KEAP1 and done? Targeting the NRF2 pathway with sulforaphane

被引:206
作者
Dinkova-Kostova, Albena T. [1 ,2 ,3 ]
Fahey, Jed W. [2 ,3 ,4 ]
Kostov, Rumen V. [1 ]
Kensler, Thomas W. [2 ,5 ]
机构
[1] Univ Dundee, Sch Med, Div Canc Res, Jacqui Wood Canc Ctr, Dundee DD1 9SY, Scotland
[2] Johns Hopkins Univ, Sch Med, Lewis B & Dorothy Cullman Chemoprotect Ctr, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA
[3] Johns Hopkins Univ, Sch Med, Dept Med, Div Clin Pharmacol, Baltimore, MD 21205 USA
[4] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Ctr Human Nutr, Baltimore, MD 21205 USA
[5] Univ Pittsburgh, Dept Pharmacol & Chem Biol, E1352 BSTWR, Pittsburgh, PA 15261 USA
基金
美国国家卫生研究院; 英国生物技术与生命科学研究理事会;
关键词
Sulforaphane; KEAP1; NRF2; Cytoprotection; Clinical trial; TYPE-2; DIABETIC-PATIENTS; BROCCOLI SPROUT EXTRACT; RANDOMIZED CLINICAL-TRIAL; TRANSCRIPTION FACTOR NRF2; CUL3-BASED E3 LIGASE; HELICOBACTER-PYLORI; OXIDATIVE STRESS; SIGNALING PATHWAY; GENE-EXPRESSION; CELL-SURVIVAL;
D O I
10.1016/j.tifs.2017.02.002
中图分类号
TS2 [食品工业];
学科分类号
0832 ;
摘要
Background: Since the re-discovery of sulforaphane in 1992 and the recognition of the bioactivity of this phytochemical, many studies have examined its mode of action in cells, animals and humans. Broccoli, especially as young sprouts, is a rich source of sulforaphane and broccoli-based preparations are now used in clinical studies probing efficacy in health preservation and disease mitigation. Many putative cellular targets are affected by sulforaphane although only one, KEAP1-NRF2 signaling, can be considered a validated target at this time. The transcription factor NRF2 is a master regulator of cell survival responses to endogenous and exogenous stressors. Scope and Approach: This review summarizes the chemical biology of sulforaphane as an inducer of NRF2 signaling and efficacy as an inhibitor of carcinogenesis. It also provides a summary of the current findings from clinical trials using a suite of broccoli sprout preparations on a series of short-term endpoints reflecting a diversity of molecular actions. Key Findings and Conclusions: Sulforaphane, as a pure chemical, protects against chemical-induced skin, oral, stomach, colon, lung and bladder carcinogenesis and in genetic models of colon and prostate carcinogenesis. In many of these settings the antitumorigenic efficacy of sulforaphane is dampened in Nrf2-disrupted animals. Broccoli preparations rich in glucoraphanin or sulforaphane exert demonstrable pharmacodynamic action in over a score of clinical trials. Measures of NRF2 pathway response and function are serving as guideposts for the optimization of dose, schedule and formulation as clinical trials with broccoli-based preparations become more commonplace and more rigorous in design and implementation. (C) 2017 The Authors. Published by Elsevier Ltd.
引用
收藏
页码:257 / 269
页数:13
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