Stilbene Resveratrol Research Articles

Resveratrol is pro-apoptotic and thyroid hormone is anti-apoptotic in glioma cells: both actions are integrin and ERK mediated

The stilbene resveratrol (RV) initiates p53-dependent apoptosis via plasma membrane integrin alphaVbeta3 in human cancer cells. A thyroid hormone (L-thyroxine, T(4)) membrane receptor also exists on alphaVbeta3. Stilbene and T(4) signals are both transduced by extracellular-regulated kinases 1 and 2 (ERK1/2); however, T(4) promotes cell proliferation in cancer cells, whereas RV is pro-apoptotic. Thyroid hormone has been shown to interfere with RV-induced apoptosis. However, the mechanisms involved are not fully understood. In this study, we examined the mechanism whereby T(4) inhibits RV-induced apoptosis in glioma cells. RV activated conventional protein kinase C and ERK1/2 and caused nuclear localization of cyclooxygenase-2 (COX-2), consequent p53 phosphorylation and apoptosis. RV-induced ERK1/2 activation is involved in not only COX-2 expression but also nuclear COX-2 accumulation. NS-398, a COX-2 inhibitor, did not affect ERK1/2 activation, but reduced the nuclear abundance of COX-2 protein and the formation of complexes of nuclear COX-2 and activated ERK1/2 that are required for p53-dependent apoptosis in RV-treated cells. T(4) inhibited RV-induced nuclear COX-2 and cytosolic pro-apoptotic protein, BcLx-s, accumulation. Furthermore, T(4) inhibited RV-induced apoptosis by interfering with the interaction of nuclear COX-2 and ERK1/2. This effect of T(4) was prevented by tetraiodothyroacetic acid (tetrac), an inhibitor of the binding of thyroid hormone to its integrin receptor. Tetrac did not, in the absence of T(4), affect induction of apoptosis by RV. Thus, the receptor sites on alphaVbeta3 for RV and thyroid hormone are discrete and activate ERK1/2-dependent downstream effects on apoptosis that are distinctive.

Biciclogermacreno, resveratrol e atividade antifúngica em extratos de folhas de Cissus verticillata (L.) Nicolson & Jarvis (Vitaceae)

Cissus verticillata L. (Vitaceae) tem sido empregada popularmente como anti-diabética. Nessa espécie foi também detectada atividade fungitóxica. O objetivo do presente trabalho foi realizar a identificação dos compostos fungitóxicos em extratos de folhas. O extrato etanólico foi submetido a fracionamento com solventes de diferentes polaridades (hexano, clorofórmio, acetato de etila e butanol) e seu efeito antifúngico foi analisado frente a Cladosporium sphaerospermum. Os extratos em clorofórmio e acetato de etila mostraram atividade, e foram fracionados por cromatografia em coluna e cromatografia preparativa em placas de sílica, respectivamente. Três terpenóides foram isolados do extrato em clorofórmio; um deles foi identificado, por análise em CG-EM, como um sesquiterpeno, o biciclogermacreno. O composto ativo do extrato em acetato de etila foi identificado, por análises em CLAE, como o estilbeno resveratrol.

Inhibition of the formation of the neurotoxin 5- S-cysteinyl-dopamine by polyphenols

The death of nigral neurons in Parkinson’s disease is thought to involve the formation of the endogenous neurotoxin, 5- S-cysteinyl-dopamine. In the present study, we show that the polyphenols, (+)-catechin and caffeic acid, which contain a catechol moiety, inhibit tyrosinase-induced formation of 5- S-cysteinyl-dopamine via their capacity to undergo tyrosinase-induced oxidation to yield cysteinyl-polyphenol adducts. In contrast, the inhibition afforded by the flavanone, hesperetin, was not accompanied by the formation of cysteinyl-hesperetin adducts, indicating that it may inhibit via direct interaction with tyrosinase. Whilst the stilbene resveratrol also inhibited 5- S-cysteinyl-dopamine formation, this was accompanied by the formation of dihydrobenzothiazine, a strong neurotoxin. Our data indicate that the inhibitory effects of polyphenols against 5- S-cysteinyl-dopamine formation are structure-dependent and shed further light on the mechanisms by which polyphenols exert protection against neuronal injury relevant to neurodegenerative diseases.

