Resveratrol has been in the news over the past few years as an anti-aging miracle molecule, and has been suggested to have anti-inflammatory benefits, anti-platelet actions, cardiovascular benefits, and anti-carcinogenic effects. I have been a fan of the studies that show benefits in a variety of areas. A new study (see below) suggests that resveratrol can improve brain function through increased blood flow, and may provide neuro-protective benefits (it has been shown to clear intracellular amyloid-β (Aβ) peptides associated with Alzheimer's Disease).
On the other hand, and most important to me, there is evidence of strong estrogenic effects. This is a long passage, but the information is new to me [although it's from 1997]. I have been a fan of resveratrol, but this information gives me pause and will require some additional research before I can safely recommend this supplement, or continue taking it for myself.
The estrogenic effects of this study (which has powerful implications for cancer) is in contradiction to many other studies that demonstrate anti-carcinogenic activity (see below). There is also little information about how this supplement acts in men regarding estrogen receptor activity - although there is evidence that resveratrol may inhibit the expression and function of the androgen receptor in prostate cancer cells, which again suggests an estrogenic action (making it useful for treating slow-growing prostrate cancer, perhaps).
There are several studies that support these findings, but there are others that suggest anti-tumor activity from resveratrol. These contradictions suggest that some people might benefit from resveratrol while others should avoid it like the plague - and until there is a genetic test to sort who benefits and who doesn't, it's a crap-shoot.By using several different assay systems, these studies demonstrate that resveratrol is a phytoestrogen. It competes with 125I-labeled estradiol for binding to the human estrogen receptor. Furthermore, it activates the expression of estrogen-responsive reporter genes in several different human cell lines, and this activation is inhibited by estrogen antagonists. Resveratrol also fully activates expression of endogenous estrogen-regulated genes, and it induces the proliferation of T47D breast cancer cells. The EC50 for estrogenic stimulation by resveratrol ranged between 3 and 10 μM, depending on the test system examined. Thus, the estrogenic effects of resveratrol occur at concentrations that are similar to those required for its reported anti-inflammatory (25, 26), anti-platelet (6), and anti-carcinogenic (8) activities.
Resveratrol produced greater maximal transcriptional activation than estradiol, but this superagonism was not seen in all cell types. For example, resveratrol produced two to four times greater activation of reporter plasmids than estradiol in MCF-7 breast cancer cells but less activation than estradiol in BG-1 ovarian carcinoma cells. These cell type-specific effects of resveratrol are reminiscent of the well known tissue-specific and species-specific effects of agents such as tamoxifen (27), which can act as an estrogen receptor agonist in some tissues such as the uterus but acts as an estrogen antagonist in the breast (27). Other recently characterized estrogen receptor ligands such as raloxifene also appear to exert tissue-selective actions (28). Superagonism was not observed in the induction of progesterone receptor expression, even in MCF-7 cells. Although this result may reflect differences in endogenous vs. transfected genes, it suggests that the effects of resveratrol may vary depending on the target gene as well as the cell type.
The mechanisms for gene- and tissue-specific effects of estrogen receptor ligands are not known. It has been shown recently that a second form of estrogen receptor exists (estrogen receptor β) (29). The different tissue distributions of the estrogen receptors α and β might contribute to the differential effects of various estrogen receptor ligands, including resveratrol. In addition, expression of different transcriptional coactivators and corepressors in various tissues (reviewed in ref. 30) and the ability of different ligands to induce various conformations of the estrogen receptor (31) may result in tissue- and ligand-specific activation of certain genes. It is also possible that, in some cell types (e.g., MCF-7), resveratrol produces superagonism by activating additional signaling pathways that converge on estrogen receptor-mediated transcription.
The potential biological impact of environmental and dietary estrogens on human health has generated considerable interest (32–34). These agents include phytoestrogens as well a variety of synthetic compounds. Chemically, many of the known phytoestrogens are flavonoids; others are coumestans or resorcylic acid lactones (35, 36), and an estrogenic hydroxystilbene recently has been reported to occur naturally in wood (37). The finding that resveratrol is estrogenic expands the spectrum of known dietary phytoestrogens.
