4.7 Article

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

Journal

REDOX BIOLOGY
Volume 48, Issue -, Pages -

Publisher

ELSEVIER
DOI: 10.1016/j.redox.2021.102184

Keywords

Proteomics; Thioredoxin reductase; Inhibition; Cancer; Mouse

Funding

  1. Knut and Alice Wallenberg Foundation [KAW 2015.0063]
  2. Karolinska Institutet
  3. Knut and Alice Wallenberg Foundations [KAW 2019.0059]
  4. Swedish Cancer Society [CAN 2018/333, 19 0330 Pj]
  5. Swedish Research Council [2017-01872]
  6. Cayman Biomedical Research Institute (CABRI)
  7. Hungarian Thematic Excellence Programme [TKP2020-NKA-26]
  8. Hungarian National Research, Development and Innovation Office [ED_18-1-20190025]
  9. Hungarian National Laboratories Excellence program (under the National Tumor Biology Laboratory project) [NLP-17]
  10. Hungarian Ministry of Human Capacities [AEEK/41872-16/2020]
  11. Ministry of Science and Higher Education of the Russian Federation [075-15-2020-899]
  12. Swedish Research Council [2017-01872] Funding Source: Swedish Research Council

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Recent studies have focused on anticancer drugs that target cellular antioxidant systems, such as Auranofin (AF) and novel TXNRD1 inhibitors (TRi-1 and TRi-2). These drugs have shown efficacy in mouse melanoma and lung adenocarcinoma cells, with TRi-1 and TRi-2 being more specific TXNRD1 inhibitors and AF triggering stronger antioxidant responses through Nrf2 activation. Additionally, AF has shown additional effects on various proteins related to glycogen metabolism, cellular differentiation, and inflammatory pathways.
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 TRi2 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.

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