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

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....

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Autores principales:	Pierre Sabatier, Christian M. Beusch, Radosveta Gencheva, Qing Cheng, Roman Zubarev, Elias S.J. Arnér
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Proteomics Thioredoxin reductase Inhibition Cancer Mouse Medicine (General) R5-920 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/2416c4c7c36649e9989635fa4100678e
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spelling	oai:doaj.org-article:2416c4c7c36649e9989635fa4100678e2021-11-16T04:10:26ZComprehensive chemical proteomics analyses reveal that the new TRi-1 and TRi-2 compounds are more specific thioredoxin reductase 1 inhibitors than auranofin2213-231710.1016/j.redox.2021.102184https://doaj.org/article/2416c4c7c36649e9989635fa4100678e2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S221323172100344Xhttps://doaj.org/toc/2213-2317Anticancer 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.Pierre SabatierChristian M. BeuschRadosveta GenchevaQing ChengRoman ZubarevElias S.J. ArnérElsevierarticleProteomicsThioredoxin reductaseInhibitionCancerMouseMedicine (General)R5-920Biology (General)QH301-705.5ENRedox Biology, Vol 48, Iss , Pp 102184- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Proteomics Thioredoxin reductase Inhibition Cancer Mouse Medicine (General) R5-920 Biology (General) QH301-705.5
spellingShingle	Proteomics Thioredoxin reductase Inhibition Cancer Mouse Medicine (General) R5-920 Biology (General) QH301-705.5 Pierre Sabatier Christian M. Beusch Radosveta Gencheva Qing Cheng Roman Zubarev Elias S.J. Arnér Comprehensive chemical proteomics analyses reveal that the new TRi-1 and TRi-2 compounds are more specific thioredoxin reductase 1 inhibitors than auranofin
description	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.
format	article
author	Pierre Sabatier Christian M. Beusch Radosveta Gencheva Qing Cheng Roman Zubarev Elias S.J. Arnér
author_facet	Pierre Sabatier Christian M. Beusch Radosveta Gencheva Qing Cheng Roman Zubarev Elias S.J. Arnér
author_sort	Pierre Sabatier
title	Comprehensive chemical proteomics analyses reveal that the new TRi-1 and TRi-2 compounds are more specific thioredoxin reductase 1 inhibitors than auranofin
title_short	Comprehensive chemical proteomics analyses reveal that the new TRi-1 and TRi-2 compounds are more specific thioredoxin reductase 1 inhibitors than auranofin
title_full	Comprehensive chemical proteomics analyses reveal that the new TRi-1 and TRi-2 compounds are more specific thioredoxin reductase 1 inhibitors than auranofin
title_fullStr	Comprehensive chemical proteomics analyses reveal that the new TRi-1 and TRi-2 compounds are more specific thioredoxin reductase 1 inhibitors than auranofin
title_full_unstemmed	Comprehensive chemical proteomics analyses reveal that the new TRi-1 and TRi-2 compounds are more specific thioredoxin reductase 1 inhibitors than auranofin
title_sort	comprehensive chemical proteomics analyses reveal that the new tri-1 and tri-2 compounds are more specific thioredoxin reductase 1 inhibitors than auranofin
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/2416c4c7c36649e9989635fa4100678e
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Comprehensive chemical proteomics analyses reveal that the new TRi-1 and TRi-2 compounds are more specific thioredoxin reductase 1 inhibitors than auranofin

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