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

被引:146
作者
Cai, Hong [1 ]
Scott, Edwina [1 ]
Kholghi, Abeer [1 ]
Andreadi, Catherine [1 ]
Rufini, Alessandro [1 ]
Karmokar, Ankur [1 ]
Britton, Robert G. [1 ]
Horner-Glister, Emma [1 ]
Greaves, Peter [1 ]
Jawad, Dhafer [1 ]
James, Mark [1 ]
Howells, Lynne [1 ]
Ognibene, Ted [2 ]
Malfatti, Michael [2 ]
Goldring, Christopher [3 ]
Kitteringham, Neil [3 ]
Walsh, Joanne [3 ]
Viskaduraki, Maria [4 ]
West, Kevin [5 ]
Miller, Andrew [5 ]
Hemingway, David [5 ]
Steward, William P. [1 ]
Gescher, Andreas J. [1 ]
Brown, Karen [1 ]
机构
[1] Univ Leicester, Dept Canc Studies, Canc Chemoprevent Grp, Leicester LE2 7LX, Leics, England
[2] Lawrence Livermore Natl Lab, Livermore, CA 94551 USA
[3] Univ Liverpool, Dept Pharmacol & Therapeut, MRC, Ctr Drug Safety Sci, Liverpool L69 3GE, Merseyside, England
[4] Univ Leicester, Bioinformat & Biostat Support Hub, Leicester LE1 9HN, Leics, England
[5] Univ Hosp Leicester NHS Trust, Leicester LE1 5WW, Leics, England
关键词
ACCELERATOR MASS-SPECTROMETRY; PROSTATE-CANCER; BETA-CAROTENE; COLORECTAL-CANCER; AGENT RESVERATROL; CLINICAL-TRIAL; APC(MIN/+); SUPPLEMENTATION; MECHANISMS; MOUSE;
D O I
10.1126/scitranslmed.aaa7619
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 [C-14]-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 [C-14]-resveratrol trial. These findings warrant a revision of developmental strategies for diet-derived agents designed to achieve cancer chemoprevention.
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页数:12
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