The therapeutic potential of resveratrol: a review of clinical trials

Adi Y Berman, Rachel A Motechin, Maia Y Wiesenfeld, Marina K Holz, Adi Y Berman, Rachel A Motechin, Maia Y Wiesenfeld, Marina K Holz

Abstract

Resveratrol is a nutraceutical with several therapeutic effects. It has been shown to mimic effects of caloric restriction, exert anti-inflammatory and anti-oxidative effects, and affect the initiation and progression of many diseases through several mechanisms. While there is a wealth of in vitro and in vivo evidence that resveratrol could be a promising therapeutic agent, clinical trials must confirm its potential. In this work, we reviewed the current clinical data available regarding the pharmacological action of resveratrol. Most of the clinical trials of resveratrol have focused on cancer, neurological disorders, cardiovascular diseases, diabetes, non-alcoholic fatty liver disease (NAFLD), and obesity. We found that for neurological disorders, cardiovascular diseases, and diabetes, the current clinical trials show that resveratrol was well tolerated and beneficially influenced disease biomarkers. However resveratrol had ambiguous and sometimes even detrimental effects in certain types of cancers and in NAFLD. In most of the clinical trials, the major obstacle presented was resveratrol's poor bioavailability. Thus, this work provides useful considerations for the planning and design of future pre-clinical and clinical research on resveratrol.

Conflict of interest statement

The authors declare that they have no competing financial interests.