Benzo[ a]pyrene-induced cytochrome P450 1A and DNA binding in cultured trout hepatocytes—Inhibition by plant polyphenols

Polycyclic aromatic hydrocarbons (PAH) such as benzo[ a]pyrene (BaP) mainly induce lung cancer in humans, but induce liver cancer in fishes. The chemoprevention of cancers through inhibition of molecular events via phytochemicals is a potentially beneficial area of research, and has been carried out in human cell cultures in the past. Carcinogenesis initiation events are thought to occur in similar ways in fish and humans. Our study investigated the feasibility of using cultured rainbow trout CRL-2301 liver cells as a model for BaP-induced carcinogenesis and its prevention by dietary phytochemicals. Treatment with 1 μM BaP resulted in extensive time-dependent covalent binding to cellular DNA and marked cytochrome P450 (CYP) 1A induction, for both about a 20-fold increase, which is similar to what has been observed in cultured human cells. A surprisingly high expression of epoxide hydrolase (EH) activity in these cells likely contributed substantially to the bioactivation of BaP. Two methoxylated flavones and the stilbene resveratrol were effective inhibitors of both the BaP-DNA binding and CYP 1A induction, in particular 5,7-dimethoxyflavone (5,7-DMF), supporting a role for these dietary compounds as cancer chemopreventive agents. Unlike in human liver or bronchial cells, the main mechanism of inhibition of BaP-induced CYP 1A activity in trout liver cells appears to be direct competition at the protein level. Different cellular responses in any particular model used can be expected and the effect of cell context on the biological responses to xenobiotics, including carcinogens as well as polyphenols, must be considered. The trout CRL-2301 cells’ sensitivity to BaP treatment is a clear advantage when contemplating a model system for studies of PAH-induced carcinogenesis and cancer chemoprevention. However, extrapolation to human organs should be done cautiously.

Prooxidant DNA breakage induced by caffeic acid in human peripheral lymphocytes: Involvement of endogenous copper and a putative mechanism for anticancer properties

Plant-derived dietary material contains several classes of polyphenols such as flavonoids, curcuminoids, stilbenes and hydroxycinnamic acids. They are recognized as naturally occurring antioxidants but also act as prooxidants catalyzing cellular DNA degradation in the presence of transition metal ions such as copper. Earlier we have shown that the stilbene resveratrol is able to mobilize endogenous copper ions leading to oxidative breakage of cellular DNA. In this paper, we show that caffeic acid (a hydroxycinnamic acid), which is a major constituent of coffee, is also capable of DNA breakage in human peripheral lymphocytes. Incubation of lymphocytes with neocuproine inhibited the DNA degradation confirming that Cu(I) is an intermediate in the DNA cleavage reaction. Further, we have also shown that caffeic acid generates oxidative stress in lymphocytes, which is inhibited by scavengers of reactive oxygen species and neocuproine. These results are in further support of our hypothesis that anticancer mechanism of plant polyphenols involves mobilization of endogenous copper, possibly chromatin bound copper, and the consequent prooxidant action.

Resveratrol exerts its antiproliferative effect on HepG2 hepatocellular carcinoma cells, by inducing cell cycle arrest, and NOS activation

The stilbene resveratrol exerts antiproliferative and proapoptotic actions on a number of different cancer cell lines, through diverse mechanisms, including antioxidant effects, enzyme, growth factor and hormone receptor binding, and nucleic acid direct or indirect interactions. Although resveratrol accumulates in the liver, its effect on hepatocellular carcinoma has not been extensively studied. We have used the human hepatocyte-derived cancer cell line HepG2 to address the possible action of resveratrol on cell growth and to examine some possible mechanisms of action. Our results indicate that the stilbene inhibits potently cell proliferation, reduces the production of reactive oxygen species and induces apoptosis, through cell cycle arrest in G 1 and G 2/M phases. Furthermore it modulates the NO/NOS system, by increasing iNOS and eNOS expression, NOS activity and NO production. Inhibition of NOS enzymes attenuates its antiproliferative effect. These data could be of value in possible prevention or adjuvant treatment of hepatocellular carcinoma, through an increased consumption of resveratrol-rich foods and beverages.

