Cancer chemoprevention

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

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, Ted Ognibene, Michael Malfatti, Christopher Goldring, Neil Kitteringham, Joanne Walsh, Maria Viskaduraki, Kevin West, Andrew Miller & 4 others David Hemingway, William P. Steward, Andreas J. Gescher, Karen Brown

Research output: Contribution to journalArticle

69 Citations (Scopus)

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 [<sup>14</sup>C]-resveratrol in colorectal tissue of cancer patients helped us to define clinically achievable levels. In Apc<sup>Min</sup> 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 [<sup>14</sup>C]-resveratrol trial. These findings warrant a revision of developmental strategies for diet-derived agents designed to achieve cancer chemoprevention.

Original languageEnglish (US)
Article number298ra117
JournalScience Translational Medicine
Volume7
Issue number298
DOIs
StatePublished - Jul 29 2015
Externally publishedYes

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Chemoprevention
Adenosine Monophosphate
Protein Kinases
Autophagy
Neoplasms
Adenoma
NAD(P)H Dehydrogenase (Quinone)
High Fat Diet
Sirolimus
Colorectal Neoplasms
Carcinogenesis
Pharmacokinetics
Phosphorylation
resveratrol
Diet
Enzymes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cancer chemoprevention : Evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice. / 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, Ted; Malfatti, Michael; Goldring, Christopher; Kitteringham, Neil; Walsh, Joanne; Viskaduraki, Maria; West, Kevin; Miller, Andrew; Hemingway, David; Steward, William P.; Gescher, Andreas J.; Brown, Karen.

In: Science Translational Medicine, Vol. 7, No. 298, 298ra117, 29.07.2015.

Research output: Contribution to journalArticle

Cai, H, Scott, E, Kholghi, A, Andreadi, C, Rufini, A, Karmokar, A, Britton, RG, Horner-Glister, E, Greaves, P, Jawad, D, James, M, Howells, L, Ognibene, T, Malfatti, M, Goldring, C, Kitteringham, N, Walsh, J, Viskaduraki, M, West, K, Miller, A, Hemingway, D, Steward, WP, Gescher, AJ & Brown, K 2015, 'Cancer chemoprevention: Evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice', Science Translational Medicine, vol. 7, no. 298, 298ra117. https://doi.org/10.1126/scitranslmed.aaa7619
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, Ted ; Malfatti, Michael ; Goldring, Christopher ; Kitteringham, Neil ; Walsh, Joanne ; Viskaduraki, Maria ; West, Kevin ; Miller, Andrew ; Hemingway, David ; Steward, William P. ; Gescher, Andreas J. ; Brown, Karen. / Cancer chemoprevention : Evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice. In: Science Translational Medicine. 2015 ; Vol. 7, No. 298.
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