Cancer chemoprevention: Evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice

Abstract

Resveratrol is widely promoted as a potential cancer chemopreventive agent, but a lack of information on the optimal dose prohibits rationally designed trials assessing efficacy. To challenge the assumption that ‘more is better’ we compared the pharmacokinetics and activity of a dietary dose with an intake 200-times higher. The dose response relationship and metabolite profile of [14C]-resveratrol in colorectal tissue of patients helped define clinically achievable concentrations. In ApcMin mice receiving a high-fat diet the low dose supressed intestinal adenoma development more potently than the higher dose. Efficacy correlated with increased AMP-activated protein kinase (AMPK) activation and the senescence marker p21. Non-linear dose responses were observed for AMPK and mTOR signalling in adenoma cells, culminating in autophagy and senescence. In human tissues low dietary exposures caused enhanced AMPK phosphorylation, autophagy and expression of the cytoprotective enzyme NQO1. These findings warrant revision of developmental strategies for diet-derived agents for cancer chemoprevention.

p53 coordinates decidual sestrin 2/AMPK/mTORC1 signaling to govern parturition timing

“…Rsv is an increasingly studied agent for its antioxidant and anticancer properties (55). It is reported to activate AMPK to ameliorate aging (17,(56)(57)(58)(59)(60).…”

Anti‑proliferative and anti‑metastasis effects of ten oligostilbenes from the seeds of Paeonia suffruticosa on human cancer cells

“…Although numerous studies have demonstrated the potential of resveratrol as a cancer chemopreventive agent in the last two decades (13,14,26,36), the poor bioavailability of resveratrol due to its rapid metabolism and secretion from the body compromises its biological and pharmacological benefits (37). Hence, significant attention has been given to the derivatives of resveratrol to overcome these drawbacks.…”

“…As one of the most promising naturally derived chemopreventive agents, the in vitro and in vivo antitumor activity of resveratrol has been extensively characterized (13,14,25,26). It is of particular interest to determine whether naturally occurring oligostilbenes or their derivatives have comparable antitumor activities to resveratrol.…”

Protective role of resveratrol on testicular germ cells in mice with testicular toxicity

“…In addition to its well-known antioxidant capacity, RES has also been suggested to have vasorelaxing effects, to regulate lipoprotein metabolism, to inhibit thrombocyte aggregation and to have protective and therapeutic effects against cancer. [15,16] All these data suggest that RES may be a molecular and/or cellular trigger which may also be true for estrogen system. [15,17] The structural similarity found between trans-resveratrol, diethylstilbestrol and estradiol has led researchers to investigate the possible estrogen modulating effects of RES.…”