Published OnlineFirst April 28, 2009; DOI: 10.1158/1940-6207.

CAPR-08-0160

Review

Cancer Prevention and Treatment with Resveratrol:

From Rodent Studies to Clinical Trials

Anupam Bishayee

Abstract Resveratrol (3,4′,5-trihydroxy-trans-stilbene) is a dietary polyphenol derived from grapes,

berries, peanuts, and other plant sources. During the last decade, resveratrol has been
shown to possess a fascinating spectrum of pharmacologic properties. Multiple biochemical
and molecular actions seem to contribute to resveratrol effects against precancerous or can-
cer cells. Resveratrol affects all three discrete stages of carcinogenesis (initiation, promotion,
and progression) by modulating signal transduction pathways that control cell division and
growth, apoptosis, inflammation, angiogenesis, and metastasis. The anticancer property of
resveratrol has been supported by its ability to inhibit proliferation of a wide variety of human
tumor cells in vitro. These in vitro data have led to numerous preclinical animal studies to
evaluate the potential of this drug for cancer chemoprevention and chemotherapy. This
review provides concise, comprehensive data from preclinical in vivo studies in various
rodent models of human cancers, highlighting the related mechanisms of action. Bioavail-
ability, pharmacokinetic, and potential toxicity studies of resveratrol in humans and ongoing
interventional clinical trials are also presented. The conclusion describes directions for future
resveratrol research to establish its activity and utility as a human cancer preventive and
therapeutic drug.

The ability of natural agents to suppress carcinogenesis has Many preclinical and clinical studies have shown that re-
attracted the widespread attention of cancer prevention and sveratrol can prevent or slow the progression of a wide variety
treatment researchers. The natural agent resveratrol (3,4′,5-trihy- of age-associated illnesses, including cancer, diabetes, arthritis,
droxy-trans-stilbene) has been shown to possess many biological and coronary, neurodegenerative, and pulmonary diseases
activities relevant to human cancer prevention and treatment (1–3). It also mimics caloric restriction, improves health, and
(1, 2). Resveratrol is a phytoalexin, or plant antibiotic, produced interferes with the aging process, all linked to its ability to ac-
in large quantities in various plants in response to environmental tivate sirtuin proteins (6, 7). Sirtuins are a conserved family of
stress and pathogenic attack and thus acts as a natural inhibitor NAD+-dependent protein deacetylases that are involved in
of cell proliferation (3). Perhaps most widely known as a constit- gene silencing processes related to aging, blockade of apopto-
uent of red wine, resveratrol has been detected in more than 70 sis, and promotion of cell survival. It has been speculated that
plant species, including grapes, berries, plums, peanuts, and the caloric restriction mimetic and antiaging mechanisms of
pines (3, 4). Epidemiologic studies have shown an inverse corre- resveratrol may contribute to its effects against cancer.
lation between red wine consumption and the incidence Extensive study over the past decade has shown both the
of cardiovascular disease, a phenomenon called the “French chemopreventive and chemotherapeutic potential of resvera-
paradox” and suggested to be due to resveratrol (5). trol (8, 9). It suppresses the proliferation of a wide variety of
human tumor cells in vitro (reviewed in ref. 9). The antitumor
activities of resveratrol are mediated through several cell sig-
Author's Affiliation: Department of Pharmaceutical Sciences, Northeastern
Ohio Universities Colleges of Medicine and Pharmacy, Rootstown, Ohio
naling pathways and include cell cycle arrest, suppression of
Received 8/8/08; revised 11/20/08; accepted 1/16/09; published OnlineFirst tumor cell proliferation, induction of apoptosis and differenti-
4/28/09. ation, reduction of inflammation and angiogenesis, and inhi-
Grant support: Research Incentive Grant from the Ohio Board of Regents,
State of Ohio.
bition of adhesion, invasion, and metastasis (Fig. 1; reviewed
Note: The author sincerely apologizes for not discussing and citing numer- in refs. 9–11). Although resveratrol anticarcinogenic potential
ous important publications because of the limitation of space and of the number has been linked with an impressive amount of data primarily
of references. This review is dedicated to the memory of Amiya K. Bishayee.
Requests for reprints: Anupam Bishayee, Department of Pharmaceutical from human cell culture systems, emerging results of cancer
Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, prevention and therapy studies in laboratory animal models
4209 State Route 44, Rootstown, OH 44272. Phone: 3303256449; Fax: provide convincing evidence that resveratrol can inhibit carci-
3303255936; E-mail: [email protected].
©2009 American Association for Cancer Research. nogenesis in several organ sites. This evidence is summarized
doi:10.1158/1940-6207.CAPR-08-0160 in this review, which also highlights underlying mechanisms

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Review

Fig. 1. Effect of resveratrol on intracellular signal transduction pathways involved in carcinogenesis [adapted from Kundu and Surh (11)]. AP-1, activator protein-1;
HIF-1α, hypoxia-inducible factor-1α; IKK, IκB kinase; MAPKs, mitogen-activated protein kinases; NF-κB, nuclear factor-κB; PI3K, phosphoinositide 3-kinase; PKC,
protein kinase C; STAT3, signal transducer and activator of transcription 3.

that provide a rationale for testing resveratrol clinically in hu- that resveratrol inhibited the expression of survivin and mar-
man populations. kers of tumor promotion, such as COX-2 and ODC, in the skin
of mice (19). In an extension of these mechanistic studies, re-
sveratrol treatment both before and after UVB exposure re-
In vivo Preclinical Studies
sulted in a significant reduction of mouse skin tumor
Skin incidence and delay in the onset of tumorigenesis involving
Conducted by Jang et al. (12), the first animal study of the up-regulated protein and mRNA levels of survivin and phos-
chemopreventive effects of resveratrol was reported in a pho-survivin protein and down-regulated proapoptotic
two-stage mouse skin carcinogenesis model. Topical resvera- Smac/DIABLO protein (20).
trol significantly reduced 7,12-dimethylbenz(a)anthracene Resveratrol via i.p. injection inhibited the growth of highly
(DMBA)–initiated and 12-O-tetradecanoylphorbol-13-acetate metastatic B16-BL6 melanoma cells in mice (21). In contrast,
(TPA)–promoted skin tumors in mice (Table 1). Subsequent oral resveratrol did not inhibit the growth of B16M melanoma
studies showed that pretreating mouse skin with resveratrol cells injected into the footpad of mice; it did, however, reduce
negated several TPA-induced effects, including increased the metastatic invasion of intrasplenically injected melanoma
expressions of cyclooxygenase (COX)-1, COX-2, c-myc, c-fos, cells into the liver (22). Moreover, resveratrol did not have a
c-Jun, transforming growth factor-β1, and tumor necrosis fac- significant effect in reducing the growth of an A375 human
tor-α (13). In the DMBA-TPA mouse skin carcinogenesis mod- melanoma xenograft in athymic mice, even stimulating this
el, resveratrol inhibited tumor promotion, possibly due at least growth at higher dose levels (23). These collective melanoma
partly to antioxidant effects (14). Soleas et al. (15) found that data suggest that resveratrol effects on melanoma depend on
resveratrol was moderately effective in inhibiting the rate of dose, route of administration, and the specific model studied.
tumor formation and reducing the number of animals devel-
oping DMBA-induced skin tumors. Resveratrol effectively Breast
prevented development of DMBA-TPA–induced mouse skin Although having no effect on tumor incidence, resveratrol
tumors through induction of apoptosis, characterized by in- in the diet strikingly reduced the incidence and multiplicity
duction of cytochrome c release, expression of p53, Bax, and of DMBA-induced mammary tumors, concurrently extending
apoptotic protease-activating factor-1, and inhibition of Bcl-2 the latency period, in mice. These findings were associated
(16). Afaq et al. (17) showed that resveratrol has the potential with decreased COX-2 and matrix metalloproteinase-9 expres-
to ameliorate edema and inflammation caused by short-term sion and suppression of nuclear factor-κB activation (24). Die-
UVB exposure in the skin of SKH-1 hairless mice, presumably tary resveratrol inhibited DMBA-induced mammary cancer in
due to inhibition of the photocarcinogen-mediated induction rats by enhancing maturation of the mammary gland, reduc-
of COX, ornithine decarboxylase (ODC), and lipid peroxida- ing cellular proliferation, and increasing apoptosis in mam-
tion, and topical resveratrol inhibited skin hyperplasia in- mary epithelial cells (25). Resveratrol combined with the soy
duced by UVB radiation in the SKH-1 hairless mouse isoflavone genistein was better than resveratrol alone in re-
model. Mechanistic studies in this model revealed that resver- ducing tumor multiplicity and extending tumor latency in rats
atrol exerted antiproliferative effects mediated through de- with DMBA-induced mammary tumors (26). Oral resveratrol
creased expression of cyclin-dependent kinase (CDK)-2, also reduced N-methyl-N-nitrosourea–induced tumorigenesis
CDK-4, CDK-6, cyclin D1, cyclin D2, proliferative cell nuclear in rats (27). However, a short-term prepubertal exposure to re-
antigen, and mitogen-activated protein kinase and increased sveratrol resulted in endocrine disruption, or altered endo-
expression of p21WAF1/CIP1 (18). Further study revealed crine function indicated by a significant increase in the