Red wine appears to be more estrogenic than bourbon or beer, which contain other phytoestrogens but not resveratrol (38). Resveratrol is found primarily in the skin of grapes and is therefore relatively abundant in red, but not white, wines. There is considerable variation in the resveratrol content even among red wines, depending on grape cultivar, vintage, and place of origin and also on the analytical technique used for measurement. Concentrations of 10–20 μM are common although higher or lower values also are found frequently (3). In addition to free resveratrol, wines contain resveratrol glycosides that may contribute to the biologically available dose (39). Unfortunately, no data have been published concerning serum levels of resveratrol after wine consumption, and there is no information about its rate of clearance from the bloodstream, the identities and activities of its metabolic products, or the potential first-pass effects of portal circulation through the liver. In the absence of such data, the physiological significance of resveratrol in wine remains uncertain.
However, the anti-oxidant (4) and anti-platelet (6, 40) activities of resveratrol have been invoked as possible mechanisms for the reported cardiovascular benefits of moderate wine consumption and the so-called “French paradox” (7). Goldberg and coworkers (6) found that resveratrol inhibited thromboxane B2 synthesis and thrombin-induced aggregation of human platelets in vitro, with IC50s of 7 μM and ≈160 μM, respectively. More recently, they examined the effects of dietary supplementation with resveratrol and found that platelets from human volunteers who consumed 2 mg (≈9 μmol) per day showed diminished thromboxane B2 synthesis and reduced thrombin-induced aggregation compared with controls (41). A few glasses of many red wines could supply this amount of resveratrol. These results suggest that daily consumption of some red wines might produce pharmacologically significant concentrations of resveratrol in the blood. Based on the concentrations required in vitro, it seems likely that doses of resveratrol that affect platelet behavior could also have some estrogenic effect. It is intriguing to consider whether the estrogenicity of resveratrol may contribute to the reported cardiovascular benefits of red wine (7). Estrogens have similar effects if administered orally; the high doses delivered to the liver via portal circulation produce beneficial changes in serum lipids (9, 10). Similarly, wine consumption may expose the liver to higher concentrations of resveratrol than occur in the systemic circulation.
The finding that resveratrol stimulates the growth of human breast cancer cells is also potentially significant. Although Jang et al. (8) found that resveratrol exerts an anticarcinogenic effect in mouse mammary cultures, our results suggest that resveratrol could exert a growth-stimulating estrogenic effect on human breast carcinomas. This apparent contradiction might be explained by the observation that, although many human breast cancers are mitogenically stimulated by estrogen, most mouse mammary cancers are estrogen-insensitive (42). Thus, although the anti-carcinogenic and anti-thrombotic activities of resveratrol show pharmacological promise, its estrogenic properties may produce undesirable side effects and limit the circumstances under which it can be used safely.
Further studies are required to assess the physiological significance of resveratrol in humans, and a more complete understanding of its estrogenic actions is needed to understand its role as a dietary substance. The superagonistic properties of resveratrol raise the possibility that structure–function studies could lead to the development of more selective estrogen receptor agonists and antagonists, which could be useful as a therapeutic agents.
Here is a bit of info on the positive role in cancer.
Resveratrol is currently being evaluated in preclinical studies as a potential cancer chemoprevention agent. It has previously been shown to have anticancer activities in both cell culture and animal carcinogenesis models of both hematological and solid tumors. Although it is widely available in the form of unregulated herbal supplements, there are relatively little clinical data characterizing its anticancer activities during human consumption. We carried out the present studies to provide further evidence to support the use of this compound in cancer prevention and therapy trials and to identify a panel of surrogate biomarkers for evaluating its in vivo treatment efficacy. Our studies demonstrate the broad antitumor properties of this agent in a wide variety of human cancer cell lines. Resveratrol caused a dose-dependent cancer cell growth inhibition, and this antiproliferative effect appears to be due to its ability to induce S-phase arrest and apoptotic cell death. Furthermore, we have identified cyclin D1, cyclin A, cyclin B1, β-catenin, apoptotic index, S-phase arrest, and possibly cox-2 as candidate biomarkers for use as surrogate intermediate end points. We have further characterized resveratrol’s mechanism of action in SW480 human colorectal cancer cells. In these cells, resveratrol decreases the expression levels of cyclin D1, cyclin A, cyclin B1, and β-catenin. The decrease in cyclin D1 expression appears to be due more to an induction of its degradation than to a suppression of its transcription.
