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Title: Cancer chemoprevention: Evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice
Authors: Cai, Hong
Scott, Edwina
Kholghi, Abeer
Andreadi, Catherine
Rufini, Alessandro
Karmokar, Ankur
Britton, Robert G.
Horner-Glister, Emma
Greaves, Peter
Jawad, Dhafer
James, Mark
Howells, Lynne
Ognibene, T
Malfatti, M
Goldring, C
Kitteringham, N
Walsh, J
Viskaduraki, Maria
West, Kevin
Miller, Andrew
Hemingway, David
Steward, William P.
Gescher, Andreas J.
Brown, Karen
First Published: 29-Jul-2015
Citation: Science Translational Medicine, 2015, 7 (298), pp. 298ra117
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.
DOI Link: 10.1126/scitranslmed.aaa7619
ISSN: 1946-6234
eISSN: 1946-6242
Version: Post-print
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2015, American Association for the Advancement of Science. Deposited with reference to the publisher’s archiving policy available on the SHERPA/RoMEO website and on
Appears in Collections:Published Articles, Dept. of Cancer Studies and Molecular Medicine

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