Cancer chemoprevention: Evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice.
الباحث الأول:
Cai, Hong
الباحثين الآخرين:
Scott E1, Kholghi A1, Andreadi C1, Rufini A1, Karmokar A1, Britton RG1, Horner-Glister E1, Greaves P1, Jawad D1, James M1, Howells L1, Ognibene T2, Malfatti M2, Goldring C3, Kitteringham N3, Walsh J3, Viskaduraki M4, West K5, Miller A5, Hemingway D5, Steward WP1, Gescher AJ1, Brown K6.
المجلة:
Sci Transl Med.
تاريخ النشر:
None
مختصر البحث:
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 compar…
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.