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Resveratrol and Cancer: In vivo and Clinical Studies

Table 1. In vivo effects of resveratrol on cancer development and growth and their possible mechanisms

Target/effects Mechanisms Dose/duration Route References

Skin
Reduces the number of skin tumors ↓COX-1; ↓COX-2; ↓c-myc; 1, 5, 10, 25 top. Jang et al. (12); Jang
initiated with DMBA and promoted ↓c-fos; ↓c-Jun; μmol and Pezzuto
by TPA in female CD-1 mice ↓TGF-β1; ↓TNF-α Twice/week for (13)
18 wk
Suppresses the development of Free radical scavenging 85 nmol/L top. Kapadia et al. (14)
DMBA-initiated and TPA-promoted 21 wk
papillomas in female ICR mice
Reduces the onset of skin tumors 1, 5, 10, 25 top. Soleas et al. (15)
with DMBA-TPA model in CD-1 mice μmol
Twice/week, 18
wk
Inhibits the development of ↑Apoptosis; ↑Bax; ↑p53; 50 μmol/mouse top. Kalra et al. (16)
DMBA-TPA–induced skin tumors ↓ Bcl-2; ↑cytochrome 3-24 week
in male Swiss albino mice c release; ↑APAF-1
Prevents UVB-mediated photocarcinogenesis ↓COX; ↓ODC; ↓lipid 25 μmol/mouse top. Afaq et al. (17)
in female SKH-1 mice peroxidation
Decreases UVB-induced skin ↑CDK-2, CDK-4, and CDK-6; 10 μmol/mouse top. Reagan-Shaw et al.
hyperplasia in female SKH-1 mice ↑ cyclin D1 and cyclin D2; 7 times, (18); Aziz et al.
↑ MAPK; ↑ p21; ↑p53; alternate days (19)
↓COX-2; ↓ODC; ↓survivin
mRNA and protein
Prevents UV radiation-mediated skin ↑Survivin mRNA and protein; 25, 50 μmol/ top. Aziz et al. (20)
tumorigenesis in female SKH-1 mice ↑ phospho-survivin; ↓Smac/ mouse
DIABLO Twice/week, 28
wk
Delays tumor growth in female 50 mg/kg i.p. Caltagirone et al. (21)
C57Bl/6N mice transplanted with 19 d
B16-BL6 melanoma cells
Does not slow down the growth of 20 mg/kg p.o. Asensi et al. (22)
B16M melanoma cells inoculated into 23 mg/mL d.w.
the footpad of male C57Bl/6J mice 10 d
Does not inhibit the growth of A375 0.005, 0.01% d.w. Niles et al. (23)
human melanoma cells xenografted 0.0025, 0.006% Diet
in male nu/nu mice 10, 25, 50, 100 s.p.
mg
Breast
Suppresses DMBA-induced mammary ↓NF-κB; ↓COX-2; ↓MMP-9 10 ppm Diet Banerjee et al. (24)
carcinogenesis in female 127 d
Sprague-Dawley rats
Suppresses DMBA-induced mammary ↓Proliferation; ↑apoptosis 100 mg/kg Diet Whitsett et al. (25)
cancer in Sprague-Dawley rats 25 wk
In combination with genistein improves 100, 333 mg/kg Diet Whitsett and
the tumor inhibitory action of Lifetime Lamartiniere (26)
resveratrol in DMBA-initiated
rat mammary carcinogenesis
Reduces MNU-induced mammary Estrogen modulation 100 mg/kg p.o. Bhat et al. (27)
tumorigenesis in female 127 d
Sprague-Dawley rats
Increases MNU-induced mammary Endocrine disruption 100 mg/kg s.c. Sato et al. (28)
carcinogenesis in female 37 wk
Sprague-Dawley rats
Inhibits the growth of MDA-MB-231 breast ↑Apoptosis; ↓angiogenesis 25 mg/kg i.p. Garvin et al. (29)
tumor explants in female athymic nude mice 3 wk

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Review

Table 1. In vivo effects of resveratrol on cancer development and growth and their possible mechanisms
(Cont'd)

Target/effects Mechanisms Dose/duration Route References

Does not influence the growth and metastasis 1, 3, 5 mg/kg i.p. Bove et al. (30)
of transplanted 4T1 mammary carcinoma 23 d
cells in female BALB/c mice
Delays the development and reduces ↑Apoptosis; ↓HER-2/neu; 0.2 mg/kg d.w. Provinciali et al. (31)
the metastatic growth of mRNA and protein 2 mo
spontaneous mammary tumors
in female HER-2/neu transgenic mice
In combination with quercetin 5, 25 mg/kg p.o. Schlachterman et al.
and catechin retards the growth of Thrice/week, (32)
xenografts of MDA-MB-231 117 d
cells in female athymic nu/nu mice

