Resveratrol and Cancers of the Prostate and Breast

By Judith Balk, MD, FACOG

The biblical figure Noah lived to be 950 years old. In Genesis, Noah "planted a vineyard and he drank of the wine and was drunken." So did drinking wine harm Noah or help him? Perhaps he protected himself from illness by drinking wine from his vineyard; perhaps his source of longevity was wine. The wine Noah drank was likely high in a chemical called resveratrol.

Scientific interest has focused on resveratrol for possible prevention of coronary heart disease and cancer. Resveratrol may be the explanation for the "French Paradox," a phenomenon of low incidence of coronary heart disease despite a relatively high-fat diet. Resveratrol also has been identified as a possible chemopreventive agent for both breast cancer and prostate cancer.

This review evaluates the evidence available for resveratrol as a chemopreventive agent. A MEDLINE search using the terms "resveratrol" and either "breast cancer" or "prostate cancer" from 1966 to the present yielded eight articles on prostate cancer and resveratrol and 12 articles on breast cancer and resveratrol.

Source and Identification

Resveratrol (3,5,4’-trihydroxystilbene) is a polyphenolic phytoalexin that is found in both free and conjugate forms in high concentrations in grapes, grape juice, red wine, mulberries, peanuts, and in other plants. It is found in the skins of grapes, which is why red wine is higher in resveratrol than white wine. Other wine polyphenols include phenolic acids (p-coumaric, cinnamic, caffeic, gentisic, ferulic, and vanillic acid), tri-hydroxystilbenes (resveratrol and polydatin), and flavonoids (catechin, peicatechin, and quercetin).1

Resveratrol also is a component of many traditional Chinese and Japanese medications used for treating inflammation and cardiovascular disease.2 Resveratrol is thought to protect plants against fungal infections.3 Its chemical structure is similar to estradiol and the synthetic estrogen, diethylstilbestrol.4

Table

Prices of available resveratrol products

Product  Strength/Size Price
KAL Resveratrol  25 mg/60 tablets $14.99
Natrol Inc.
Resveratrol/Protykin 
50 mg/60 capsules $18.99
Source Naturals Inc.
Resveratrol 
10 mg/30 tablets $18.98
Source Naturals Inc.
Resveratrol 
10 mg/60 tablets $35.98
Vitaline Formulas
Resveratrol Forte
400 mcg/60 tablets $21.80
Source: Online dietary supplement suppliers

Pharmacology and Metabolism

Resveratrol exists in two geometrical isomers, the (E)- or trans-isomer and the (Z)- or cis-isomer.5 Both isomers are present in red wine, and both appear to have biologic activity. Polyphenols are absorbed from the upper gastrointestinal tract after wine ingestion. They are distributed in the body, showing an increased affinity for the heart, liver, and kidney, but chronic ingestion is necessary to obtain bioeffective concentrations.1 Limited information is available about the pharmacokinetics of resveratrol metabolism in the human body. It is believed that two glasses of red wine could provide a concentration of resveratrol in which most of the pharmacologic effects of resveratrol are observed.6

Mechanism of Action

Multiple mechanisms of action have been suggested for a possible chemopreventive effect. Resveratrol has been shown to inhibit the growth of both estrogen-receptor positive cells and estrogen-receptor negative cells;6 it may have both hormonal and non-hormonal effects. Among the non-hormonal effects suggested, resveratrol has been found to inhibit cell proliferation and prevent oxidative damage.3 It appears to inhibit mutagen-induced cytochrome 1A1 mRNA and related enzyme activity in breast cancer cells.2 It also can induce apoptosis,7 and can inhibit DNA synthesis in prostate cancer cells.4 Multiple signaling pathways lead to growth inhibition, based on gene expression patterns in prostate cancer cells in vitro.8 Resveratrol significantly lowered both intracellular and secreted prostate-specific antigen in a prostate cancer cell line.9

Hormonal mechanisms are complex, inconclusive, and not well elucidated, despite many studies investigating these mechanisms. Resveratrol has been shown to be an estrogen agonist10 and an antagonist,6 depending on the dosage,5 and depending on the absence or presence of estradiol.11 The most likely mechanism appears to be competitive inhibition, which also has been suggested as a mechanism for phytoestrogens such as soy. Resveratrol may have an antiestrogenic effect because of its direct competition with estradiol for binding to the estrogen receptor.6

Thus, it is possible that the estrogenic milieu plays a role in the effect seen. In a high endogenous estrogen milieu, such as premenopause, it is possible that resveratrol is an estrogen antagonist and thus protective against breast cancer. In a low endogenous estrogen state, such as postmenopause, it is possible that resveratrol could be an agonist, thus increasing the risk of breast cancer. Of course, the distribution, binding, and function of the estrogen receptors would play a role in determining the ultimate outcome. In prostate cancer cells, resveratrol has been found to inhibit the expression and function of the androgen receptor.12

Animal Studies

Most of the research studies on resveratrol are in vitro studies; few animal studies exist. One study included both in vitro and in vivo aspects.13 In vitro, resveratrol inhibited growth of breast cancer cells in a dose- and time-dependent manner. In vivo, however, resveratrol had no effect on the length of time for the development of tumors, tumor growth, or metastasis when administered to tumor-bearing mice. It also did not affect body weight, organ histology, or estrous cycling. However, in this study, the resveratrol was given intraperitoneally, rather than orally. It is possible that the actions of resveratrol depend on being absorbed through the gut, as it is in humans.

