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

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posted on 07.10.2015, 09:55 by Hong Cai, Edwina Scott, Abeer Kholghi, Catherine Andreadi, Alessandro Rufini, Ankur Karmokar, Robert G. Britton, Emma Horner-Glister, Peter Greaves, Dhafer Jawad, Mark James, Lynne Howells, T Ognibene, M Malfatti, C Goldring, N Kitteringham, J Walsh, Maria Viskaduraki, Kevin West, Andrew Miller, David Hemingway, William P. Steward, Andreas J. Gescher, Karen Brown
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.

History

Citation

Science Translational Medicine, 2015, 7 (298), pp. 298ra117

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cancer Studies and Molecular Medicine

Version

AM (Accepted Manuscript)

Published in

Science Translational Medicine

issn

1946-6234

eissn

1946-6242

Copyright date

2015

Available date

07/10/2015

Publisher version

http://stm.sciencemag.org/content/7/298/298ra117

Language

en

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