Prostate
Suppresses prostate cancer ↑ER-β; ↑IGF-I; 625 mg/kg Diet Harper et al. (33)
progression in male TRAMP model ↓phospho-ERK-1and ERK-2 7-23 wk
Suppresses prostate cancer ↑Apoptosis; ↓AR; 50, 100, d.w. Seeni et al. (34)
growth in male TRAP rats ↓GK11 mRNA 200 μg/mL
7 wk
Gastrointestinal tract
Inhibits AOM-induced colon ↑Bax; ↑p21 200 μg/kg d.w. Tessitore et al. (35)
carcinogenesis in male F344 rats 100 d
Suppresses DMH-induced Modulation of antioxidant defense 8 mg/kg p.o. Sengottuvelan et al.
colon carcinogenesis in and biotransformation enzymes 15-29 wk (36–38)
male Wistar rats
Prevents the formation of colon tumors ↓Cyclin D1 and cyclin D2; ↓DP1; ↓YB1; 0.01% d.w. Schneider et al. (39)
and reduces small intestinal ↑TGF-β; ↑TSG101 (all mRNA) 7 wk
tumors in ApcMin/+ mice
Decreases intestinal adenoma ↓COX-1; ↓COX-2; ↓PGE2 240 mg/kg Diet Sale et al. (40)
formation in ApcMin/+ mice 10-14 wk
Does not affect intestinal tumorigenesis 4, 20, 90 mg/kg Diet Ziegler et al. (41)
in male ApcMin/+ mice 7 wk
Inhibits NMBA-induced esophageal ↓COX-1 and COX-2 1, 2 mg/kg p.o. or Li et al. (42)
tumorigenesis in male F344 rats mRNA; ↓PGE2 16-20 wk i.p.
Inhibits the growth of implanted ↑Apoptosis; ↑Bax and ↓Bcl-2 500, 1,000, i.t. Zhou et al. (43)
human primary gastric carcinoma cells in (mRNA and protein) 1,500 mg/kg
female BALB/c nude mice 6 times in 11 d
Does not modify BOP-induced pancreatic 10 ppm Diet Kuroiwa et al. (44)
carcinogenesis in male Syrian hamsters 3-14 wk
Decreases the growth of transplanted ↑Cells in G2-M phase; 1 mg/kg i.p. Carbó et al. (45)
Yoshida AH-130 ascites hepatoma ↑apoptosis 7d
cells in male Wistar rats
Suppresses tumor growth and ↓Serum TG; ↓VLDL; ↓LDL 50 ppm Diet Miura et al. (46)
metastasis in male Donryu rats 20 d
implanted with AH-109A ascites hepatoma
cells
Inhibits the weight of tumors in BALB/ Immunomodulation 500, 1,000, abd Liu et al. (47)
c mice implanted with H22 hepatoma cells 1500 mg/kg
10 d
Reduces the volume of tumors in BALB/c ↓Cyclin B1; ↓p34cdc2 5, 10, 15 mg/kg abd Yu et al. (48)
mice implanted with H22 tumors 10 d
Enhances the antitumor effect of ⊥S phase 5, 10, 15 mg/kg abd Wu et al. (49)
5-fluorouracil in male BALB/c mice 10 d
implanted with H22 tumors

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Resveratrol and Cancer: In vivo and Clinical Studies

Table 1. In vivo effects of resveratrol on cancer development and growth and their possible mechanisms
(Cont'd)

Target/effects Mechanisms Dose/duration Route References

Inhibits DENA-initiated hepatocarci ↓Proliferation; ↑apoptosis; ↑Bax; 50, 100, 300 Diet Bishayee and Dhir
nogenesis in female Sprague-Dawley rats ↓Bcl-2 mg/kg (50)
20 wk
Lung
Does not influence lung tumorigenesis induced 500 ppm Diet Hecht et al. (51)
by B[a]P and NNK in female A/J mice 25 wk
Does not reduce the number or size of 6-8 mg/kg Diet Berge et al. (52)
B[a]P-induced lung tumors in female ∼5 mo
A/J mice
Inhibits tumor growth and lung me ↑Apoptosis; ↓DNA synthesis; 2.5, 10 mg/kg i.p. Kimura and Okuda
tastasis in female C57Bl/6 mice ↓angiogenesis 21 d (53)
transplanted
with Lewis lung carcinoma cells
Decreases metastasis of implanted ↓Angiogenesis 5, 25 mg/kg i.p. Busquets et al. (54)
Lewis lung carcinoma cells in 15 d
C57Bl/6 mice
Inhibits tumor growth in female ↑Apoptosis; ↓angiogenesis 20 mg/kg i.p. Lee et al. (55)
C57Bl/6 mice inoculated with 17 d
Lewis lung carcinoma cells; an
analogue is found more potent

Other systems
Suppresses the growth of implanted ↑Apoptosis; ⊥S phase; 40 mg/kg i.p. Chen et al. (56)
neuro-2a neuroblastoma cells ↓p21; ↑cyclin E 28 d
in male A/J mice
Inhibits the growth of implanted RT-2 ↑Apoptosis; ↓angiogenesis 40 or 100 mg/ i.p. Tseng et al. (57)
glioma cells in F344 rats kg
4 wk
Represses tumor growth in Fischer ↓Angiogenesis; ↓CD31 40 mg/kg i.p. Chen et al. (58)
rats inoculated with RT-2 glioma cells 4 wk
Diminishes the growth of NGP ↑Apoptosis; mitochondrial 2, 10, 50 mg/kg p.o. van Ginkel et al. (59)
and SK-N-AS neuroblastoma dysfunction; ↑cytochrome c release; 5 wk
cells in athymic mice ↑Smac/
DIABLO release; ↑caspases
Exhibits weak antileukemic ↑Apoptosis; ↑caspase-3 80 mg/kg p.o. Gao et al. (60)
effects in male C3H (H-2k) 5 times/week;
mice with 32Dp210 cells 14-60 d
Enhances antitumor immune ↑Apoptosis; ↓Bcl-2; ↓IL-6 mRNA 12.5, 25, 50 i.g. Li et al. (61)
activity in male BALB/c and protein mg/kg
mice bearing L1210 lymphocytic 3 wk
leukemic cells
Inhibits the growth of implanted ↓Angiogenesis 1 mg/kg d.w. Bråkenhielm et al.
T241 fibrosarcoma cells in C57Bl6/J mice ∼23 d (62)
Retards the growth of inoculated ↑Apoptosis; mitochondrial 0.4-50 mg/kg p.o. van Ginkel et al. (63)
C918 and Mum2b cells in athymic mice dysfunction; ↑cytochrome 3-5 wk
c release; ↑Smac/
DIABLO release; ↑caspase-3

Abbreviations: TGF, transforming growth factor; TNF, tumor necrosis factor; APAF-1, apoptotic protease-activating factor-1; MAPK, mito-
gen-activated protein kinase; MMP-9, matrix metalloproteinase-9; MNU, N-methyl-N-nitrosourea; IGF-I, insulin-like growth factor-I;
TRAMP, transgenic adenocarcinoma mouse prostate; TRAP, transgenic rat for adenocarcinoma of prostate; AR, androgen receptor;
GK11, glandular kallikrein 11; AOM, azoxymethane; DMH, 1,2-dimethylhydrazine; NMBA, N-nitrosomethylbenzylamine; BOP, N-nitroso-
bis(2-oxopropyl)amine; TG, triglyceride; VLDL, very low-density lipoprotein; LDL, low-density lipoprotein; DENA, diethylnitrosamine;
NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; IL-6, interleukin-6; top., topical; p.o., per os; d.w., drinking water; s.p., slow-release
pellet; abd, abdominal injection; i.t., intratumoral.

