumption of resveratrol (5 g) does not causeany serious adverse effects in healthy volunteers,but the peak plasma level (2.4 lmol/L) remainsmuch below the minimum required concentration(5 lmol/L) of the compound to exert the chemopre-ventive effect in cultured cells [151]. The study alsoindicates the presence of several fold higher plasmalevels of resveratrol monoglucuronides and resvera-trol-3-sulfate. A phase-I clinical trial for evaluatingthe safety and the pharmacokinetic profile ofrepeated administration of resveratrol has recentlybeen launched [4]. Another phase-I colon cancerprevention trial is currently underway at the Univer-sity of California, Irvine, USA [4]. Results of thesephase I trials will provide important backgroundinformation useful in designing large scale clinicaltrials to ascertain the chemopreventive and chemo-therapeutic efficacy of resveratrol. Pharmacokineticdata from studies with murine models suggest apoor bioavailability of resveratrol. Thus, furtherstudies are necessary to enhance the bioavailabilityof resveratrol by modulating its metabolism, devis-ing an appropriate formulation, identifying possibleinteractions with other dietary factors, and develop-ing more bioavailable analogues of the compound.Nevertheless, currently available preclinical andmechanistic data suggest that resveratrol might bea promising candidate to be applied for the molecu-lar target-based cancer prevention and adjuvanttherapy.

Acknowledgements

This work was supported by the National Re-search Laboratory Fund from the Ministry of Sci-ence and Technology and the Grant (B050007)from the Ministry of Health and Welfare, Republicof Korea.

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Cancer Chemo Preventive and Therapeutic Potential

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