Synthesis of polyhydroxylated ester analogs of the stilbene resveratrol using decarbonylative Heck couplings

Protected 3,5-hydroxy-benzoyl chlorides 3 were coupled with styrenes 4 to give hydroxylated stilbenes, analogs of resveratrol, an important antioxidant disease preventative agent isolated from grape skins and other dietary sources. Levulinate and chloroacetate protecting groups allowed for the selective production of mono- and di-acetate variations under palladium- N-heterocyclic carbene (NHC) catalyzed decarbonylative coupling conditions. Fluorinated analogs were also produced using Heck conditions with bromofluorobenzenes. Human HL-60 cell assays showed the 4′-acetoxy variant 11 to have improved activity (ED 50 17 μM) relative to resveratrol (24 μM).

Pathway engineering for healthy phytochemicals leading to the production of novel flavonoids in tomato fruit

Flavonoids are a large family of plant polyphenolic secondary metabolites. Although they are widespread throughout the plant kingdom, some flavonoid classes are specific for only a few plant species. Due to their presumed health benefits there is growing interest in the development of food crops with tailor-made levels and composition of flavonoids, designed to exert an optimal biological effect. In order to explore the possibilities of flavonoid engineering in tomato fruits, we have targeted this pathway towards classes of potentially healthy flavonoids which are novel for tomato. Using structural flavonoid genes (encoding stilbene synthase, chalcone synthase, chalcone reductase, chalcone isomerase and flavone synthase) from different plant sources, we were able to produce transgenic tomatoes accumulating new phytochemicals. Biochemical analysis showed that the fruit peel contained high levels of stilbenes (resveratrol and piceid), deoxychalcones (butein and isoliquiritigenin), flavones (luteolin-7-glucoside and luteolin aglycon) and flavonols (quercetin glycosides and kaempferol glycosides). Using an online high-performance liquid chromatography (HPLC) antioxidant detection system, we demonstrated that, due to the presence of the novel flavonoids, the transgenic tomato fruits displayed altered antioxidant profiles. In addition, total antioxidant capacity of tomato fruit peel with high levels of flavones and flavonols increased more than threefold. These results on genetic engineering of flavonoids in tomato fruit demonstrate the possibilities to change the levels and composition of health-related polyphenols in a crop plant and provide more insight in the genetic and biochemical regulation of the flavonoid pathway within this worldwide important vegetable.

Biosynthesis of plant-specific stilbene polyketides in metabolically engineered Escherichia coli

BackgroundPhenylpropanoids are the precursors to a range of important plant metabolites such as the cell wall constituent lignin and the secondary metabolites belonging to the flavonoid/stilbene class of compounds. The latter class of plant natural products has been shown to function in a wide range of biological activities. During the last few years an increasing number of health benefits have been associated with these compounds. In particular, they demonstrate potent antioxidant activity and the ability to selectively inhibit certain tyrosine kinases. Biosynthesis of many medicinally important plant secondary metabolites, including stilbenes, is frequently not very well understood and under tight spatial and temporal control, limiting their availability from plant sources. As an alternative, we sought to develop an approach for the biosynthesis of diverse stilbenes by engineered recombinant microbial cells.ResultsA pathway for stilbene biosynthesis was constructed in Escherichia coli with 4-coumaroyl CoA ligase 1 4CL1) from Arabidopsis thaliana and stilbene synthase (STS) cloned from Arachis hypogaea. E. coli cultures expressing these enzymes together converted the phenylpropionic acid precursor 4-coumaric acid, added to the growth medium, to the stilbene resveratrol (>100 mg/L). Caffeic acid, added in the same way, resulted in the production of the expected dihydroxylated stilbene, piceatannol (>10 mg/L). Ferulic acid, however, was not converted to the expected stilbene product, isorhapontigenin. Substitution of 4CL1 with a homologous enzyme, 4CL4, with a preference for ferulic acid over 4-coumaric acid, had no effect on the conversion of ferulic acid. Accumulation of tri- and tetraketide lactones from ferulic acid, regardless of the CoA-ligase expressed in E. coli, suggests that STS cannot properly accommodate and fold the tetraketide intermediate to the corresponding stilbene structure.ConclusionPhenylpropionic acids, such as 4-coumaric acid and caffeic acid, can be efficiently converted to stilbene compounds by recombinant E. coli cells expressing plant biosynthetic genes. Optimization of precursor conversion and cyclization of the bulky ferulic acid precursor by host metabolic engineering and protein engineering may afford the synthesis of even more structurally diverse stilbene compounds.

Does Resveratrol Prevent Free Radical-induced Acute Pancreatitis?