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Review

incidence of irregular estrous cycle with a prolonged estrus ApcMin/+ mice has been associated with inhibition of COX en-
phase, which culminated in increased incidence and multiplic- zymes and interference with prostaglandin E2 (PGE2) genera-
ity of mammary tumors in rats (28). tion (40). In contrast, a powdered admixture of resveratrol in
In a xenograft animal model, resveratrol inhibited the the diet did not affect intestinal tumorigenesis or COX-2 ex-
growth of estrogen receptor (ER)-α–negative and ER-β–posi- pression in ApcMin/+ mice (41). Although poor bioavailability
tive MDA-MB-231 tumor explants, increased apoptosis, and may explain the lack of effect of the resveratrol powder (41),
decreased angiogenesis in nude mice (29). Resveratrol had additional experiments are required to better understand this
no effect on the in vivo growth and metastasis of transplanted finding mechanistically.
ER-α–negative 4T1 murine mammary cancer cells in nude Oral or i.p. resveratrol reduced the number and size of
mice (30). It has been shown that resveratrol, believed to be esophageal tumors induced by N-nitrosomethylbenzylamine
a phytoestrogen, functions as a mixed agonist/antagonist on in rats (42). Increased expressions of COX-1, COX-2, and
the ER and exhibits higher transcriptional activity when PGE2 in this N-nitrosomethylbenzylamine–induced system
bound to ER-β than when bound to ER-α. In addition, resver- were significantly decreased by resveratrol. High doses of re-
atrol seems to have antagonist activity with ER-α but not with sveratrol injected directly next to tumors resulting from im-
ER-β. Therefore, the growth-inhibitory effects of resveratrol in planted human primary gastric cancer cells inhibited tumor
these models may be mediated by ER-β or may be ER inde- growth in nude mice (43). Resveratrol also induced apoptosis
pendent. Resveratrol supplementation in drinking water de- in these tumors by down-regulating the expression of Bcl-2
layed the development of spontaneous mammary tumors in and up-regulating the expression of Bax. Dietary resveratrol
HER-2/neu transgenic mice and reduced the mean number had no anticarcinogenic effect against N-nitrosobis(2-oxopro-
and size of mammary tumors by down-regulating HER-2/ pyl)amine–induced pancreatic carcinogenesis in hamsters (44).
neu gene expression and increasing apoptosis in the mammary Resveratrol caused a significant decrease in the cell count
glands of these mice (31). Recently, the combined polyphenols of a fast-growing tumor (Yoshida AH-130 ascites hepatoma)
resveratrol, quercetin, and catechin administered by gavage injected into rats, inducing apoptosis in the tumor cell popu-
reduced the primary growth of xenografts of MDA-MB-231 lation (45). Resveratrol in the diet suppressed (in a modest
breast cancer cells in nude mice, as monitored by in situ dose-dependent fashion) the growth and metastasis of ascites
fluorescence image analysis of fluorescently tagged tumor hepatomas arising from implanted AH-109A cells in rats (46).
cells (32). Resveratrol also suppressed the serum levels of triglyceride,
very low-density lipoprotein cholesterol, and low-density
Prostate lipoprotein cholesterol in these hepatoma-bearing rats.
Dietary resveratrol significantly reduced the incidence of Resveratrol (500-1,500 mg/kg) inhibited the growth of trans-
prostatic adenocarcinoma in the transgenic adenocarcinoma planted H22 murine tumors by nonspecific host immunomo-
mouse prostate model. The decrease in cell proliferation and dulatory activity (47). Resveratrol was able to exhibit tumor
insulin-like growth factor-I, down-regulation of phospho-ex- growth-inhibitory effects even at lower doses (5-15 mg/kg),
tracellular signal-regulated kinase (ERK)-1 and ERK-2, and in- which might involve the inhibition of the cell cycle progres-
crease in ER-β provided a biochemical basis for resveratrol- sion through decreased expression of cyclin B1 and p34cdc2
mediated suppression of prostate cancer development (33). (48). Finally, resveratrol was found to enhance the antitumor
Resveratrol in the drinking water suppressed prostate cancer effect of 5-fluorouracil on H22 murine hepatoma and marked-
growth in the transgenic rat for adenocarcinoma of prostate ly antagonize its toxicity (49).
model with induction of apoptosis. Moreover, resveratrol Resveratrol has been well studied and shown to be effective
not only down-regulated the androgen receptor expression for treating but not preventing liver cancer in animals. There-
but also suppressed the androgen-responsive glandular kalli- fore, our laboratory is conducting studies of resveratrol for
krein 11 at the mRNA level (34). prevention in a rat model of chemically-induced liver car-
cinogenesis. We recently reported the first published study
Gastrointestinal tract showing that dietary resveratrol exerts a significant chemopre-
Oral resveratrol inhibited the number and multiplicity of ventive effect on diethylnitrosamine-initiated and phenobarbi-
azoxymethane-induced aberrant crypt foci, completely abol- tal-promoted hepatocarcinogenesis in rats through inhibition
ishing large aberrant crypt foci, in the colon of rats, and these of cell proliferation and induction of apoptosis (50). According
effects were linked to mechanisms involving changes in Bax to our study, resveratrol-induced apoptogenic signal during
and p21 expression (35). In rats, resveratrol markedly reduced rat liver carcinogenesis may be mediated through the down-
the number of 1,2-dimethylhydrazine–induced aberrant crypt regulation of Bcl-2 and up-regulation of Bax expression.
foci and incidence and size of 1,2-dimethylhydrazine–induced
tumors, possibly through the modulation of antioxidant Lung
defense status and activities of carcinogen-detoxifying en- A study in A/J mice (51) showed that resveratrol in the
zymes (36–38). Resveratrol in drinking water administered diet during the post-tumor initiation phase had no effect on
to ApcMin/+ mice prevented the formation of colon and small the multiplicity of lung tumors induced by benzo[a]pyrene
intestine tumors by down-regulating genes that are directly (B[a]P) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone;
involved in cell cycle progression or cell proliferation (39). ad libitum access to a diet containing resveratrol (0.4%) had
Resveratrol and its synthetic analogue trans 3,4,5,4′-tetra- no effect on B[a]P-induced lung tumorigenesis, and that res-
methoxystilbene (DMU-212) decreased the adenoma load in veratrol did not change the expression of B[a]P metabolizing
Apc Min/+ mice, with resveratrol showing slightly greater genes such as cytochrome P450 1A1 (CYP1A1) and CYP1B1 or
potency. This chemopreventive effect of resveratrol in the level of B[a]P-protein adducts in lung tissue (52). The lack