Another animal study used oral intake by gavage to female Sprague Dawley rats.11 The rats were treated with resveratrol beginning one week prior to treatment with a carcinogen. Resveratrol reduced carcinogen-induced mammary tumorigenesis. A different type of rodent model in the same study found that resveratrol inhibited the formation of estrogen-dependent preneoplastic ductal lesions induced by a mutagen. These studies show that in these animals, oral intake of resveratrol may have beneficial effects if used as a chemopreventive agent for breast cancer.

Clinical Trials

No prospective clinical trials investigating resveratrol for chemoprevention of cancer have been published. The latency of the disease and large sample size necessary could make a chemoprevention clinical trial difficult. However, epidemiological studies have been conducted.

Total alcohol consumption, including beer, wine, and liquor, has been found to be associated with increased risk of breast cancer among postmenopausal women but not premenopausal or perimenopausal women.14 Risk of fatal breast cancer data were presented by these investigators for menopausal status and total alcohol consumption, but the type of alcohol consumed was not noted. Alcohol has been shown to raise estrogen concentrations, and this might be the source of the increased breast cancer risk; however, the data on resveratrol as an agonist/antagonist also were consistent with post-menopausal women being affected (an agonist effect) and premenopausal women not being affected (an antagonist effect).

The Harvard Alumni Health Study investigated the effects of alcohol consumption on the risk of prostate cancer.15 Both wine and beer consumption were not significantly associated with prostate cancer, but moderate liquor consumption was associated with a significant 61-67% increased risk of prostate cancer. Wine did not appear to be protective.

Adverse Effects and Drug Interactions

No adverse effects were noted in the animal studies. Obviously, red wine has alcohol, and alcohol is not free of risks. Studies using grape juice have not been published, but grape juice and de-alcoholized wine also have been reported to contain high concentrations of resveratrol.2

Formulations and Dosage

The amount of wine and dosage of resveratrol that is likely to be beneficial to prevent breast or prostate cancer is unknown. In one rat study, rats received 10 mg/kg and 100 mg/kg of resveratrol; the low dose did not differ from the control in tumorigenesis, but the high dose showed reduced tumorigenesis.11

See Table for prices of available resveratrol products.

Conclusion

The literature on resveratrol is still in its infancy. Dosage, type of formulation, risks, and benefits all need to be better delineated. It is quite possible, however, that consumption of resveratrol could be beneficial. According to Basly, "the pharmacokinetic behavior of resveratrol could insure a non-proliferative and antiestrogenic intracellular concentration of resveratrol. More complete studies are needed to evaluate its role as a dietary substance."5

Recommendation

As with many other facets of life, moderation is key. Because the dosage of resveratrol for chemoprevention is unknown, and because the issue of agonism/antagonism for hormone receptors is controversial, the use of resveratrol supplements for chemoprevention of breast or prostate cancer cannot be recommended at the present time. The data are not complete on risks or benefits regarding cancer chemoprevention, although moderate consumption of wine likely provides cardiovascular benefits.16  

References

1. Damianaki A, et al. Potent inhibitory action of red wine polyphenols on human breast cancer cells. J Cell Biochem 2000;78:429-441.

2. Lee JE, Safe S. Involvement of a post-transcriptional mechanism in the inhibition of CYP1A1 expression by resveratrol in breast cancer cells. Biochem Pharmacol 2001;62:1113-1124.

3. Sgambato A, et al. Resveratrol, a natural phenolic compound, inhibits cell proliferation and prevents oxidative DNA damage. Mutation Res 2001;496: 171-180.

4. Kuwajerwala N, et al. Resveratrol induces prostate cancer cell entry into s phase and inhibits DNA synthesis. Cancer Res 2002;62:2488-2492.

5. Basly JP, et al. Estrogenic/antiestrogenic and scavenging properties of (E)- and (Z)-resveratrol. Life Sci 2000;66:769-777.

6. Lu R, Serrero G. Resveratrol, a natural product derived from grape, exhibits antiestrogenic activity and inhibits the growth of human breast cancer cells. J Cell Physiol 1999;179:297-304.

7. Nakagawa H, et al. Resveratrol inhibits human breast cancer cell growth and may mitigate the effect of linoleic acid, a potent breast cancer cell stimulator. J Cancer Res Clin Oncol 2001;127:258-264.

8. Narayanan BA, et al. Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci 2002;70:1821-1839.

9. Hsieh T, Wu JM. Differential effects on growth, cell cycle arrest, and induction of apoptosis by resveratrol in human prostate cancer cell lines. Exp Cell Res 1999; 249:109-115.

10. Gehm BD, et al. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc Natl Acad Sci U S A 1997;94: 14138-14143.

11. Bhat KP, et al. Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models. Cancer Res 2001;61:7456-7463.

12. Mitchell SH, et al. Resveratrol inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Cancer Res 1999;59:5892-5895.

13. Bove K. Effect of resveratrol on growth of 4T1 breast cancer cells in vitro and in vivo. Biochem Biophys Res Commun 2002;291:1001-1005.

14. Feigelson HS, et al. Alcohol consumption increases the risk of fatal breast cancer (United States). Cancer Causes Control 2001;12:895-902.

15. Sesso HD, et al. Alcohol consumption and risk of prostate cancer: The Harvard Alumni Health Study. Int J Epidemiol 2001;30:749-755.

16. Pace-Asciak CR, et al. The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation and eicosanoid synthesis: Implications for protection against coronary heart disease. Clin Chim Acta 1995;235:207-219.