Resveratrol has been previously shown to have growth-inhibitory activity in several human cancer cell lines of both hematological and epithelial origin, including HL60 leukemia (3) , CaCo-2 colorectal carcinoma (6) , and A431 epidermoid carcinoma cells (7) . In breast cancer cell lines, however, its effects on cell growth were not consistent. At higher doses (≥50 μm), resveratrol generally inhibited cell growth in both ER+ and ER− breast cancer cell lines (9 , 11) , although one study reported growth inhibition in the 22–175 μm dose range (8) . At lower doses (≤25 μm), resveratrol stimulated cell growth in ER+ breast cancer cells (9, 10, 11) . Structurally, resveratrol resembles the synthetic estrogen diethylstilbesterol (12) and can bind to rat uterine ERs (12 , 30) , although at a much lower affinity than estradiol. Resveratrol has also been shown to activate transcription of estrogen-responsive reporter constructs (10 , 31) . However, when given s.c. to Wistar rats, resveratrol failed to induce significant uterotrophic responses, suggesting that its potential estrogenic activity may not be relevant in in vivo models (12 , 30) . However, because of its estrogenic potential, caution should be used when evaluating its clinical role in breast cancer therapy and prevention.
Resveratrol has also been previously shown to induce apoptosis in leukemia, mammary, and epidermoid cell lines (3 , 5 , 7) . The doses of resveratrol used to induce cellular changes, including growth inhibition, cell cycle arrest, and apoptosis, can be divided into three different dose ranges. Whereas resveratrol can induce specific biochemical effects in cell culture models in the 1–10 μm range, its cytostatic and cytotoxic effects usually require 25–100 and 100–200 μm concentrations, respectively. Previous investigators have demonstrated resveratrol’s abilities to decrease cyclin D1 expression (7 , 32) , reduce [3H]thymidine incorporation (33) , inhibit phorbol ester-mediated cox-2 induction (34) , decrease ornithine decarboxylase activity (6) , and reduce indices of oxidative damage (35) at concentrations in the 10–30 μm range. Two previous studies evaluated concentrations in the 1–10 μm range (3 , 7) . In both studies, however, the majority of resveratrol-induced effects, including significant growth inhibition, occurred only at concentrations above 25 μm. Thus, the latter and other studies have shown that doses of resveratrol in the range of 25–100 μm are required to inhibit growth in various human cancer and leukemia cell lines (3 , 4 , 6 , 7 , 9 , 32 , 35) and that treatment with concentrations below this range had little effect on growth (4 , 6) . Similar doses were also able to induce cell cycle arrest (3 , 6 , 7 , 32 , 35 , 36) . Two previous studies demonstrated resveratrol’s ability to induce apoptosis at its IC50 dose for growth inhibition (3 , 7) . However, in most of the previous studies, resveratrol did not induce significant apoptosis or have cytotoxic effects at cytostatic doses (6 , 32 , 35 , 36) . Thus, doses required for resveratrol to induce apoptosis were often higher than those that induced growth inhibition and cell cycle arrest (4) and were often in the 100–200 μm range (32 , 37 , 38) . In the present study, we chose a dose of 300 μm to convincingly demonstrate the ability of resveratrol to induce apoptosis in a variety of human cancer cell lines, including esophageal and colorectal carcinoma cells, types of cancer in which resveratrol may have a role in chemoprevention.
