Ethaselen: a potent mammalian thioredoxin reductase 1 inhibitor and novel organoselenium anticancer agent

被引:126
作者
Wang, Lihui [1 ,2 ,3 ]
Yang, Zhiyu [1 ,2 ]
Fu, Jianing [1 ,2 ]
Yin, Hanwei [4 ]
Xiong, Kun [4 ]
Tan, Qiang [1 ,5 ]
Jin, Hongwei [2 ]
Li, Jing [1 ,2 ]
Wang, Tianyu [4 ]
Tang, Wanchen [1 ,2 ]
Yin, Jin [1 ,2 ]
Cai, Gaoxiong [1 ,2 ]
Liu, Mi [1 ,2 ]
Kehr, Sebastian [3 ]
Becker, Katja [3 ]
Zeng, Huihui [1 ,2 ]
机构
[1] Peking Univ, Sch Pharmaceut Sci, Beijing 100191, Peoples R China
[2] Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
[3] Univ Giessen, Interdisciplinary Res Ctr, D-35392 Giessen, Germany
[4] Peking Univ, Coll Life Sci, Beijing 100075, Peoples R China
[5] Peking Univ, Hosp 1, Beijing 100034, Peoples R China
基金
中国国家自然科学基金;
关键词
Mammalian thioredoxin reductase 1; Thioredoxin; Ethaselen; Enzyme inhibitor; Selenium compound; Anticancer agent; Free radicals; GLUTATHIONE-REDUCTASE; CANCER-THERAPY; MOLECULAR-MECHANISM; GROWTH-INHIBITION; ANTITUMOR QUINOLS; ESCHERICHIA-COLI; CARCINOMA-CELLS; LUNG-CARCINOMA; HUMAN PLACENTA; IN-VITRO;
D O I
10.1016/j.freeradbiomed.2011.11.034
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mammalian thioredoxin reductase 1 (TrxR1) is considered to be an important anticancer drug target and to be involved in both carcinogenesis and cancer progression. Here, we report that ethaselen, a novel organoselenium compound with anticancer activity, specifically binds to the unique selenocysteine-cysteine redox pair in the C-terminal active site of mammalian TrxR1. Ethaselen was found to be a potent inhibitor rather than an efficient substrate of mammalian TrxR1. It effectively inhibits wild-type mammalian TrxR1 at submicromolar concentrations with an initial mixed-type inhibition pattern. By using recombinant human TrxR1 variants and human glutathione reductase, we prove that ethaselen specifically targets the C-terminal but not the N-terminal active site of mammalian TrxR1. In A549 human lung cancer cells, ethaselen significantly suppresses cell viability in parallel with direct inhibition of TrxR1 activity. It does not, however, alter either the disulfide-reduction capability of thioredoxin or the activity of glutathione reductase. As a downstream effect of TrxR1 inactivation, ethaselen causes a dose-dependent thioredoxin oxidation and enhances the levels of cellular reactive oxygen species in A549 cells. Thus, we propose ethaselen as the first selenium-containing inhibitor of mammalian TrxR1 and provide evidence that selenium compounds can act as anticancer agents based on mammalian TrxR1 inhibition. (C) 2011 Elsevier Inc. All rights reserved.
引用
收藏
页码:898 / 908
页数:11
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