Resveratrol

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For Patients & Caregivers

How It Works

In laboratory studies, resveratrol was found to reduce inflammation and have antitumor properties, but studies in cancer patients are quite limited and have not established benefit.

A naturally occurring compound in the skin of red grapes and other botanicals, resveratrol has been shown to have anti-inflammatory and antioxidant properties. Some studies suggest it may help symptoms of type 2 diabetes or arthritis. It may also help to protect against thickening of arterial walls and heart disease, but eating a diet rich in resveratrol does not lower the risk of dying from cancer or heart disease.

Animal studies suggest that resveratrol may prevent certain cancer cells from dividing, enhance chemotherapy or radiation effects, or protect against radiation side effects. However, human studies are quite limited and have not established benefit. In a group of multiple myeloma patients, a special high-dose formulation actually caused harm and the study was stopped. In addition, resveratrol has hormone-like properties that may stimulate some types of cancer cells. It may also interact with certain drugs. Therefore, larger well-designed trials are needed to determine the conditions under which resveratrol would be safe and effective.

Purported Uses

To prevent or treat heart disease
There is limited scientific evidence to support this use.
To treat arthritis
A few studies suggest resveratrol may help as an add-on to some medications, but more studies are needed.
To prevent or treat diabetes
A few studies suggest resveratrol may improve some markers and symptoms of type 2 diabetes, but it did not appear to improve metabolic syndrome in obese patients.
To improve memory
Although one study showed that resveratrol may affect some markers of Alzheimer’s disease, other trials found no significant impact on memory or cognitive function in older adults.
For cancer prevention or as add-on treatment
Several laboratory studies suggest resveratrol may prevent the growth of cancer cells. However, some of these experiments used very high doses, which in one human study caused serious adverse events. Other studies in humans were too small to draw any conclusions. In addition, resveratrol has hormone-like properties that may stimulate some types of cancer cells.
To reduce radiation side effects
Although a few lab experiments suggest utility, no human studies have been conducted.

Patient Warnings

Given the potential for interactions and hormone-like properties, use of this supplement should be discussed with the treating physician.

Do Not Take If

You have a hormone-sensitive cancer: Resveratrol has hormone-like properties that may stimulate some types of cancer cells.
You are taking antiplatelet drugs: In lab studies, resveratrol also has blood-thinning properties, so bleeding risk may increase when used along with blood-thinning drugs. Therefore, use of this supplement should be avoided or discussed with the treating physician.
You are taking cytochrome P450 substrate drugs: Resveratrol may increase the risk of side effects of some drugs and make others less effective.
You are taking carbamazepine: An herbal supplement rich in resveratrol was found to increase blood levels of this antiepileptic drug in mice.

Side Effects

Mild to moderate gastrointestinal symptoms and diarrhea at high doses

For Healthcare Professionals

Scientific Name

3,5,4'-trihydroxystilbene

Clinical Summary

Resveratrol is a polyphenolic compound found in many botanical products. Red wine is a natural source of resveratrol as it is rich in grape skin and seeds. However, resveratrol is usually consumed as a dietary supplement for its purported antioxidant and anti-inflammatory properties. It is also marketed as an anti-aging supplement based on findings that it prolongs the life span of yeast cells ⁽¹⁾ ⁽²⁾. This effect has not yet been demonstrated in humans.

A long-term randomized double-blind trial indicates that resveratrol and its major metabolites penetrate the blood-brain barrier to have effects on some biomarkers associated with Alzheimer’s disease ⁽⁴⁵⁾, but a meta-analysis did not find any significant effect on memory or cognitive performance ⁽⁴⁷⁾. Recent double-blind trials have also not found benefit with resveratrol on cognitive function in older adults ⁽⁵²⁾ ⁽⁵³⁾.

Resveratrol is also thought to have cardioprotective effects. Earlier studies found it reduces low density lipoprotein (LDL) oxidation, inhibits platelet aggregation, and may protect against atherogenesis ⁽³⁾ ⁽⁴⁾. Consumption of wine or a resveratrol-rich grape supplement is associated with reduced risk of cardiovascular disease ⁽⁵⁾ ⁽⁶⁾ and may help promote circulatory system health ⁽⁷⁾ ⁽⁸⁾ ⁽⁹⁾. However, it does not decrease risk of all-cause mortality in older adults ⁽⁴²⁾. Data on effectiveness of resveratrol against non-alcoholic fatty liver disease are conflicting ⁽⁴⁴⁾ ⁽⁴⁸⁾.