Figures

Fig. 1
Fig. 1
Clinical benefits of resveratrol

References

    1. Aggarwal BB, et al. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res. 2004;24:2783–2840.
    1. Bavaresco L, P. D, Cantu E, et al. Elicitation and accumulation of stilbene phytoalexins in grapevine berries infected by Botrytis cinerea. Vitis. 1997;36:77–83.
    1. Langcake PWVM. The relationship of resveratrol production to infection of grapevine leaves by Botrytis cinerea. Vitis. 1979;18:244–253.
    1. Shukla Y, Singh R. Resveratrol and cellular mechanisms of cancer prevention. Ann. N Y Acad. Sci. 2011;1215:1–8. doi: 10.1111/j.1749-6632.2010.05870.x.
    1. Renaud S, de Lorgeril M. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet. 1992;339:1523–1526. doi: 10.1016/0140-6736(92)91277-F.
    1. Kopp P. Resveratrol, a phytoestrogen found in red wine. A possible explanation for the conundrum of the ‘French paradox’? Eur. J. Endocrinol. 1998;138:619–620. doi: 10.1530/eje.0.1380619.
    1. Chung S, et al. Regulation of SIRT1 in cellular functions: role of polyphenols. Arch. Biochem. Biophys. 2010;501:79–90. doi: 10.1016/j.abb.2010.05.003.
    1. Sarkar FH, Li Y, Wang Z, Kong D. Cellular signaling perturbation by natural products. Cell. Signal. 2009;21:1541–1547. doi: 10.1016/j.cellsig.2009.03.009.
    1. Li H, et al. 3,3’,4,5,5’-Pentahydroxy-trans-stilbene, a resveratrol derivative, induces apoptosis in colorectal carcinoma cells via oxidative stress. Eur. J. Pharmacol. 2010;637:55–61. doi: 10.1016/j.ejphar.2010.04.009.
    1. Boocock DJ, et al. Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidemiol. Biomarkers Prev. 2007;16:1246–1252. doi: 10.1158/1055-9965.EPI-07-0022.
    1. Pervaiz S. Resveratrol—from the bottle to the bedside? Leuk. Lymphoma. 2001;40:491–498. doi: 10.3109/10428190109097648.
    1. Kundu JK, Shin YK, Kim SH, Surh YJ. Resveratrol inhibits phorbol ester-induced expression of COX-2 and activation of NF-kappaB in mouse skin by blocking IkappaB kinase activity. Carcinogenesis. 2006;27:1465–1474. doi: 10.1093/carcin/bgi349.
    1. Vanamala J, Reddivari L, Radhakrishnan S, Tarver C. Resveratrol suppresses IGF-1 induced human colon cancer cell proliferation and elevates apoptosis via suppression of IGF-1R/Wnt and activation of p53 signaling pathways. BMC Cancer. 2010;10:238. doi: 10.1186/1471-2407-10-238.
    1. Park ES, et al. Pterostilbene, a natural dimethylated analog of resveratrol, inhibits rat aortic vascular smooth muscle cell proliferation by blocking Akt-dependent pathway. Vascul. Pharmacol. 2010;53:61–67. doi: 10.1016/j.vph.2010.04.001.
    1. Bai Y, et al. Resveratrol induces apoptosis and cell cycle arrest of human T24 bladder cancer cells in vitro and inhibits tumor growth in vivo. Cancer Sci. 2010;101:488–493. doi: 10.1111/j.1349-7006.2009.01415.x.
    1. Parekh P, Motiwale L, Naik N, Rao KV. Downregulation of cyclin D1 is associated with decreased levels of p38 MAP kinases, Akt/PKB and Pak1 during chemopreventive effects of resveratrol in liver cancer cells. Exp. Toxicol. Pathol. 2011;63:167–173. doi: 10.1016/j.etp.2009.11.005.
    1. Alayev A, Berger SM, Kramer MY, Schwartz NS, Holz MK. The combination of rapamycin and resveratrol blocks autophagy and induces apoptosis in breast cancer cells. J. Cell. Biochem. 2015;116:450–457. doi: 10.1002/jcb.24997.
    1. Alayev A, Doubleday PF, Berger SM, Ballif BA, Holz MK. Phosphoproteomics reveals resveratrol-dependent inhibition of Akt/mTORC1/S6K1 signaling. J. Proteome Res. 2014;13:5734–5742. doi: 10.1021/pr500714a.
    1. Alayev A, et al. Combination of rapamycin and resveratrol for treatment of bladder cancer. J. Cell. Physiol. 2017;232:436–446. doi: 10.1002/jcp.25443.
    1. Alayev A, et al. Effects of combining rapamycin and resveratrol on apoptosis and growth of TSC2-deficient xenograft tumors. Am. J. Respir. Cell. Mol. Biol. 2015;53:637–646. doi: 10.1165/rcmb.2015-0022OC.
    1. Alayev A, et al. Resveratrol prevents rapamycin-induced upregulation of autophagy and selectively induces apoptosis in TSC2-deficient cells. Cell Cycle. 2014;13:371–382. doi: 10.4161/cc.27355.
    1. Alayev A, Berger SM, Holz MK. Resveratrol as a novel treatment for diseases with mTOR pathway hyperactivation. Ann. N Y Acad. Sci. 2015;1348:116–123. doi: 10.1111/nyas.12829.
    1. Higdon, J., Drake, V. J. & Delage, B. Resveratrol. Micronutrient Information Center (2005).
    1. Walle T. Bioavailability of resveratrol. Ann. N Y Acad. Sci. 2011;1215:9–15. doi: 10.1111/j.1749-6632.2010.05842.x.
    1. Walle T, Hsieh F, DeLegge MH, Oatis JE, Jr., Walle UK. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab. Dispos. 2004;32:1377–1382. doi: 10.1124/dmd.104.000885.
