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Sci Transl Med. 2015 Jul 29;7(298):298ra117. doi: 10.1126/scitranslmed.aaa7619.

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

Author information

1
Cancer Chemoprevention Group, Department of Cancer Studies, University of Leicester, Leicester LE2 7LX, UK.
2
Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, CA 94551, USA.
3
MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Building, Ashton Street, Liverpool L69 3GE, UK.
4
Bioinformatics and Biostatistics Support Hub, University of Leicester, Maurice Shock Building, Leicester LE1 9HN, UK.
5
University Hospitals of Leicester NHS Trust, Leicester LE1 5WW, UK.
6
Cancer Chemoprevention Group, Department of Cancer Studies, University of Leicester, Leicester LE2 7LX, UK. kb20@le.ac.uk.

Abstract

Resveratrol is widely promoted as a potential cancer chemopreventive agent, but a lack of information on the optimal dose prohibits rationally designed trials to assess 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 for concentrations generated and the metabolite profile of [(14)C]-resveratrol in colorectal tissue of cancer patients helped us to define clinically achievable levels. In Apc(Min) mice (a model of colorectal carcinogenesis) that received a high-fat diet, the low resveratrol dose suppressed intestinal adenoma development more potently than did the higher dose. Efficacy correlated with activation of adenosine monophosphate-activated protein kinase (AMPK) and increased expression of the senescence marker p21. Nonlinear dose responses were observed for AMPK and mechanistic target of rapamycin (mTOR) signaling in mouse adenoma cells, culminating in autophagy and senescence. In human colorectal tissues exposed to low dietary concentrations of resveratrol ex vivo, we measured enhanced AMPK phosphorylation and autophagy. The expression of the cytoprotective NAD(P)H dehydrogenase, quinone 1 (NQO1) enzyme was also increased in tissues from cancer patients participating in our [(14)C]-resveratrol trial. These findings warrant a revision of developmental strategies for diet-derived agents designed to achieve cancer chemoprevention.

PMID:
26223300
PMCID:
PMC4827609
DOI:
10.1126/scitranslmed.aaa7619
[Indexed for MEDLINE]
Free PMC Article

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