Resveratrol

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Resveratrol

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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

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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

  2. Howitz KT, Bitterman KJ, Cohen HY, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. Sep 11 2003;425(6954):191-196.

  8. Wong RH, Howe PR, Buckley JD, et al. Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure. Nutr Metab Cardiovasc Dis. Nov 2011;21(11):851-856.

  9. Magyar K, Halmosi R, Palfi A, et al. Cardioprotection by resveratrol: A human clinical trial in patients with stable coronary artery disease. Clin Hemorheol Microcirc. 2012;50(3):179-187.

  11. Crandall JP, Oram V, Trandafirescu G, et al. Pilot study of resveratrol in older adults with impaired glucose tolerance. J Gerontol A Biol Sci Med Sci. Dec 2012;67(12):1307-1312.

  15. ElAttar TM, Virji AS. Modulating effect of resveratrol and quercetin on oral cancer cell growth and proliferation. Anticancer Drugs. Feb 1999;10(2):187-193.

  18. Gehm BD, McAndrews JM, Chien PY, 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. Dec 9 1997;94(25):14138-14143.

  19. Wang TT, Hudson TS, Wang TC, et al. Differential effects of resveratrol on androgen-responsive LNCaP human prostate cancer cells in vitro and in vivo. Carcinogenesis. Oct 2008;29(10):2001-2010.

  20. Zhang C, Feng Y, Qu S, et al. Resveratrol attenuates doxorubicin-induced cardiomyocyte apoptosis in mice through SIRT1-mediated deacetylation of p53. Cardiovascular Research. Jun 1 2011;90(3):538-545.

  21. Fabbrocini G, Staibano S, De Rosa G, et al. Resveratrol-containing gel for the treatment of acne vulgaris: A single-blind, vehicle-controlled, pilot study. Am J Clin Dermatol. Apr 1 2011;12(2):133-141.

  23. Liu J, Wang Q, Wu DC, et al. Differential regulation of CYP1A1 and CYP1B1 expression in resveratrol-treated human medulloblastoma cells. Neurosci Lett. Jun 17 2004;363(3):257-261.

  24. Gresele P, Pignatelli P, Guglielmini G, et al. Resveratrol, at concentrations attainable with moderate wine consumption, stimulates human platelet nitric oxide production. J Nutr. Sep 2008;138(9):1602-1608.

  26. Jang M, Cai L, Udeani GO, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. Jan 10 1997;275(5297):218-220.

  28. Gertz M, Nguyen GT, Fischer F, et al. A molecular mechanism for direct sirtuin activation by resveratrol. PloS One. 2012;7(11):e49761.

  29. Zhu W, Qin W, Zhang K, et al. Trans-resveratrol alters mammary promoter hypermethylation in women at increased risk for breast cancer. Nutr Cancer. Apr 2012;64(3):393-400.

  31. Tang FY, Su YC, Chen NC, et al. Resveratrol inhibits migration and invasion of human breast-cancer cells. Mol Nutr Food Res. Jun 2008;52(6):683-691.

  34. Vaz-da-Silva M, Loureiro AI, Falcao A, et al. Effect of food on the pharmacokinetic profile of trans-resveratrol. Int J Clin Pharmacol Ther. Nov 2008;46(11):564-570.

  35. Rotches-Ribalta M, Andres-Lacueva C, Estruch R, et al. Pharmacokinetics of resveratrol metabolic profile in healthy humans after moderate consumption of red wine and grape extract tablets. Pharmacol Res. Nov 2012;66(5):375-382.

  36. Boocock DJ, Faust GE, Patel KR, et al. Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidemiol Biomarkers Prev. Jun 2007;16(6):1246-1252.

  39. Chow HH, Garland LL, Hsu CH, et al. Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study. Cancer Prev Res. Sep 2010;3(9):1168-1175.