As with other types of chemoprevention agents, including nonsteroidal anti-inflammatory drugs and retinoid compounds, the antitumor and antiproliferative activities of resveratrol probably reflect several mechanisms of action. In the present studies, growth inhibition and induction of apoptosis were observed within 48 h of treatment. A slight amount of apoptosis could be detected after only 24 h of treatment by flow cytometry using an annexin V-based staining assay (data not shown). After only 24 h of treatment, resveratrol prevented cells from entering the G2 phase of the cell cycle, resulting in the accumulation of cells in either the G1 or S phase. Most of the cell lines demonstrated an accumulation in S phase, but in Bic-1 cells, resveratrol treatment led to G1-phase arrest (Table 2)<$REFLINK> . Resveratrol did not appear to alter the cell cycle distribution in Seg-1 cells, perhaps because of the extensive apoptosis (50%) seen after only 24 h of treatment (Table 2)<$REFLINK> . The ability of resveratrol to block the S-G2 transition has been reported previously in HL60 leukemia (4) , U937 lymphoma (36) , and CaCo-2 colon cancer cells (6) . However, other investigators have reported an arrest in the G1 phase with A431 cells (7) . In the Yoshida rat hepatoma model, Carbo et al. (14) demonstrated a G2-M-phase cell cycle arrest. The latter authors suggested that in their in vivo model, lower cellular proliferation rates and host factors, including immune system-mediated events, might explain this difference. Therefore, the effects of resveratrol on cell cycle progression can vary in different experimental systems.
When I began this post, I had no intention of getting into the cancer research, but a quick use of Google Scholar turned up some articles I had not seen mentioned in the media.
The original point was to talk about this new article that shows strong neuro-protective benefits from resveratrol, even at low (relatively speaking) dose levels. This is a well-designed study, so the results are useful and provide another level of information.
Your Brain On Resveratrol
Can Resveratrol, the so-called miracle molecule found in red wine, peanuts and an obnoxious plant called Chinese Giant Knotweed, actually improve your brain function?
Scientists at Northumbria University in the UK have just published a double-blind, peer-reviewed study in the journal, American Journal of Clinical Nutrition, which concludes that a relatively modest dose of this compound in the form of one or two capsules may just do that. In their study, 24 subjects were given one capsule of a supplement called Biotivia Bioforte Resveratrol containing 250 mg of the trans-Resveratrol isomer in each dose.
In previous studies of Resveratrol the compound has been shown to have potent anti-aging properties in animals, as well as the ability to protect cells against a remarkable range of diseases. Resveratrol seems to perform much the same function in animals the same way it does in plants; that is, act as the organism's immune and defense system. The supplement's ability to activate certain genes called sirtuins was discovered by Dr. David Sinclair at Harvard about three years ago and since that time has been the subject of hundreds of studies and trials. Albert Einstein Medical School, for example, has applied to present the results of its trial on diabetes patients to the American Diabetes Association Science Meeting in June.
In the Northumbria study, Bioforte resveratrol increased the brain blood flow in the human subjects while they were performing mental tasks by a substantial amount. The effect seemed to be turned on by the increased demand caused by the cognitive tasks being performed by the student subjects. This implies that the effect of Resveratrol on cerebral blood flow is activated on demand when the brain is called upon to perform a challenging mental task. Could this mean that the compound can be taken in the morning before taking an exam, for example, and spring into action when needed to boost the brain's ability to cope with the exam? Possibly; however, much more study is needed to determine the proper dosage and timing for this application.
James Betz PhD, the managing director of Biotivia, the company whose supplement was purchased on the open market for use in the Northumbria trial, stated in response to this question, "This study is extremely important because it is a peer-reviewed human clinical trial, not an animal study or a study of cells in a culture. What this study tells us is that Resveratrol clearly does improve one of the key parameters of brain performance. Whether this translates into improved cognition over the short or long term is still to be determined. In the meantime, there are heaps of other reasons to take Resveratrol and given that it has not been found to be in any way toxic, it may be worth considering as a primary daily addition to your supplement regimen."
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