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学科主题: 药学
题名:
Ethaselen: a potent mammalian thioredoxin reductase 1 inhibitor and novel organoselenium anticancer agent
作者: Wang, Lihui1,2,3; Yang, Zhiyu1,2; Fu, Jianing1,2; Yin, Hanwei4; Xiong, Kun4; Tan, Qiang1,5; Jin, Hongwei2; Li, Jing1,2; Wang, Tianyu4; Tang, Wanchen1,2; Yin, Jin1,2; Cai, Gaoxiong1,2; Liu, Mi1,2; Kehr, Sebastian3; Becker, Katja3; Zeng, Huihui1,2
关键词: Mammalian thioredoxin reductase 1 ; Thioredoxin ; Ethaselen ; Enzyme inhibitor ; Selenium compound ; Anticancer agent ; Free radicals
刊名: FREE RADICAL BIOLOGY AND MEDICINE
发表日期: 2012-03-01
DOI: 10.1016/j.freeradbiomed.2011.11.034
卷: 52, 期:5, 页:898-908
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Biochemistry & Molecular Biology ; Endocrinology & Metabolism
研究领域[WOS]: Biochemistry & Molecular Biology ; Endocrinology & Metabolism
关键词[WOS]: GLUTATHIONE-REDUCTASE ; CANCER-THERAPY ; MOLECULAR-MECHANISM ; GROWTH-INHIBITION ; ANTITUMOR QUINOLS ; ESCHERICHIA-COLI ; CARCINOMA-CELLS ; LUNG-CARCINOMA ; HUMAN PLACENTA ; IN-VITRO
英文摘要:

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.

语种: 英语
所属项目编号: 30472036 ; Be 1540/11-1
项目资助者: National Natural Science Foundation of China ; Deutsche Forschungsgemeinschaft
WOS记录号: WOS:000300739800009
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/65825
Appears in Collections:北京大学药学院_期刊论文

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作者单位: 1.Peking Univ, Coll Life Sci, Beijing 100075, Peoples R China
2.Peking Univ, Hosp 1, Beijing 100034, Peoples R China
3.Peking Univ, Sch Pharmaceut Sci, Beijing 100191, Peoples R China
4.Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
5.Univ Giessen, Interdisciplinary Res Ctr, D-35392 Giessen, Germany

Recommended Citation:
Wang, Lihui,Yang, Zhiyu,Fu, Jianing,et al. Ethaselen: a potent mammalian thioredoxin reductase 1 inhibitor and novel organoselenium anticancer agent[J]. FREE RADICAL BIOLOGY AND MEDICINE,2012,52(5):898-908.
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