  40. Chi YC, Lin SP, Hou YC. A new herb-drug interaction of Polygonum cuspidatum, a resveratrol-rich nutraceutical, with carbamazepine in rats. Toxicol Appl Pharmacol. Sep 15 2012;263(3):315-322.

  41. Patel KR, Brown VA, Jones DJ, et al. Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res. Oct 1 2010;70(19):7392-7399.

  42. Semba R, Ferrucci L, Bartali B, et al. Resveratrol levels and all-cause mortality in older community-dwelling adults. JAMA Intern Med. 2014 Jul;174(7):1077-84. 

  45. Turner RS, Thomas RG, Craft S, et al. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology. Oct 20 2015;85(16):1383-1391.

  47. Farzaei MH, Rahimi R, Nikfar S, Abdollahi M. Effect of resveratrol on cognitive and memory performance and mood: A meta-analysis of 225 patients. Pharmacol Res. 2018 Feb;128:338-344.

  48. Elgebaly A, Radwan IA, AboElnas MM, et al. Resveratrol Supplementation in Patients with Non-Alcoholic Fatty Liver Disease: Systematic Review and Meta-analysis. J Gastrointestin Liver Dis. 2017 Mar;26(1):59-67.

  49. Fogacci F, Tocci G, Presta V, Fratter A, Borghi C, Cicero AFG. Effect of resveratrol on blood pressure: A systematic review and meta-analysis of randomized, controlled, clinical trials. Crit Rev Food Sci Nutr. 2018 Jan 23:1-14.

  50. Imamura H, Yamaguchi T, Nagayama D, Saiki A, Shirai K, Tatsuno I. Resveratrol Ameliorates Arterial Stiffness Assessed by Cardio-Ankle Vascular Index in Patients With Type 2 Diabetes Mellitus. Int Heart J. 2017 Aug 3;58(4):577-583.

  53. Anton SD, Ebner N, Dzierzewski JM, et al. Effects of 90 Days of Resveratrol Supplementation on Cognitive Function in Elders: A Pilot Study. J Altern Complement Med. Jul 2018;24(7):725-732.

  56. Khojah HM, Ahmed S, Abdel-Rahman MS, et al. Resveratrol as an effective adjuvant therapy in the management of rheumatoid arthritis: a clinical study. Clin Rheumatol. Aug 2018;37(8):2035-2042.

  58. Fischer N, Seo EJ, Efferth T. Prevention from radiation damage by natural products. Phytomedicine. Aug 1 2018;47:192-200.

  59. Carsten RE, Bachand AM, Bailey SM, et al. Resveratrol reduces radiation-induced chromosome aberration frequencies in mouse bone marrow cells. Radiat Res. Jun 2008;169(6):633-638.

  60. Xu L, Yang X, Cai J, et al. Resveratrol attenuates radiation-induced salivary gland dysfunction in mice. Laryngoscope. Nov 2013;123(11):E23-29.

  61. Zhang H, Yan H, Zhou X, et al. The protective effects of Resveratrol against radiation-induced intestinal injury. BMC Complement Altern Med. Aug 16 2017;17(1):410.

  62. Banegas YC, Ocolotobiche EE, Padula G, et al. Evaluation of resveratrol radiomodifying potential for radiotherapy treatment. Mutat Res. Dec 2018;836(Pt B):79-83.

  64. Voellger B, Waldt N, Rupa R, et al. Combined effects of resveratrol and radiation in GH3 and TtT/GF pituitary adenoma cells. J Neurooncol. Jun 5 2018.

  69. Popat R, Plesner T, Davies F, et al. A phase 2 study of SRT501 (resveratrol) with bortezomib for patients with relapsed and or refractory multiple myeloma. Br J Haematol. Mar 2013;160(5):714-717.

  71. Bertelli AA, Giovannini L, Giannessi D, et al. Antiplatelet activity of synthetic and natural resveratrol in red wine. Int J Tissue React. 1995;17(1):1-3.
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