The purpose of this study was to examine protective and antioxidative effect of stilbene derivatives, resveratrol and diethylstilbestrol, in experimental acute pancreatitis (EAP). EAP was induced in male Wistar rats by retrograde injection of tert-butyl hydroperoxide (ButOOH) solution, a well-known prooxidant agent, into the common bile pancreatic duct. After a 3-hour observation, the animals were killed. Blood samples were collected. Each pancreas was removed and weighed. Tissue samples were taken for microscopic studies. The carbonyl and sulfhydryl (SH) group levels were estimated in the homogenate. Examination using light microscopy revealed morphologic changes in pancreata removed from EAP rats, namely focal edema, acinar cell vacuolization, and focal necrosis of pancreatic acini. The electron microscopic analysis also showed changes in their subcellular structures: dilated cisternae of the rough endoplasmic reticulum, swollen mitochondria, and "debris" of mitochondrial cristae. These changes corresponded with higher activities of serum amylase and tissue carbonyl groups levels and decreased SH group level compared with controls. Changes in pancreata were much less pronounced in the rats that received resveratrol or diethylstilbestrol for 8 days prior to ButOOH injection. Stilbene derivatives prevent pancreatic cells from structural changes during ButOOH-induced acute pancreatitis.

Effect of Stilbene Resveratrol on Haematological Indices of Rats

Doubek J., T. Voln˘, A. Lojek, Z. Knotkova, V. Kotrbaaek, P. Scheer, Z. Hole‰ovska: Effect of Stilbene Resveratrol on Haematological Indices of Rats. Acta Vet. Brno 2005, 74: 205-208. The objective of this study was to find whether the short-time intake of stilbene-resveratrol can influence some haematological indices. The tested compound extracted from the fleeceflower knotweed (Polygonum cuspidatum) was dissolved in saline and administered by a gastric cannula to 15 experimental male rats of Wistar outbreeeding for a week at a daily dose of 4 mg/kg0.75 of body weight. The effects of resveratrol were compared with 15 control rats that received saline in the same way. The SPF rats (Anlab, Prague) were kept individually in cages and were provided with drinking water and complete feed mixture “Biostan Mypo” ad libitum. The feed contained all necessary energy nutrients, vitamins and minerals for the given animal species and their age. Using a colorimetric method and the Griess agent plasma concentrations of nitrites were determined in blood samples taken at the end of experimental period. Total antioxidative capacity (TRAP) of blood was determined luminometrically and using the aggregometer APACT II employing the turbidimetric method by Born functional tests of platelets were performed. ADP and collagen were employed to induce aggregation. Resveratrol administration did not influence plasma nitrites. No changes were observed in total antioxidative capacity of blood and aggregation characteristics of platelets. However, platelet disaggregation was significantly enhanced (p < 0.01) and their counts significantly decreased (p < 0.01). The results indicate that parameters important for haemostasis can be influenced by the short-time intake of resveratrol administered at the given dose.

Expression of the grapevine stilbene synthase gene VST1 in papaya provides increased resistance against diseases caused by Phytophthora palmivora.

The phytoalexin resveratrol (trans-3,5,4'-trihydroxy-stilbene), a natural component of resistance to fungal diseases in many plants, is synthesized by the enzyme trihydroxystilbene synthase (stilbene synthase, EC 2.3.1.95), which appears to be deficient or lacking in susceptible plants. Earlier workers isolated a stilbene synthase gene (Vst1) from grapevine (Vitis vinifera L.), which has subsequently been introduced as a transgene into a range of species to increase resistance of hosts to pathogens to which they were originally susceptible. Papaya (Carica papaya L.) is susceptible to a variety of fungal diseases, including root, stem, and fruit rot caused by the pathogen Phytophthora palmivora. Since resveratrol at 1.0 mM inhibited mycelium growth of P. palmivora in vitro, we hypothesized that papaya resistance to this pathogen might be increased by transformation with the grapevine stilbene synthase construct pVst1, containing the Vst1 gene and its pathogen-inducible promoter. Multiple transformed lines were produced, clonally propagated, and evaluated with a leaf disk bioassay and whole plant response to inoculation with P. palmivora. RNA transcripts of stilbene synthase and resveratrol glycoside were induced in plant lines transformed with the grapevine pVst1 construct shortly after pathogen inoculation, and the transformed papaya lines exhibited increased resistance to P. palmivora. The immature transformed plants appear normal and will be advanced to field trials to evaluate their utility.

Polyphenol glucosylating activity in cell suspensions of grape (Vitis vinifera).

