Comprehensive chemical proteomics analyses reveal that the new TRi-1 and TRi-2 compounds are more specific thioredoxin reductase 1 inhibitors than auranofin

Pierre Sabatier; Christian M Beusch; Radosveta Gencheva; Qing Cheng; Roman Zubarev; Elias S J Arnér

doi:10.1016/j.redox.2021.102184

Comprehensive chemical proteomics analyses reveal that the new TRi-1 and TRi-2 compounds are more specific thioredoxin reductase 1 inhibitors than auranofin

Redox Biol. 2021 Nov 11:48:102184. doi: 10.1016/j.redox.2021.102184. Online ahead of print.

Authors

Pierre Sabatier¹, Christian M Beusch¹, Radosveta Gencheva², Qing Cheng², Roman Zubarev³, Elias S J Arnér⁴

Affiliations

¹ Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, 17177, Sweden.
² Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, 17177, Sweden.
³ Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, 17177, Sweden; Department of Pharmacological & Technological Chemistry, I.M. Sechenov First Moscow State Medical University, Moscow, 119146, Russia; The National Medical Research Center for Endocrinology, 115478, Moscow, Russia. Electronic address: roman.zubarev@ki.se.
⁴ Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, 17177, Sweden; Department of Selenoprotein Research, National Institute of Oncology, 1122, Budapest, Hungary. Electronic address: elias.arner@ki.se.

Abstract

Anticancer drugs that target cellular antioxidant systems have recently attracted much attention. Auranofin (AF) is currently evaluated in several clinical trials as an anticancer agent that targets the cytosolic and mitochondrial forms of the selenoprotein thioredoxin reductase, TXNRD1 and TXNRD2. Recently, two novel TXNRD1 inhibitors (TRi-1 and TRi-2) have been developed that showed anticancer efficacy comparable to AF, but with lower mitochondrial toxicity. However, the cellular action mechanisms of these drugs have not yet been thoroughly studied. Here we used several proteomics approaches to determine the effects of AF, TRi-1 and TRi-2 when used at IC50 concentrations with the mouse B16 melanoma and LLC lung adenocarcinoma cells, as these are often used for preclinical mouse models in evaluation of anticancer drugs. The results demonstrate that TRi-1 and TRi-2 are more specific TXNRD1 inhibitors than AF and reveal additional AF-specific effects on the cellular proteome. Interestingly, AF triggered stronger Nrf2-driven antioxidant responses than the other two compounds. Furthermore, AF affected several additional proteins, including GSK3A, GSK3B, MCMBP and EEFSEC, implicating additional effects on glycogen metabolism, cellular differentiation, inflammatory pathways, DNA replication and selenoprotein synthesis processes. Our proteomics data provide a resource for researchers interested in the multidimensional analysis of proteome changes associated with oxidative stress in general, and the effects of TXNRD1 inhibitors and AF protein targets in particular.

Keywords: Cancer; Inhibition; Mouse; Proteomics; Thioredoxin reductase.