Phase I Dose Escalation Pharmacokinetic Study in Healthy Volunteers of Resveratrol, a Potential Cancer Chemopreventive Agent

Abstract

The red grape constituent resveratrol possesses cancer chemopreventive properties in rodents. The hypothesis was tested that, in healthy humans, p.o. administration of resveratrol is safe and results in measurable plasma levels of resveratrol. A phase I study of oral resveratrol (single doses of 0.5, 1, 2.5, or 5 g) was conducted in 10 healthy volunteers per dose level. Resveratrol and its metabolites were identified in plasma and urine by high-performance liquid chromatography-tandem mass spectrometry and quantitated by highperformance liquid chromatography-UV. Consumption of resveratrol did not cause serious adverse events. Resveratrol and six metabolites were recovered from plasma and urine. Peak plasma levels of resveratrol at the highest dose were 539 F 384 ng/mL (2.4 Mmol/L, mean F SD; n = 10), which occurred 1.5 h post-dose. Peak levels of two monoglucuronides and resveratrol-3-sulfate were 3-to 8-fold higher. The area under the plasma concentration curve (AUC) values for resveratrol-3-sulfate and resveratrol monoglucuronides were up to 23 times greater than those of resveratrol. Urinary excretion of resveratrol and its metabolites was rapid, with 77% of all urinary agent-derived species excreted within 4 h after the lowest dose. Cancer chemopreventive effects of resveratrol in cells in vitro require levels of at least 5 Mmol/L. The results presented here intimate that consumption of high-dose resveratrol might be insufficient to elicit systemic levels commensurate with cancer chemopreventive efficacy. However, the high systemic levels of resveratrol conjugate metabolites suggest that their cancer chemopreventive properties warrant investigation. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1246 -52)

Suberoylanilide hydroxamic acid (SAHA) causes tumor growth slowdown and triggers autophagy in glioblastoma stem cells

“…60 It is also important to point out that chronic effects of low doses as metronomic chemotherapy are especially important in view of in vivo studies showing that high micromolar concentrations are very difficult to attain, especially in the central nervous system. 61,62 Therefore, SAHA may be a potential therapeutic agent for the induction of terminal differentiation of GSCs.…”

Resveratrol Induces p53-independent, X-linked Inhibitor of Apoptosis Protein (XIAP)-mediated Bax Protein Oligomerization on Mitochondria to Initiate Cytochrome c Release and Caspase Activation

“…It is generally believed that for chemoprevention or cancer therapy doses of resveratrol used to induce apoptotic cell death may not easily be achieved under physiological conditions through regular diets. However, various lines of evidence indicate that in vitro doses that have been shown to induce apoptotic cell death could be achieved in cancer cells through higher intake of resveratrol (87)(88)(89)(90)(91). For example, resveratrol at daily doses of up to 5 g for 29 days is not toxic to humans, and daily doses of 0.5 or 1 g produce levels of resveratrol in tumor cells that are sufficient to elicit anticancer effects such as induction of apoptosis in cancer cells (88).…”

The antioxidant resveratrol protects against chondrocyte apoptosis via effects on mitochondrial polarization and ATP production

“…It has been shown to exhibit antiinflammatory and antioxidant effects in various cell types and has been suggested to have therapeutic potential for treatment of various diseases, including diabetes. In a phase I clinical study in healthy volunteers, the concentration of resveratrol in plasma reached a mean Ϯ SD 539 Ϯ 384 ng/ml (equivalent to 2-3 M), which was attained after 30 minutes of oral application of 0.5-5 gm of resveratrol (9,28). In this study, we investigated the effects of resveratrol on chondrocyte metabolism, in particular, the catabolic effects induced by the OA-associated proinflammatory cytokine IL-1␤.…”