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Resveratrol and Cancer: In vivo and Clinical Studies

of chemopreventive activity seems to be related to insufficient (marked by the expression of CD31; ref. 58). Recently, it has
concentrations or nonreactive forms of resveratrol in the lungs been shown that resveratrol significantly diminished tumor
of experimental animals (52). growth through apoptosis induction, which involved direct
Contrary to reports cited above, Kimura and Okuda (53) activation of the mitochondrial intrinsic apoptotic pathway,
found that resveratrol significantly reduced tumor volume, tu- in the SK-N-AS and NGP xenograft models of human neuro-
mor weight, and metastasis to the lung in mice bearing highly blastoma (59).
metastatic Lewis lung carcinoma. Resveratrol also inhibited Although producing a weak antileukemic effect, oral resver-
DNA synthesis, increased apoptosis, and suppressed tumor- atrol did not affect the survival of mice injected with 32Dp210
induced neovascularization (53). In another study, resveratrol leukemia cells (60). However, oral resveratrol significantly im-
had no effect on the growth of implanted Lewis lung carcino- proved the survival of mice bearing lymphocytic leukemia
ma in mice, but it exhibited a clear antimetastatic effect, de- L1210 cells, producing a normalization of CD4/CD8 ratios
creasing both the number and weight of lung metastases and an enhancement of natural killer cell activities and anti-
(54). Furthermore, resveratrol and its tetramer heyneanol sheep RBC titers. Furthermore, resveratrol suppressed inter-
decreased tumor growth in mouse Lewis lung carcinoma. leukin-6 cellular content, release, and mRNA expression (61).
The tumor inhibitory effect was accompanied by a marked The antiangiogenic effect of resveratrol led researchers to in-
increase in tumor cell apoptosis as detected by cleaved vestigate whether it could inhibit the growth of a murine
caspase-3, decreased tumor cell proliferation index, and di- fibrosarcoma, and resveratrol-supplemented water signifi-
minished tumor microvessel density; these findings support cantly inhibited the growth of T241 fibrosarcoma in mice
the involvement of apoptotic and antiangiogenic activities in through suppression of angiogenesis (62). Oral resveratrol
the anticancer effects of resveratrol (55). treatment effectively inhibited tumor growth in two xenograft
models of human uveal melanoma in mice. The underlying
Other systems antitumor mechanisms of resveratrol in these models might
Resveratrol treatment (40 mg/kg for 28 days) efficiently have involved activation of the intrinsic mitochondrial path-
suppressed the growth rate of neuroblastomas and increased way leading to release of cytochrome c and Smac/DIABLO,
apoptosis, which was accompanied by down-regulation of activation of caspase-9 and caspase-3, and tumor cell death
p21 and up-regulation of cyclin E (56). Resveratrol significant- by apoptosis (63).
ly inhibited cerebral tumors via induction of apoptosis and in-
hibition of glioma-induced angiogenesis (57). Rats treated
with resveratrol (40 mg/kg, i.p.) had slower glioma growth Clinical Studies
rates, which correlated with tumor blood flow (indicated by Although several reports have described the pharmacoki-
the color Doppler vascularity index) and microvessel density netics of resveratrol in animal model systems (reviewed in

Table 2. Clinical studies of resveratrol as a pure compound or given in beverages

Human subjects Objectives Findings Dose Route References

Healthy humans (10)* Bioavailability Plasma-free and conjugates peak in 30 min; 25 mg/person Oral Soleas et al. (64)
∼25% recovered in urine over 24 h
Healthy males (12) Bioavailability Peak glucuronide and sulfate conjugates 25 mg/70 kg Oral Goldberg et al. (65)
appear in serum in 30 min; urinary 24-h
excretion is 16-17% of the dose
Healthy males (3)/ Bioavailability Absorption is 70% with plasma half-life of 25 mg/person Oral; i.v Walle et al. (66)
females (3) 9.2 h; mostly excreted in urine
Healthy males (3) Bioavailability Pure and derivatives are detectable in 0.03, 0.5, 1 mg/kg Oral Meng et al. (67)
plasma and urine; 25-50% resveratrol is
recovered in urine during 24 h
Healthy humans (4) Bioavailability Six major conjugate metabolites are detected 1 g/person Oral Boocock et al. (68)
in and separated from serum and urine
Healthy humans (40) Phase I dose escalation Does not exhibit adverse effects; peak 0.5, 1, 2.5, 5 Oral Boocock et al. (69)
pharmacokinetics plasma levels occur in 1.5 h; 77% of g/person
all urinary species excreted in 24 h
Healthy males (14)/ Bioavailability Pure or glucuronide conjugate is found 3.4, 7.5, 33 μg/kg Oral Vitaglione et al. (70)
females (11) in serum; meal does not affect
bioavailability
Healthy males (10)/ Urinary excretion Increase in total metabolites, which could 0.36, 0.4, 2.6 Oral Zamora-Ross
females (10) be used as biomarkers for clinical studies mg/person et al. (71)

*The number of human subjects is indicated in the parenthesis.

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 Published OnlineFirst April 28, 2009; DOI: 10.1158/1940-6207.CAPR-08-0160