Resveratrol may increase insulin sensitivity in diabetic patients ⁽¹⁰⁾ ⁽¹¹⁾ ⁽⁴³⁾, and supplementation improved arterial stiffness and reduced oxidative stress ⁽⁵⁰⁾. However, it did not improve metabolic patterns or reduce C-reactive protein ⁽⁴⁶⁾, and data on whether it controls metabolic syndrome in obese subjects are inconclusive ⁽¹²⁾ ⁽¹³⁾. Other studies suggest benefit with resveratrol in diabetic patients on bone density and levels of SIRT-1, a key protein in metabolism and inflammation ⁽⁵⁴⁾ ⁽⁵⁵⁾. It may also help as adjunctive therapy to improve symptoms in rheumatoid and osteoarthritis ⁽⁵⁶⁾ ⁽⁵⁷⁾.

Preclinical experiments suggest that resveratrol has antiproliferative ⁽¹⁴⁾ ⁽¹⁵⁾ ⁽¹⁶⁾ ⁽¹⁷⁾ ⁽¹⁸⁾ ⁽¹⁹⁾ and antioxidant effects ⁽⁵⁸⁾. In combination with radiation exposure, it exhibited dose-dependent radioprotective ⁽⁵⁹⁾ ⁽⁶⁰⁾ ⁽⁶¹⁾, radiomodulatory ⁽⁶²⁾, radiosensitizing ⁽⁶³⁾, cytotoxic ⁽⁶⁴⁾, and neuroprotective ⁽⁶⁵⁾ effects. Other experiments suggest effects including chemotherapeutic potentiation ⁽⁶⁶⁾ ⁽⁶⁷⁾ and protection against chemo-induced cardiotoxicity ⁽²⁰⁾.

However, data on use of resveratrol in cancer patients are quite limited. In phase 1 pilots of colorectal cancer patients, one study suggests resveratrol may decrease tumor cell proliferation ⁽⁴¹⁾ while another suggests utility may be limited to prevention rather than established cancers ⁽⁶⁸⁾. Study of a high-dose micronized formula in multiple myeloma patients was stopped due to serious adverse events that included renal failure ⁽⁶⁹⁾. In addition, resveratrol exhibits estrogen-like properties and activates transcription by both estrogen and androgen receptors that can lead to the stimulation of cancer cell proliferation ⁽¹⁸⁾. Therefore, larger well-designed trials are needed to determine the circumstances under which resveratrol might demonstrate utility and safety.

Whereas resveratrol appears to be well tolerated in some studies, high doses can cause gastrointestinal side effects such as diarrhea. It also inhibits cytochrome P450 enzymes ⁽²²⁾ ⁽²³⁾ and may increase the risk of adverse effects of certain drugs. Given its phytoestrogenic properties and potential for interactions, use of this supplement should be discussed with the treating physician.

Food Sources

Grape skins and seeds
Peanuts, pistachios
Mulberries, blueberries, cranberries
Polygonum cuspidatum or Japanese knotweed

Purported Uses

Cancer prevention or treatment
Diabetes
Heart disease
Memory and cognitive function

Mechanism of Action

Resveratrol acts as an antioxidant and inhibits oxidation of low density lipoproteins (LDL) ⁽²¹⁾, platelet aggregation, and eicosanoid synthesis ⁽⁴⁾; induces nitric oxide (NO) production ⁽²⁴⁾ ⁽²⁵⁾ and increases arterial blood flow ⁽⁸⁾. These actions may contribute to its purported cardiovascular health benefits. Resveratrol also acts as an anti-inflammatory agent by inhibiting cyclooxygenase (COX) activity ⁽²⁶⁾. It has been shown to decrease C-reactive protein and tumor necrosis factor, and to increase anti-inflammatory interleukin-10 and intercellular adhesion molecule-1 in humans ⁽⁵⁾. Other effects include decreasing oxidative stress and improving insulin sensitivity by increasing protein kinase activities ⁽¹⁰⁾. Resveratrol was also shown to decrease circulating insulin-like growth factor-1 (IGF-I) and IGF-binding protein-3 (IGFBP-3) levels ⁽²⁷⁾ which may account for its anti-diabetic effects in humans. Preliminary data suggest that it increases the life span of yeast cells by activating sirtuins ⁽¹⁾ ⁽²⁾, inhibiting human Sirt3 along with stimulating Sirt5 and Sirt1 ⁽²⁸⁾. The neuroprotective effects of resveratrol were shown to be via regulating autophagy and apoptosis mediated by the Akt/mTOR pathway ⁽⁵¹⁾.

