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Inhibition of thioredoxin reductase 1 correlates with platinum-based chemotherapeutic induced tissue injury.

Authors
  • Cheng, Ping1
  • Liu, Huan1
  • Li, Yinchuan1
  • Pi, Peiling1
  • Jiang, Yu1
  • Zang, Shaozhen1
  • Li, Xiaorong1
  • Fu, Ailing1
  • Ren, Xiaoyuan2
  • Xu, Jianqiang3
  • Holmgren, Arne2
  • Lu, Jun4
  • 1 College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China. , (China)
  • 2 Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institute, SE-171 77 Stockholm, Sweden. , (Sweden)
  • 3 School of Life and Pharmaceutical Sciences & Panjin Institute of Industrial Technology, Dalian University of Technology, Panjin 124221, China. , (China)
  • 4 College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China. Electronic address: [email protected] , (China)
Type
Published Article
Journal
Biochemical pharmacology
Publisher
New York, NY : Elsevier Science Inc
Publication Date
Feb 21, 2020
Volume
175
Pages
113873–113873
Identifiers
DOI: 10.1016/j.bcp.2020.113873
PMID: 32092292
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Platinum-containing drugs (PtDs; e.g. cisplatin, carboplatin, and oxaliplatin) have been widely used as anticancer reagents against various cancers. However, treatment with these drugs results in undesirable adverse effects with unknown mechanisms. Herein, we found a strong correlation between the inhibitory effects of PtDs on cytosolic thioredoxin reductase (TXNRD1) and tissue injury. Of the PtDs tested, cisplatin was found to be the most effective inhibitory PtD against TXRND1, causing the severest kidney injury. The initial inhibition of TXNRD1 in the kidney resulted from cisplatin-induced transcriptional activation of Nrf2-regulated genes including Txnrd1. However, the antioxidant responses in the kidney did not reverse the cisplatin-induced oxidation process. Nephrotoxicity was accompanied with an increase of protein glutathionylation and a cellular thiol redox environment oxidation. These results suggest that the changes of the cellular thiol-dependent redox environment regulated by TXNRD1 is a major event in the adverse effects of cisplatin in kidney. Copyright © 2020 Elsevier Inc. All rights reserved.

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