Review

ref. 1), there are few similar studies in humans to date. Table 2 of transplanted 4T1 breast cancer cells in mice, whereas it in-
summarizes the widely varying circumstances under which hibited the in vitro growth of the same cancer cells (30). Again,
resveratrol, as a pure compound or in wine and/or other based on reports presented here, resveratrol could be more ef-
beverages, has been investigated in human subjects (64–71). fective in inhibiting the growth of established tumors in a par-
It is clear from the tabular clinical observations that resveratrol ticular organ (e.g., the lung) than in preventing tumors in the
is rapidly absorbed following oral administration; levels are same site. However, an opposite trend has also been observed
detectable in both plasma and urine, with the maximum plas- (e.g., for skin and breast tumors). There is an obvious need for
ma concentrations being reached between 30 and 60 min after further studies to address the tissue specificity of resveratrol
administration. Circulating levels of this polyphenol are low, so as to determine where resveratrol may have the strongest
partly explained, perhaps, by its rapid and extensive phase II preventive potential.
metabolism, which generates glucuronide and sulfate con- The conundrum posed by the undeniable efficacy of resver-
jugates. The preclinical in vivo studies described above show atrol in preclinical models in spite of its low bioavailability has
great promise for resveratrol in human cancer prevention and not been resolved yet. Likewise, the question of whether re-
treatment. An extension of these in vivo data is a recently con- sveratrol itself can accumulate to bioactive levels in target or-
cluded 10-year epidemiologic study showing a 50% or greater gans remains unanswered. To enhance the bioavailability of
reductions in breast cancer risk in women with resveratrol resveratrol, active research should examine resveratrol deliv-
consumption from grapes, but not from wine (72). The inverse ery routes and formulations and modulation of resveratrol
relationship between resveratrol and breast cancer risk could metabolism, as well as possible interactions of resveratrol with
not be explained by several potential confounding factors, in- other food components.
cluding alcohol intake, nor was it attributable to a nonspecific Developing novel resveratrol derivatives is another
favorable effect of fruit on breast cancer risk (72). Several possible approach for enhancing bioavailability. A series of
phase I/II clinical trials of oral resveratrol as a pure compound cis-stilbenes and trans-stilbenes related to resveratrol with
or in resveratrol-rich products (grapes and grape juice) are varying functional groups have been synthesized, and some
under way.1 A phase I study will define the effect of grape- of these compounds are more potent than is resveratrol
derived low-dose resveratrol on biomarkers related to the in suppressing the growth of human cancer cells in vitro
Wnt pathway, a key signaling pathway activated in >85% of (reviewed in ref. 2). Researchers have started to explore the
colon cancers, and will evaluate the utility of this approach anticancer effects of resveratrol derivatives in vivo (40, 55,
for colon cancer prevention. A phase II study in lymphoma 73–75), and at least one study indicated that a tetramer of
patients will assess the ability of resveratrol in grape juice to resveratrol (heyneanol) had comparable or better anticancer
induce apoptosis, inhibit cell proliferation, and modulate efficacy than did resveratrol in a mouse lung cancer model
tumor cell infiltrate. A phase I/II clinical trial will examine (55). However, more in vivo studies of head-to-head compar-
the effects of resveratrol directly on colon cancer and surround- isons between resveratrol and its analogues are ongoing
ing normal colonic mucosa. A National Cancer Institute– and no doubt will help elucidate the anticancer potential of
sponsored phase I trial is studying the side effects and best specific compounds.
regimen of resveratrol in patients with colorectal cancer that Since the first report on the biological activity of resveratrol,
can be removed by surgery. Results of these trials may pro- an enormous body of work has revealed many important
vide a foundation for designing future large-scale clinical biological properties (e.g., anti-inflammatory, antioxidant,
trials to ascertain the full chemopreventive and chemothera- caloric restriction mimetic, and antiaging effects) of this natu-
peutic efficacy of resveratrol. rally occurring polyphenol. Much more study is needed, how-
ever, including studies to identify resveratrol-binding proteins
Future Directions and Conclusion and the pathways through which resveratrol functions and
thus may exert clinical effects, and to develop mechanism-
From the studies described in this review, it is clear that re- based markers for evaluating clinical outcome. Long-term
sveratrol holds great potential not only in the prevention but epidemiologic studies and controlled clinical trials are also
also in the therapy of a wide variety of cancers. Tumor cells necessary for developing resveratrol to become a standard
use multiple survival pathways to prevail over normal cells. clinical agent. The preclinical and clinical data examined in
Therefore, agents such as resveratrol that can suppress multi- this review strongly suggest that resveratrol is a promising
ple cellular pathways may have a strong potential for cancer candidate in chemopreventive and chemotherapeutic strate-
prevention and treatment. It may be speculated that the anti- gies and a potential weapon in the effort to alleviate the
cancer effects of resveratrol cannot be explained by a unique burden of human cancer.
mechanism of action but likely stem from various complemen-
tary actions of several molecular, biochemical, and physiologic
pathways involved in carcinogenesis. Disclosure of Potential Conflicts of Interest
Several reports suggest that resveratrol could be ineffective
No potential conflicts of interest were disclosed.
in inhibiting tumor growth in certain animal models despite
its in vitro antitumor action in related cells. For example, re-
sveratrol had no effect on the in vivo growth and metastasis
Acknowledgments
I thank Cornelis J. (Neels) Van der Schyf, D.Sc., DTE, and Altaf Darvesh,
Ph.D., for carefully reading the manuscript and providing valuable comments;
Werner J. Geldenhuys, Ph.D., for technical assistance with illustrations; and
1
http://clinicaltrials.gov/ct2/home (accessed 2008 July 12). Laura Colwell and Lisa Barker for assistance with the references.

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 Published OnlineFirst April 28, 2009; DOI: 10.1158/1940-6207.CAPR-08-0160

