Ethaselen: a potent mammalian thioredoxin reductase 1 inhibitor and novel organoselenium anticancer agent.
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.
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China.
Lihui
L
Wang
Zhiyu
Z
Yang
Jianing
J
Fu
Hanwei
H
Yin
Kun
K
Xiong
Qiang
Q
Tan
Hongwei
H
Jin
Jing
J
Li
Tianyu
T
Wang
Wanchen
W
Tang
Jin
J
Yin
Gaoxiong
G
Cai
Mi
M
Liu
Sebastian
S
Kehr
Katja
K
Becker
Huihui
H
Zeng
D020816:Amino Acid Motifs; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D020134:Catalytic Domain; D002417:Cattle; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011485:Protein Binding; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D054481:Thioredoxin Reductase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism
C478160:(1,2-bis(1,2-benzisoselenazolone-3(2H)-ketone))ethane; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D016566:Organoselenium Compounds; D017382:Reactive Oxygen Species; D013879:Thioredoxins; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1