    1. Howells LM, et al. Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases--safety, pharmacokinetics, and pharmacodynamics. Cancer Prev. Res. (Phila) 2011;4:1419–1425. doi: 10.1158/1940-6207.CAPR-11-0148.
    1. Popat R, et al. A phase 2 study of SRT501 (resveratrol) with bortezomib for patients with relapsed and or refractory multiple myeloma. Br. J. Haematol. 2013;160:714–717. doi: 10.1111/bjh.12154.
    1. Cai H, et al. Cancer chemoprevention: evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice. Sci. Transl. Med. 2015;7:298ra117. doi: 10.1126/scitranslmed.aaa7619.
    1. Tome-Carneiro J, et al. Resveratrol and clinical trials: the crossroad from in vitro studies to human evidence. Curr. Pharm. Des. 2013;19:6064–6093. doi: 10.2174/13816128113199990407.
    1. Jang M, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. 1997;275:218–220. doi: 10.1126/science.275.5297.218.
    1. Kulkarni SS, Canto C. The molecular targets of resveratrol. Biochim. Biophys. Acta. 2015;1852:1114–1123. doi: 10.1016/j.bbadis.2014.10.005.
    1. Pezzuto JM. Resveratrol as an inhibitor of carcinogenesis. Pharm. Biol. 2008;46:443–573. doi: 10.1080/13880200802116610.
    1. Paller CJ, et al. A phase I study of muscadine grape skin extract in men with biochemically recurrent prostate cancer: safety, tolerability, and dose determination. Prostate. 2015;75:1518–1525. doi: 10.1002/pros.23024.
    1. Kjaer TN, et al. Resveratrol reduces the levels of circulating androgen precursors but has no effect on, testosterone, dihydrotestosterone, PSA levels or prostate volume. A 4-month randomised trial in middle-aged men. Prostate. 2015;75:1255–1263. doi: 10.1002/pros.23006.
    1. Schneider Y, et al. Anti-proliferative effect of resveratrol, a natural component of grapes and wine, on human colonic cancer cells. Cancer Lett. 2000;158:85–91. doi: 10.1016/S0304-3835(00)00511-5.
    1. Sale S, et al. Comparison of the effects of the chemopreventive agent resveratrol and its synthetic analog trans 3,4,5,4’-tetramethoxystilbene (DMU-212) on adenoma development in the Apc(Min+) mouse and cyclooxygenase-2 in human-derived colon cancer cells. Int. J. Cancer. 2005;115:194–201. doi: 10.1002/ijc.20884.
    1. Patel KR, et al. Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res. 2010;70:7392–7399. doi: 10.1158/0008-5472.CAN-10-2027.
    1. Jazirehi AR, Bonavida B. Resveratrol modifies the expression of apoptotic regulatory proteins and sensitizes non-Hodgkin’s lymphoma and multiple myeloma cell lines to paclitaxel-induced apoptosis. Mol. Cancer Ther. 2004;3:71–84. doi: 10.4161/cbt.3.1.683.
    1. Zhu W, et al. Trans-resveratrol alters mammary promoter hypermethylation in women at increased risk for breast cancer. Nutr. Cancer. 2012;64:393–400. doi: 10.1080/01635581.2012.654926.
    1. Potter GA, et al. The cancer preventative agent resveratrol is converted to the anticancer agent piceatannol by the cytochrome P450 enzyme CYP1B1. Br. J. Cancer. 2002;86:774–778. doi: 10.1038/sj.bjc.6600197.
    1. Pasinetti GM, Wang J, Ho L, Zhao W, Dubner L. Roles of resveratrol and other grape-derived polyphenols in Alzheimer’s disease prevention and treatment. Biochim. Biophys. Acta. 2015;1852:1202–1208. doi: 10.1016/j.bbadis.2014.10.006.
    1. Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell. 2012;148:1204–1222. doi: 10.1016/j.cell.2012.02.040.
    1. Moussa C, et al. Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease. J. Neuroinflammation. 2017;14:1. doi: 10.1186/s12974-016-0779-0.
    1. Turner RS, et al. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology. 2015;85:1383–1391. doi: 10.1212/WNL.0000000000002035.
    1. Thordardottir S, et al. The effects of different familial Alzheimer’s disease mutations on APP processing in vivo. Alzheimers Res. Ther. 2017;9:9. doi: 10.1186/s13195-017-0234-1.
    1. Feigin VL, et al. Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet. 2014;383:245–254. doi: 10.1016/S0140-6736(13)61953-4.
    1. Saver JL. Improving reperfusion therapy for acute ischaemic stroke. J. Thromb. Haemost. 2011;9:333–343. doi: 10.1111/j.1538-7836.2011.04371.x.
    1. Chen J, Bai Q, Zhao Z, Sui H, Xie X. Resveratrol improves delayed r-tPA treatment outcome by reducing MMPs. Acta Neurol. Scand. 2016;134:54–60. doi: 10.1111/ane.12511.
    1. World Health Organization. Cardiovascular Diseases (CVDs) (2016).
    1. Voloshyna I, Hussaini SM, Reiss AB. Resveratrol in cholesterol metabolism and atherosclerosis. J. Med. Food. 2012;15:763–773. doi: 10.1089/jmf.2012.0025.
    1. Cho S, et al. Cardiovascular protective effects and clinical applications of resveratrol. J. Med. Food. 2017;20:323–334. doi: 10.1089/jmf.2016.3856.