Resveratrol and Cancer: In vivo and Clinical Studies

References
1. Baur JA, Sinclair DA. Therapeutic potential of re- grape constituent resveratrol: relevance to human 38. Sengottuvelan M, Nalini N. Dietary supplementa-
sveratrol: the in vivo evidence. Nat Rev Drug Discov disease? FASEB J 2005;19:1193–5. tion of resveratrol suppresses colonic tumour inci-
2006;5:493–506. 21. Caltagirone S, Rossi C, Poggi A, et al. Flavonoids dence in 1,2-dimethylhydrazine-treated rats by
2. Saiko P, Szakmary A, Jaeger W, Szekeres T. Re- apigenin and quercetin inhibit melanoma growth modulating biotransforming enzymes and aberrant
sveratrol and its analogs: defense against cancer, and metastatic potential. Int J Cancer 2000;87: crypt foci development. Br J Nutr 2006;96:145–53.
coronary disease and neurodegenerative maladies 595–600. 39. Schneider Y, Duranton B, Gossé F, Schleiffer R,
or just a fad? Mutat Res 2008;658:68–94. 22. Asensi M, Medina I, Ortega A, et al. Inhibition Seiler N, Raul F. Resveratrol inhibits intestinal tu-
3. Harikumar KB, Aggarwal BB. Resveratrol. A multi- of cancer growth by resveratrol is related to its morigenesis and modulates host-defense-regulat-
targeted agent for age-associated chronic dis- low bioavailability. Free Rad Biol Med 2002;33: ed gene expression in an animal model of human
eases. Cell Cycle 2008;7:1020–37. 387–98. familial adenomatous polyposis. Nutr Cancer
23. Niles RM, Cook CP, Meadows GG, Fu Y-M, 2001;39:102–7.
4. Shishodia S, Aggarwal BB. Resveratrol: a polyphe-
nol for all seasons. In: Aggarwal BB, Shishodia S, McLaughlin JL, Rankin GO. Resveratrol is rapidly 40. Sale S, Tunstall RG, Ruparelia KC, Potter GA,
editors. Resveratrol in health and disease. Boca metabolized in athymic (Nu/Nu) mice and does Steward WP, Gescher AJ. Comparison of the ef-
Raton: CRC Press; 2006. p. 1-16. not inhibit human melanoma xenograft tumor fects of the chemopreventive agent resveratrol
growth. J Nutr 2006;136:2542–6. and its synthetic analog trans 3,4,5,4′-tetramethox-
5. Kopp P. Resveratrol, a phytoestrogen found in red
wine. A possible explanation for the conundrum of 24. Banerjee S, Bueso-Ramos C, Aggarwal BB. Sup- ystilbene (DMU-212) on adenoma development in
pression of 7,12-dimethylbenz(a)anthracene- the ApcMin/+ mouse and cycloooygenase-2 in hu-
the ‘French paradox’? Eur J Endocrinol 1998;138:
619–20. induced mammary carcinogenesis in rats by re- man-derived colon cancer cells. Int J Cancer
sveratrol: role of nuclear factor-κB, cyclooxygenase 2005;115:194–201.
6. Baur JA, Pearson KJ, Price NL, et al. Resveratrol
improves health and survival of mice on a high-cal- 2, and matrix metalloprotease 9. Cancer Res 2002; 41. Ziegler CC, Rainwater L, Whelan J, McEntee F.
62:4945–54. Dietary resveratrol does not affect intestinal tumor-
orie diet. Nature 2006;444:337–42.
25. Whitsett T, Carpenter M, Lamartiniere CA. Re- igenesis in ApcMin/+ mice. J Nutr 2004;134:5–10.
7. Lagouge M, Argmann C, Gerhart-Hines Z, et al.
Resveratrol improves mitochondrial function and sveratrol, but not EGCG, in the diet suppresses 42. Li ZG, Hong T, Shimada Y, et al. Suppression of
DMBA-induced mammary cancer in rats. J Carci- N-nitrosomethylbenzylamine (NMBA)-induced
protects against metabolic disease by activating
nog 2006;5:15. esophageal tumorigenesis in F344 rats by resvera-
SIRT1 and PGC-1α. Cell 2006;127:1109–22.
26. Whitsett TG, Jr., Lamartiniere CA. Genistein and trol. Carcinogenesis 2002;23:1531–6.
8. Pezzuto JM, Kondratyuk T, Shalaev E. Cancer
chemoprevention by wine polyphenols and re- resveratrol: mammary cancer chemoprevention 43. Zhou H-B, Chen J-J, Wang W-X, Cai J-T, Du Q.
and mechanisms of action in the rat. Expert Rev Anticancer activity of resveratrol on implanted hu-
sveratrol. In: Baer-Dubowska W, Brtoszek A,
Malejka-Giganti D, editors. Carcinogenic and an- Anticancer Ther 2006;6:1699–706. man primary gastric carcinoma cells in nude mice.
ticarcinogenic food components. Boca Raton: 27. Bhat KLP, Lantvit D, Christov K, Mehta RG, Moon World J Gastroenterol 2005;11:280–4.
CRC Press; 2006. p. 239-82. RC, Pezzuto JM. Estrogenic and antiestrogenic 44. Kuroiwa Y, Nishikawa A, Kitamura Y, et al. Pro-
properties of resveratrol in mammary tumor mod- tective effects of benzyl isothiocyanate and sulfor-
9. Aggarwal BB, Bhardwaj A, Aggarwal RS, Seeram
NP, Shishodia S, Takada Y. Role of resveratrol in els. Cancer Res 2001;61:7456–63. aphane but not resveratrol against initiation of
28. Sato M, Pei R-J, Yuri T, Danbara N, Nakane Y, pancreatic carcinogenesis in hamsters. Cancer Lett
prevention and therapy of cancer: preclinical
Tsubura A. Prepubertal resveratrol exposure accel- 2006;241:275–80.
and clinical studies. Anticancer Res 2004;24:
2783–840. erates N-methyl-N-nitrosourea-induced mammary 45. Carbó N, Costelli P, Baccino FM, López-Soriano
10. Shankar S, Singh G, Srivastava RK. Chemopre- carcinoma in female Sprague-Dawley rats. Cancer FJ, Argilés JM. Resveratrol, a natural product pres-
Lett 2003;202:137–45. ent in wine, decreases tumour growth in a rat tu-
vention by resveratrol: molecular mechanisms
and therapeutic potential. Front Biosci 2007;12: 29. Garvin S, Öllinger K, Dabrosin C. Resveratrol in- mour model. Biochem Biophys Res Commun
4839–54. duces apoptosis and inhibits angiogenesis in hu- 1999;254:739–43.
man breast cancer xenografts in vivo. Cancer Lett 46. Miura D, Miura Y, Yagasaki K. Hypolipidemic ac-
11. Kundu JK, Surh Y-J. Cancer chemopreventive
2006;231:113–22. tion of dietary resveratrol, a phytoalexin in grapes
and therapeutic potential of resveratrol: mechanis-
30. Bove K, Lincoln DW, Tsan M-F. Effect of resver- and red wine, in hepatoma-bearing rats. Life Sci
tic perspectives. Cancer Lett 2008;269:243–61.
atrol on growth of 4T1 breast cancer cells in vitro 2003;73:1393–400.
12. Jang M, Cai L, Udeani GO, et al. Cancer chemo-
and in vivo. Biochem Biophys Res Commun 2002; 47. Liu H-S, Pan C-E, Yang W, Liu X-M. Antitumor
preventive activity of resveratrol, a natural product and immunomodulatory activity of resveratrol on
derived from grapes. Science 1997;275:218–20. 291:1001–5.
31. Provinciali M, Re F, Donnini A, et al. Effect of re- experimentally implanted tumor of H22 in Balb/c
13. Jang M, Pezzuto JM. Effects of resveratrol on 12- mice. World J Gastroenterol 2003;9:1474–6.
O-tetradecanoylphorbol-13-acetate-induced oxi- sveratrol on the development of spontaneous
mammary tumors in HER-2/neu transgenic mice. 48. Yu L, Sun Z-J, Wu S-L, Pan C-E. Effect of resver-
dative events and gene expression in mouse skin. atrol on cell cycle proteins in murine transplantable
Cancer Lett 1998;134:81–9. Int J Cancer 2005;115:36–45.
32. Schlachterman A, Valle F, Wall KM, et al. Com- liver cancer. World J Gastroenterol 2003;9:2341–3.
14. Kapadia GJ, Azuine MA, Tokuda H, et al. Chemo- 49. Wu S-L, Sun Z-J, Yu L, Meng K-W, Qin X-L, Pan
bined resveratrol, quercetin, and catechin treat-
preventive effect of resveratrol, sesamol, sesame C-E. Effect of resveratrol and in combination with
ment reduces breast tumor growth in a nude
oil and sunflower oil in the Epstein-Barr virus early 5-FU on murine liver cancer. World J Gastroenterol
mouse model. Translational Oncol 2008;1:19–27.
antigen activation assay and the mouse skin two- 2004;10:3048–52.
stage carcinogenesis. Pharmacol Res 2002;45: 33. Harper CE, Patel BB, Wang J, Arabshahi A,
Eltoum IA, Lamartiniere CA. Resveratrol sup- 50. Bishayee A, Dhir N. Resveratrol-mediated che-
499–505.
presses prostate cancer progression in transgenic moprevention of diethylnitrosamine-initiated hepa-
15. Soleas GJ, Grass L, Josephy PD, Goldberg DM, tocarcinogenesis: inhibition of cell proliferation
mice. Carcinogenesis 2007;28:1946–53.
Diamandis EP. A comparison of the anticarcino- and induction of apoptosis. Chem-Biol Interact
genic properties of four red wine polyphenols. Clin 34. Seeni A, Takahashi S, Takeshita K, et al. Sup-
pression of prostate cancer growth by resveratrol 2009;179:131–44.
Biochem 2002;35:119–24. 51. Hecht SS, Kenney PMJ, Wang M, et al. Evalua-
in the transgenic rat for adenocarcinoma of pros-
16. Kalra N, Roy P, Prasad S, Shukla Y. Resveratrol tate (TRAP) model. Asian Pac J Cancer Prev tion of butylated hydroxyanisole, myo-inositol, cur-
induces apoptosis involving mitochondrial path- 2008;9:7–14. cumin, esculetin, resveratrol and lycopene as
ways in mouse skin tumorigenesis. Life Sci 2008; inhibitors of benzo[a]pyrene plus 4-(methylnitrosa-
35. Tessitore L, Davit A, Sarotto I, Caderni G. Resver-
82:348–58. mino)-1-(3-pyridyl)-1-butanone-induced lung tu-
atrol depresses the growth of colorectal aberrant
17. Afaq F, Adhami VM, Ahmad N. Prevention of crypt foci by affecting bax and p21CIP expression. morigenesis in A/J mice. Cancer Lett 1999;137:
short-term ultraviolet B radiation-mediated da- Carcinogenesis 2000;21:1619–22. 123–30.
mages by resveratrol in SKH-1 hairless mice. Tox- 52. Berge G, Øvrebø S, Haugen A, Mollerup S. Anal-
36. Sengottuvelan M, Viswanathan P, Nalini N. Che-
icol Appl Pharmacol 2003;186:28–37. ysis of resveratrol as a lung cancer chemopreven-
mopreventive effect of trans-resveratrol—a phyto-
18. Reagan-Shaw S, Afaq F, Aziz MH, Ahmad N. alexin against colonic aberrant crypt foci and cell tive agent in A/J mice exposed to benzo[a]pyrene.
Modulation of critical cell cycle regulatory events proliferation in 1,2-dimethylhydrazine induced co- Br J Cancer 2004;91:1380–3.
during chemoprevention of ultraviolet B-mediated lon carcinogenesis. Carcinogenesis 2006;27: 53. Kimura Y, Okuda H. Resveratrol isolated from
responses by resveratrol in SKH-1 hairless mouse 1038–46. Polygonum cuspidatum root prevents tumor
skin. Oncogene 2004;23:5151–60. 37. Sengottuvelan M, Senthilkumar R, Nalini N. Mod- growth and metastasis to lung and tumor-induced
19. Aziz MH, Afaq F, Ahmad N. Prevention of ultravi- ulatory influence of dietary resveratrol during differ- neovascularization in Lewis lung carcinoma-bearing
olet-B radiation damage by resveratrol in mouse ent phases of 1,2-dimethylhydrazine induced mice. J Nutr 2001;131:1844–9.
skin is mediated via modulation in survivin. Photo- mucosal lipid-peroxidation, antioxidant status and 54. Busquets S, Ametller E, Fuster G, et al. Resvera-
chem Photobiol 2005;81:25–31. aberrant crypt foci development in rat colon carci- trol, a natural diphenol, reduces metastatic growth
20. Aziz MH, Reagan-Shaw S, Wu J, Longley BJ, nogenesis. Biochim Biophys Acta 2006;1760: in an experimental cancer model. Cancer Lett 2007;
Ahmad N. Chemoprevention of skin cancer by 1175–83. 245:144–8.

