title: 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 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.
authors.affiliation: Cancer Chemoprevention Group, Department of Cancer Studies, University of Leicester, Leicester LE2 7LX, UK.
authors.forename: Hong
authors.initials: H
authors.lastname: Cai
authors.affiliation: Cancer Chemoprevention Group, Department of Cancer Studies, University of Leicester, Leicester LE2 7LX, UK.
authors.forename: Edwina
authors.initials: E
authors.lastname: Scott
authors.affiliation: Cancer Chemoprevention Group, Department of Cancer Studies, University of Leicester, Leicester LE2 7LX, UK.
authors.forename: Abeer
authors.initials: A
authors.lastname: Kholghi
authors.affiliation: Cancer Chemoprevention Group, Department of Cancer Studies, University of Leicester, Leicester LE2 7LX, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Andreadi
authors.affiliation: Cancer Chemoprevention Group, Department of Cancer Studies, University of Leicester, Leicester LE2 7LX, UK.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rufini
authors.affiliation: Cancer Chemoprevention Group, Department of Cancer Studies, University of Leicester, Leicester LE2 7LX, UK.
authors.forename: Ankur
authors.initials: A
authors.lastname: Karmokar
authors.affiliation: Cancer Chemoprevention Group, Department of Cancer Studies, University of Leicester, Leicester LE2 7LX, UK.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Britton
authors.affiliation: Cancer Chemoprevention Group, Department of Cancer Studies, University of Leicester, Leicester LE2 7LX, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Horner-Glister
authors.affiliation: Cancer Chemoprevention Group, Department of Cancer Studies, University of Leicester, Leicester LE2 7LX, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Greaves
authors.affiliation: Cancer Chemoprevention Group, Department of Cancer Studies, University of Leicester, Leicester LE2 7LX, UK.
authors.forename: Dhafer
authors.initials: D
authors.lastname: Jawad
authors.affiliation: Cancer Chemoprevention Group, Department of Cancer Studies, University of Leicester, Leicester LE2 7LX, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: James
authors.affiliation: Cancer Chemoprevention Group, Department of Cancer Studies, University of Leicester, Leicester LE2 7LX, UK.
authors.forename: Lynne
authors.initials: L
authors.lastname: Howells
authors.affiliation: Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, CA 94551, USA.
authors.forename: Ted
authors.initials: T
authors.lastname: Ognibene
authors.affiliation: Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, CA 94551, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Malfatti
authors.affiliation: MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Building, Ashton Street, Liverpool L69 3GE, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Goldring
authors.affiliation: MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Building, Ashton Street, Liverpool L69 3GE, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Kitteringham
authors.affiliation: MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Building, Ashton Street, Liverpool L69 3GE, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Walsh
authors.affiliation: Bioinformatics and Biostatistics Support Hub, University of Leicester, Maurice Shock Building, Leicester LE1 9HN, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Viskaduraki
authors.affiliation: University Hospitals of Leicester NHS Trust, Leicester LE1 5WW, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: West
authors.affiliation: University Hospitals of Leicester NHS Trust, Leicester LE1 5WW, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Miller
authors.affiliation: University Hospitals of Leicester NHS Trust, Leicester LE1 5WW, UK.
authors.forename: David
authors.initials: D
authors.lastname: Hemingway
authors.affiliation: Cancer Chemoprevention Group, Department of Cancer Studies, University of Leicester, Leicester LE2 7LX, UK.
authors.forename: William P
authors.initials: WP
authors.lastname: Steward
authors.affiliation: Cancer Chemoprevention Group, Department of Cancer Studies, University of Leicester, Leicester LE2 7LX, UK.
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Gescher
authors.affiliation: Cancer Chemoprevention Group, Department of Cancer Studies, University of Leicester, Leicester LE2 7LX, UK. kb20@le.ac.uk.
authors.forename: Karen
authors.initials: K
authors.lastname: Brown
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000236:Adenoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D001343:Autophagy / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D000077185:Resveratrol; D015398:Signal Transduction; D013267:Stilbenes / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D013267:Stilbenes; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000077185:Resveratrol