    1. Magyar K, et al. Cardioprotection by resveratrol: a human clinical trial in patients with stable coronary artery disease. Clin. Hemorheol. Microcirc. 2012;50:179–187.
    1. Agarwal B, et al. Resveratrol for primary prevention of atherosclerosis: clinical trial evidence for improved gene expression in vascular endothelium. Int. J. Cardiol. 2013;166:246–248. doi: 10.1016/j.ijcard.2012.09.027.
    1. Tome-Carneiro J, et al. Consumption of a grape extract supplement containing resveratrol decreases oxidized LDL and ApoB in patients undergoing primary prevention of cardiovascular disease: a triple-blind, 6-month follow-up, placebo-controlled, randomized trial. Mol. Nutr. Food Res. 2012;56:810–821. doi: 10.1002/mnfr.201100673.
    1. Tome-Carneiro J, et al. One-year consumption of a grape nutraceutical containing resveratrol improves the inflammatory and fibrinolytic status of patients in primary prevention of cardiovascular disease. Am. J. Cardiol. 2012;110:356–363. doi: 10.1016/j.amjcard.2012.03.030.
    1. Biesinger S, et al. A combination of isolated phytochemicals and botanical extracts lowers diastolic blood pressure in a randomized controlled trial of hypertensive subjects. Eur. J. Clin. Nutr. 2016;70:10–16. doi: 10.1038/ejcn.2015.88.
    1. Bo S, et al. Anti-inflammatory and antioxidant effects of resveratrol in healthy smokers a randomized, double-blind, placebo-controlled, cross-over trial. Curr. Med. Chem. 2013;20:1323–1331. doi: 10.2174/0929867311320100009.
    1. Zortea K, et al. Resveratrol supplementation in schizophrenia patients: a randomized clinical trial evaluating serum glucose and cardiovascular risk factors. Nutrients. 2016;8:73. doi: 10.3390/nu8020073.
    1. van der Made SM, Plat J, Mensink RP. Resveratrol does not influence metabolic risk markers related to cardiovascular health in overweight and slightly obese subjects: a randomized, placebo-controlled crossover trial. PLoS One. 2015;10:e0118393. doi: 10.1371/journal.pone.0118393.
    1. World Health Organization. Diabetes (2016).
    1. Hausenblas HA, Schoulda JA, Smoliga JM. Resveratrol treatment as an adjunct to pharmacological management in type 2 diabetes mellitus--systematic review and meta-analysis. Mol. Nutr. Food Res. 2015;59:147–159. doi: 10.1002/mnfr.201400173.
    1. Thazhath SS, et al. Administration of resveratrol for 5 wk has no effect on glucagon-like peptide 1 secretion, gastric emptying, or glycemic control in type 2 diabetes: a randomized controlled trial. Am. J. Clin. Nutr. 2016;103:66–70. doi: 10.3945/ajcn.115.117440.
    1. Bhatt JK, Thomas S, Nanjan MJ. Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Nutr. Res. 2012;32:537–541. doi: 10.1016/j.nutres.2012.06.003.
    1. Brasnyo P, et al. Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Br. J. Nutr. 2011;106:383–389. doi: 10.1017/S0007114511000316.
    1. Crandall JP, et al. Pilot study of resveratrol in older adults with impaired glucose tolerance. J. Gerontol. A Biol. Sci. Med. Sci. 2012;67:1307–1312. doi: 10.1093/gerona/glr235.
    1. Charytoniuk T, Drygalski K, Konstantynowicz-Nowicka K, Berk K, Chabowski A. Alternative treatment methods attenuate the development of NAFLD: a review of resveratrol molecular mechanisms and clinical trials. Nutrition. 2017;34:108–117. doi: 10.1016/j.nut.2016.09.001.
    1. Heeboll S, et al. Placebo-controlled, randomised clinical trial: high-dose resveratrol treatment for non-alcoholic fatty liver disease. Scand. J. Gastroenterol. 2016;51:456–464. doi: 10.3109/00365521.2015.1107620.
    1. Zhang C, et al. Efficacy of resveratrol supplementation against non-alcoholic fatty liver disease: a meta-analysis of placebo-controlled clinical trials. PLoS. One. 2016;11:e0161792. doi: 10.1371/journal.pone.0161792.
    1. Chachay VS, et al. Resveratrol does not benefit patients with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 2014;12:2092–2103. doi: 10.1016/j.cgh.2014.02.024.
    1. Chen S, et al. Resveratrol improves insulin resistance, glucose and lipid metabolism in patients with non-alcoholic fatty liver disease: a randomized controlled trial. Dig. Liver Dis. 2015;47:226–232. doi: 10.1016/j.dld.2014.11.015.
    1. Faghihzadeh F, Adibi P, Rafiei R, Hekmatdoost A. Resveratrol supplementation improves inflammatory biomarkers in patients with nonalcoholic fatty liver disease. Nutr. Res. 2014;34:837–843. doi: 10.1016/j.nutres.2014.09.005.
    1. Timmers S, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011;14:612–622. doi: 10.1016/j.cmet.2011.10.002.
    1. Poulsen MM, et al. High-dose resveratrol supplementation in obese men: an investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body composition. Diabetes. 2013;62:1186–1195. doi: 10.2337/db12-0975.

Source: PubMed

3
Předplatit