Stilbenes are phenolic molecules that have antifungal effects in the plant and antioxidant and anti-cancer effects when consumed in the human diet. Glycosylation of stilbenes increases their solubility and may make them more easily absorbed by the intestine. We have found an activity in extracts of cultured cells of Vitis vinifera (cv. Gamay Freaux) that glucosylates the stilbene resveratrol to form piceid. The Km for UDP-Glucose was 1.2 mM, and the Km for resveratrol was 0.06 mM, values similar to those of other phenolic glucosyltransferases. We investigated the resveratrol glucosylating activity of the enzyme extracted from cells grown under different light treatments (dark, visible light, light + ultraviolet (UVC) radiation) and found the activity to be unaffected or slightly reduced. In contrast, UVC light strongly stimulated extractable quercetin glucosyltransferase activity. These results, combined with analysis of phenolic compounds extracted from the differently treated cells, suggest that the resveratrol glucosyltransferase is distinct from the glucosyltransferase(s) active on other phenolics.

Styrylquinazolines: A New Class of Inhibitors on Prostaglandin E2 Production in Lipopolysaccharide‐Activated Macrophage Cells.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Interaction of the breast cancer resistance protein with plant polyphenols

Multidrug transporters influence drug distribution in vivo and are often associated with tumour drug resistance. Here we show that plant-derived polyphenols that interact with P-glycoprotein can also modulate the activity of the recently discovered ABC transporter, breast cancer resistance protein (BCRP/ABCG2). In two separate BCRP-overexpressing cell lines, accumulation of the established BCRP substrates mitoxantrone and bodipy- fl-prazosin was significantly increased by the flavonoids silymarin, hesperetin, quercetin, and daidzein, and the stilbene resveratrol (each at 30 μM) as measured by flow cytometry, though there was no corresponding increase in the respective wild-type cell lines. These compounds also stimulated the vanadate-inhibitable ATPase activity in membranes prepared from bacteria ( Lactococcus lactis) expressing BCRP. Given the high dietary intake of polyphenols, such interactions with BCRP, particularly in the intestines, may have important consequences in vivo for the distribution of these compounds as well as other BCRP substrates.

Antifungal activity of stilbenes in in vitro bioassays and in transgenic Populus expressing a gene encoding pinosylvin synthase.

The effect of two stilbene compounds, pinosylvin and resveratrol, on the growth of several fungi was evaluated in plate tests. Wood decay tests were carried out with birch and aspen samples impregnated with the two stilbenes. In plate experiments, resveratrol had an enhancing effect on growth at concentrations where pinosylvin was already enough to prevent the growth of most fungi studied. Pinosylvin impregnated at 0.2% (w/w) concentration significantly reduced the decay caused by all fungi except Phellinus tremulae. In contrast, a resveratrol content of 0.8%, did not protect the wood from decay. A pinosylvin-synthase-encoding gene from Pinus sylvestris was transferred into aspen ( Populus tremula) and two hybrid aspen clones ( Populus tremulax tremuloides) by Agrobacterium tumefaciens-mediated transformation. Transgenic plants accumulated pinosylvin synthase-specific mRNA and showed stilbene synthase enzyme activity in vitro. Transgenic aspen line H4 showed increased resistance to Phellinus tremulae, while two hybrid aspen transformants decayed faster than the control trees. However, we were unable to detect the accumulation of stilbenes in the transgenic plantlets.

Styrylquinazolines: a new class of inhibitors on prostaglandin E2 production in lipopolysaccharide-activated macrophage cells.

A series of styrylquinazoline derivatives (2a-k) were prepared and evaluated for their inhibiton of prostaglandin E(2) (PGE(2)) production by cyclooxygenase-2 (COX-2). The latter was induced by lipopolysaccharide-stimulated macrophage cells RAW264.7. 3', 4'-Dihydroxylated styrylquinazolines (2a-c), 3'-hydroxylated styrylquinazolines (2h, 2i), and 3'-acetoxy-styrylquinazolines (2j, 2k) exhibited good inhibitory effects of PGE(2) production by COX-2 with a range of IC(50) values of 1.19 approximately 3.56 microM. The potencies were comparable or better than that of the representative stilbene resveratrol (IC(50) = 3.07 microM). These results indicate that styrylquinazolines can be considered as potential resveratrol analogues in the modulation of prostaglandin production by COX-2.

