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Ethaselen: a potent mammalian thioredoxin reductase 1 inhibitor and novel organoselenium anticancer agent
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
2012-03-01
DOI10.1016/j.freeradbiomed.2011.11.034
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
资助者National Natural Science Foundation of China ; Deutsche Forschungsgemeinschaft ; National Natural Science Foundation of China ; Deutsche Forschungsgemeinschaft
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
资助者National Natural Science Foundation of China ; Deutsche Forschungsgemeinschaft ; National Natural Science Foundation of China ; Deutsche Forschungsgemeinschaft
WOS记录号WOS:000300739800009
引用统计
被引频次:45[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/65825
专题北京大学药学院
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
推荐引用方式
GB/T 7714
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.
APA Wang, Lihui.,Yang, Zhiyu.,Fu, Jianing.,Yin, Hanwei.,Xiong, Kun.,...&Zeng, Huihui.(2012).Ethaselen: a potent mammalian thioredoxin reductase 1 inhibitor and novel organoselenium anticancer agent.FREE RADICAL BIOLOGY AND MEDICINE,52(5),898-908.
MLA Wang, Lihui,et al."Ethaselen: a potent mammalian thioredoxin reductase 1 inhibitor and novel organoselenium anticancer agent".FREE RADICAL BIOLOGY AND MEDICINE 52.5(2012):898-908.
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