In-Human Studies

Few in-human studies have been conducted that evaluate the effect of resveratrol on cancer.5 Most studies evaluated tumor cell markers rather than clinical outcomes.

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A randomized, placebo-controlled study of 66 middle-aged men with metabolic syndrome found that 1000 mg of resveratrol daily decreased serum androgen precursor levels, but not testosterone or dihydrotestosterone, prostate-specific antigen levels, or prostate volume.6 A phase 1 study of 14 patients with biochemically recurrent prostate cancer with a median Gleason score of 7 demonstrated no dose-limiting toxicities with up to 4000 mg of muscadine grape skin extract.7 Mild gastrointestinal symptoms such as flatulence, soft stools, and eructation were the most common adverse effects. The median PSA doubling time increased from 9.4 months pretreatment to 11.6 months after treatment and 7 of the patients remained on the study for longer than the median follow-up of 19.2 months.

A randomized, blinded study of 39 women at an increased risk for breast cancer demonstrated decreased methylation of RASSF-1α, a tumor suppressor gene, which was associated with increasing serum levels of trans-resveratrol.8 Treatment with a 5 mg or 50 mg dose resulted in a measurable increase in serum levels of trans-resveratrol and its glucuronidated metabolite.

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In a study of 20 patients with colorectal cancer (CRC), resveratrol and its metabolites were identified in CRC tissue, particularly of the right side, resected after 8 days of 0.5 g or 1.0 g of daily.9 Resveratrol also significantly decreased tumor cell proliferation as indicated by Ki-67 staining. Resveratrol was well-tolerated with no treatment-related adverse events. Another study evaluated the micronized formulation of resveratrol, SRT501, in patients with CRC and hepatic metastases.10 Patients received 5 g of SRT501 for 14 days, which resulted in high plasma resveratrol levels and detectable levels in hepatic tissue compared with placebo. The cancerous hepatic tissues also demonstrated a 39% increase in apoptosis as measured by cleaved caspase-3 compared with placebo. Most patients experienced gastrointestinal adverse events, which were most commonly diarrhea and nausea.

Another study also evaluated SRT501, but in 24 patients with relapsed/refractory multiple myeloma.11 Patients received 5 g of SRT501 daily for 20 days as part of a 21-day cycle with or without bortezomib for up to 12 cycles. No patients who received SRT501 monotherapy and 2 patients (22%) who received SRT501 plus bortezomib experienced a response. Importantly, SRT501 was associated with severe renal impairment, leading to renal failure in 5 patients within the first 2 cycles. Elevated serum creatinine, however, was present in 3 of the 5 patients prior to the first dose of SRT501. This finding was unexpected because renal toxicity did not occur in other trials of healthy volunteers or patients with diabetes or CRC. The investigators concluded that renal toxicity appears to be unique to patients with MM, likely due to prior renal impairment that is characteristic of the disease.

Conclusions

Preclinical studies suggest that resveratrol has anticancer properties that warrant further investigation. Most in-human studies indicate that oral administration of resveratrol or a micronized formulation increases serum levels of resveratrol. Oral resveratrol is generally well-tolerated with the most common adverse effects including gastrointestinal symptoms. Micronized resveratrol, however, is not safe for patients with multiple myeloma due to unacceptable renal toxicity. It is unknown whether non-micronized resveratrol can cause renal toxicity in this population.

In-human trials have not studied clinical outcomes associated with resveratrol administration among patients with cancer; therefore, there are insufficient data to suggest efficacy. Supplementation with resveratrol, however, is unlikely to cause harm.

References

  1. Ko J-H, Sethi G, Um J-Y, et al. The role of resveratrol in cancer therapy. Int J Mol Sci. 2017;18:2589-2625. doi: 10.3390/ijms18122589
  2. Smoliga JM, Blanchard O. Enhancing the delivery of resveratrol in humans: if low bioavailability is the problem, what is the solution? Molecules. 2014;19:17154-17172. doi: 10.3390/molecules191117154
  3. Yousef M, Vlachogiannis IA, Tsiani E. Effects of resveratrol against lung cancer: in vitro and in vivo studies. Nutrients. 2017;9:1231-1245. doi: 10.3390/nu9111231
  4. Bartolacci C, Andreani C, Amici A, Marchini C. Walking a tightrope: a perspective of resveratrol effects on breast cancer. Curr Protein Peptide Sci. 2018;19:311-322. doi: 10.2174/1389203718666170111115914
  5. Berman AY, Motechin RA, Wiesenfeld MY, Holz MK. The therapeutic potential of resveratrol: a review of clinical trials. NPJ Precis Oncol. 2017;1:35-4. doi: 10.1038/s41698-017-0038-6
  6. Kjaer TN, Ornstrup MJ, Poulsen MM, 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
  7. Paller CJ, Rudek MA, Zhou XC, 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;75:1518-25. doi: 10.1002/pros.23024
  8. Zhu W, Qin W, Zhang K, 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
  9. Patel KR, Brown VA, Jones DJL, et al. Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res. 2010;70:7392-9. doi: 10.1158/0008-5472.CAN-10-2027
  10. Howells LM, Berry DP, Elliott PJ, 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. 2011;4:1419-25. doi: 10.1158/1940-6207.CAPR-11-0148
  11. 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. 2013;160:714-6. doi: 10.1111/bjh.12154

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