Metabolic engineering of Saccharomyces cerevisiae for the synthesis of the wine-related antioxidant resveratrol.

The stilbene resveratrol is a stress metabolite produced by Vitis vinifera grapevines during fungal infection, wounding or UV radiation. Resveratrol is synthesised particularly in the skins of grape berries and only trace amounts are present in the fruit flesh. Red wine contains a much higher resveratrol concentration than white wine, due to skin contact during fermentation. Apart from its antifungal characteristics, resveratrol has also been shown to have cancer chemopreventive activity and to reduce the risk of coronary heart disease. It acts as an antioxidant and anti-mutagen and has the ability to induce specific enzymes that metabolise carcinogenic substances. The objective of this pilot study was to investigate the feasibility of developing wine yeasts with the ability to produce resveratrol during fermentation in both red and white wines, thereby increasing the wholesomeness of the product. To achieve this goal, the phenylpropanoid pathway in Saccharomyces cerevisiae would have to be introduced to produce p-coumaroyl-CoA, one of the substrates required for resveratrol synthesis. The other substrate for resveratrol synthase, malonyl-CoA, is already found in yeast and is involved in de novo fatty-acid biosynthesis. We hypothesised that production of p-coumaroyl-CoA and resveratrol can be achieved by co-expressing the coenzyme-A ligase-encoding gene (4CL216) from a hybrid poplar and the grapevine resveratrol synthase gene (vst1) in laboratory strains of S. cerevisiae. This yeast has the ability to metabolise p-coumaric acid, a substance already present in grape must. This compound was therefore added to the synthetic media used for the growth of laboratory cultures. Transformants expressing both the 4CL216 and vst1 genes were obtained and tested for production of resveratrol. Following beta-glucosidase treatment of organic extracts for removal of glucose moieties that are typically bound to resveratrol, the results showed that the yeast transformants had produced the resveratrol beta-glucoside, piceid. This is the first report of the reconstruction of a biochemical pathway in a heterologous host to produce resveratrol.

Phytoestrogens: Recent Developments

Phytoestrogens are polyphenolic non-steroidal plant compounds with estrogen-like biological activity. Based on their chemical structure, phytoestrogens can be classified into four main groups, i. e., isoflavonoids, flavonoids, stilbenes, and lignans. For each group, the chemistry, dietary sources and biotransformation of the most interesting compounds will be discussed. Since phytoestrogens are structurally very similar to the estrogen 17beta-estradiol, they may exhibit selective estrogen receptor modulating activities. Therefore, special attention will be given to the hormonal effects of various isoflavonoids, including genistein, daidzein, coumestrol and equol, several prenylated flavonoids, especially 8-prenylnaringenin, and the stilbene resveratrol. Furthermore, their non-hormonal effects will be discussed briefly. Finally, the latest developments on the potential protective properties of phytoestrogens and phytoestrogen-containing foods against hormone-dependent breast and prostate cancers and cardiovascular diseases, and as estrogen replacement therapy for postmenopausal women will be discussed.

Resveratrol: A Candidate Nutritional Substance for Prostate Cancer Prevention

The dietary stilbene resveratrol is a major constituent of a variety of edible plant products, including grapes and peanuts. Resveratrol has been identified as an excellent candidate cancer chemopreventive, based on its safety and efficacy in animal models of carcinogenesis. Resveratrol is a prototype of a plethora of bioactive polyphenols in the food supply that has just begun to be mined for cancer preventive agents. For example, polyphenolic grapeseed fractions were shown recently to potently antagonize chemical carcinogenesis. Taking into consideration that the identification of resveratrol as a cancer preventive agent is largely owed to its high abundance in nature (e.g., it accounts for 5-10% of the grapeskin biomass), it is logical to expect that naturally occurring stilbenes that are superior to resveratrol in their cancer preventive properties await identification. Thus, resveratrol may represent the tip of the iceberg of a broad class of stilbene and related polyphenolic natural products that include safe and highly effective agents for cancer prevention. We hypothesize that resveratrol may be especially suitable as a lead agent for prostate cancer prevention given its ability to: 1) inhibit each stage of multistage carcinogenesis, 2) scavenge incipient populations of androgen-dependent prostate cancer cells through androgen receptor antagonism, and 3) scavenge incipient populations of androgen-independent prostate cancer cells by short-circuiting the epidermal growth factor-receptor (EGFR)-dependent autocrine loops in the cancer cells.