Pharmacological investigation of clinically achievable concentrations of resveratrol in colorectal cancer

Resveratrol, a polyphenol present in red wine and peanuts exerts an array of beneficial effects, including anticancer activity and calorie restriction (CR) mimicry. Work from our laboratory has shown for the first time that low doses of resveratrol, comparable to amounts contained in a glass of red wine significantly reduced adenoma development in ApcMin/+ mice when given with a high fat diet. The protective effect was more pronounced than that caused by higher amounts, equivalent to doses used in clinical trials. The CR activity of resveratrol is mediated via the energy regulator AMP-activated kinase (AMPK). This study aims to investigate whether AMPK signalling contributes to the chemopreventive effect of resveratrol. The extent of AMPK activation in vivo correlated with the degree of adenoma inhibition; AMPK expression and phosphorylation was evident in mucosa of resveratrol treated mice, but not in control animals, with highest levels in those that ingested the low dose. This chronic resveratrol treatment was also associated with increased expression of p21, a biomarker of senescence, particularly at the low dose. Moreover, we identify a bell-shaped dose-response to resveratrol: In Apc10.1 cells resveratrol caused significant increases in AMPK phosphorylation at 0.01, 0.1 and 1μM, but not at 10μM, consistent with a bell-shaped dose-response. Activity was accompanied by significantly reduced phosphorylation of mTOR, which is regulated by AMPK signalling, plus its downstream targets p70S6K and 4E-BP1. Furthermore, these concentrations also increased autophagy and senescence, as measured by LC3-II and p21 expression, respectively. Modulation of cellular energy balance by increasing the AMP/ATP and/or ADP/ATP ratios and ability of resveratrol to produce ROS are most likely to be two of the mechanisms responsible for resveratrol stimulating AMPK activation in Apc10.1cells. The novel finding that low amounts of resveratrol are more efficient than higher does will influence future attempts towards clinical implementation of resveratrol for cancer chemoprevention.