Cancer chemoprevention: Evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice.
Cancer chemoprevention: Evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice.
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DOI：
10.1126/scitranslmed.aaa7619
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发表时间：
2015-07-29
影响因子：
17.1
通讯作者：
Brown K
中科院分区：
文献类型：
--
作者：
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
白藜芦醇作为一种潜在的癌症化学预防剂被广泛推广，但缺乏最佳剂量的信息阻碍了合理设计的疗效评估试验。为了挑战“越多越好”的假设，我们将膳食剂量与摄入量高 200 倍的药代动力学和活性进行了比较。患者结直肠组织中[14C]-白藜芦醇的剂量反应关系和代谢特征有助于确定临床可达到的浓度。在接受高脂肪饮食的 ApcMin 小鼠中，低剂量比高剂量更能有效地抑制肠腺瘤的发展。功效与 AMP 激活蛋白激酶 (AMPK) 激活和衰老标志物 p21 的增加相关。在腺瘤细胞中观察到 AMPK 和 mTOR 信号传导的非线性剂量反应，最终导致自噬和衰老。在人体组织中，低膳食暴露会导致 AMPK 磷酸化、自噬和细胞保护酶 NQO1 表达增强。这些发现需要修订饮食源性癌症化学预防药物的开发策略。
Resveratrol is widely promoted as a potential cancer chemopreventive agent, but a lack of information on the optimal dose prohibits rationally designed trials assessing 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 and metabolite profile of [14C]-resveratrol in colorectal tissue of patients helped define clinically achievable concentrations. In ApcMin mice receiving a high-fat diet the low dose supressed intestinal adenoma development more potently than the higher dose. Efficacy correlated with increased AMP-activated protein kinase (AMPK) activation and the senescence marker p21. Non-linear dose responses were observed for AMPK and mTOR signalling in adenoma cells, culminating in autophagy and senescence. In human tissues low dietary exposures caused enhanced AMPK phosphorylation, autophagy and expression of the cytoprotective enzyme NQO1. These findings warrant revision of developmental strategies for diet-derived agents for cancer chemoprevention.