www.aacrjournals.org 417 Cancer Prev Res 2009;2(5) May 2009

Downloaded from cancerpreventionresearch.aacrjournals.org on July 4, 2016. © 2009 American Association for

Cancer Research.
 Published OnlineFirst April 28, 2009; DOI: 10.1158/1940-6207.CAPR-08-0160

Review

55. Lee E-O, Lee H-J, Hwang H-S, et al. Potent inhi- leukemia both in vitro and in vivo. Int Immunophar- performance liquid chromatography. J Chromatogr
bition of Lewis lung cancer growth by heyneanol A macol 2007;7:1221–31. B 2007;848:182–7.
from the roots of Vitis amurensis through apoptotic 62. Bråkenhielm E, Cao R, Cao Y. Suppression of an- 69. Boocock DJ, Faust GES, Patel KR, et al. Phase I
and anti-angiogenic activities. Carcinogenesis giogenesis, tumor growth, and wound healing by dose escalation pharmacokinetic study in healthy
2006;27:2059–69. resveratrol, a natural compound in red wine and volunteers of resveratrol, a potential cancer chemo-
56. Chen Y, Tseng S-H, Lai H-S, Chen W-J. Resver- grapes. FASEB J 2001;15:1798–800. preventive agent. Cancer Epidemiol Biomarkers
atrol-induced cellular apoptosis and cell cycle 63. van Ginkel PR, Darjatmoko SR, Sareen D, et al. Prev 2007;16:1246–52.
arrest in neuroblastoma cells and antitumor ef- Resveratrol inhibits uveal melanoma tumor growth 70. Vitaglione P, Sforza S, Galaverna G, et al. Bio-
fects on neuroblastoma in mice. Surgery 2004; via early mitochondrial dysfunction. Invest Ophthal- availability of trans-resveratrol from red wine in hu-
136:57–66. mol Vis Sci 2008;49:1299–306. mans. Mol Nutr Food Res 2005;49:495–504.
57. Tseng S-H, Lin S-M, Chen J-C, et al. Resveratrol 64. Soleas GJ, Yan J, Goldberg DM. Ultrasensitivity 71. Zamora-Ross R, Urpí-Sardà M, Lamuela-Raventós
suppresses the angiogenesis and tumor growth assay for the three polyphenols (catechin, quercetin RM, et al. Diagnostic performance of urinary resvera-
of gliomas in rats. Clin Cancer Res 2004;10: and resveratrol) and their conjugates in biological trol metabolites as a biomarker of moderate wine
2190–202. fluids utilizing gas chromatography with mass selec- consumption. Clin Chem 2006;52:1373–80.
58. Chen J-C, Chen Y, Lin J-H, Wu J-M, Tseng S-H. tive detection. J Chromatogr B 2002;757:161–72. 72. Levi F, Pasche C, Lucchini F, Ghidoni R, Ferraroni
Resveratrol suppresses angiogenesis in gliomas: 65. Goldberg DM, Yan J, Soleas GJ. Absorption of M, La Vecchia C. Resveratrol and breast cancer
evaluation by color Doppler ultrasound. Anticancer three wine-related polyphenols in three different risk. Eur J Cancer Prev 2005;14:139–42.
Res 2006;26:1237–46. matrices by healthy subjects. Clin Biochem 2003; 73. Suh N, Paul S, Hao X, et al. Pterostilbene, an ac-
59. van Ginkel PR, Sareen D, Subramanian L, et al. 36:79–87. tive constituent of blueberries, suppresses aberrant
Resveratrol inhibits tumor growth of human neuro- 66. Walle T, Hsieh F, DeLegge MH, Oatis JE, Walle crypt foci formation in the azoxymethane-induced
blastoma and mediates apoptosis by directly tar- UK. High absorption but very low bioavailability of colon carcinogenesis model in rats. Clin Cancer
geting mitochondria. Clin Cancer Res 2007;13: oral resveratrol in humans. Drug Metab Disp 2004; Res 2007;13:350–5.
5162–9. 32:1377–82. 74. Shibata M-A, Akao Y, Shibata E, et al. Vaticanol
60. Gao X, Xu YX, Divine G, Janakiraman N, 67. Meng X, Maliaki P, Lu H, Lee M-J, Yang CS. Uri- C, a novel resveratrol tetramer, reduces lymph
Chapman RA, Gautam SC. Disparate in vitro nary and plasma levels of resveratrol and quercetin node and lung metastases of mouse mammary car-
and in vivo antileukemic effects of resveratrol, a in humans, mice, and rats after ingestion of pure cinoma carrying p53 mutation. Cancer Chemother
natural polyphenolic compound found in grapes. compounds and grape juice. J Agric Food Chem Pharmacol 2007;60:681–91.
Nutr Cancer 2002;132:2076–81. 2004;52:935–42. 75. Pan M-H, Gao J-H, Lai C-S, et al. Antitumor ac-
61. Li T, Fan G-X, Wang W, Yuan Y-K. Resveratrol 68. Boocock DJ, Patel KR, Faust GES, et al. Quanti- tivity of 3,5,4′-trimethoxystilbene in COLO 205 cells
induces apoptosis, influences IL-6 and exerts im- tation of trans-resveratrol and detection of its me- and xenografts in SCID mice. Mol Carcinog 2008;
munomodulatory effects on mouse lymphocytic tabolites in human plasma and urine by high 47:184–96.

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Cancer Prevention and Treatment with Resveratrol: From

Rodent Studies to Clinical Trials
Anupam Bishayee

Cancer Prev Res 2009;2:409-418. Published OnlineFirst April 28, 2009.

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