Resveratrol has also been investigated for its anticancer potential. It was found to inhibit proliferation of cancer cells via apoptosis and by exerting anti-estrogenic effects ⁽¹⁴⁾ ⁽¹⁵⁾ ⁽¹⁶⁾ ⁽¹⁷⁾. Trans-resveratrol appears to decrease methylation of the tumor suppressor gene RASSF-1alpha in women at increased breast cancer risk ⁽²⁹⁾. In addition, reductions in breast cancer cell migration and invasion were observed after supplementation ⁽³⁰⁾ ⁽³¹⁾. Resveratrol growth factor heregulin-beta1 (HRG-beta1) mediated matrix metallopeptidase 9 (MMP-9) expressions in human breast cancer cells ⁽³⁰⁾. However, contradictory data show that resveratrol mimics phytoestrogens and could activate genes that are normally regulated by estrogens ⁽¹⁸⁾ or androgens ⁽¹⁹⁾. In other studies resveratrol helped reduce prostate tumorigenesis through a reduction in prostatic levels of mTOR complex 1 (mTORC1) activity and increased expression of SIRT1 ⁽³²⁾; and modulated steroid hormone-dependent pathways to inhibit prostate cancer cell growth. However, it also increases angiogenesis and inhibits apoptosis in vivo ⁽¹⁹⁾. Further research is needed.

Additional findings show that resveratrol downregulates p21 and upregulates cyclin E leading to S-phase accumulation and apoptosis in neuroblastoma cells ⁽¹⁴⁾. It also inhibits CYP1A1, CYP1A2, and CYP1B1 enzymes in tumor cells, perhaps exerting antitumor effects as some of these enzymes are known to be involved in the activation of procarcinogens and toxins ⁽²²⁾ ⁽²³⁾. Protective effects of resveratrol against doxorubicin-induced cardiotoxicity are due to upregulation of SIRT1-mediated p53 deacetylation ⁽²⁰⁾. Also, it protects against cisplatin-induced cardiotoxicity by suppressing oxidative stress ⁽¹⁹⁾.

Contraindications

Patients with hormone-sensitive cancers should use caution, as resveratrol—at concentrations between 3 and 10 μM, similar to those needed for its other biological effects—exhibits estrogen-like properties and activates transcription by both estrogen and androgen receptors that lead to the stimulation of cancer cell proliferation ⁽¹⁸⁾.

Adverse Reactions

Mild to moderate gastrointestinal symptoms and diarrhea at high doses (2.5 and 5 g daily) ⁽²⁷⁾ ⁽³³⁾.

Herb-Drug Interactions

Antiplatelet drugs: Although clinical relevance is yet to be determined, resveratrol inhibits platelet aggregation in vitro, so concurrent use with antiplatelet drugs may increase bleeding risk ⁽⁷⁰⁾ ⁽⁷¹⁾. Therefore, use of this supplement should be discussed with the treating physician.
Cytochrome P450 substrates: Resveratrol inhibited CYP3A4, CYP2D6, CYP2C9, and induced CYP1A2 in healthy volunteers following daily intake of one gram of resveratrol for 4 weeks. Therefore, it can affect the levels of drugs that are metabolized by these enzymes ⁽³⁹⁾.
Carbamazepine: Polygonum cuspidatum, an herbal supplement rich in resveratrol, increased carbamazepine blood levels due to CYP3A inhibition and multidrug resistance-associated protein 2 (MRP 2) in a murine model ⁽⁴⁰⁾. Clinical relevance is yet to be determined.

Dosage (OneMSK Only)

References

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