Journal Article

DKFZ-2018-00240

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Irreversible inhibition of cytosolic thioredoxin reductase 1 as a mechanistic basis for anticancer therapy.

Stafford, W. C. ; Peng, X. ; Olofsson, M. H. ; Zhang, X. ; Luci, D. K. ; Lu, L. ; Cheng, Q. ; Trésaugues, L. ; Dexheimer, T. S. ; Coussens, N. P. ; Augsten, M.DKFZ* ; Ahlzén, H. M. ; Orwar, O. ; Östman, A. ; Stone-Elander, S. ; Maloney, D. J. ; Jadhav, A. ; Simeonov, A. ; Linder, S. ; Arnér, E. S. J.

2018
AAAS Washington, DC

This record in other databases:  

Please use a persistent id in citations: doi:10.1126/scitranslmed.aaf7444

Abstract: Cancer cells adapt to their inherently increased oxidative stress through activation of the glutathione (GSH) and thioredoxin (TXN) systems. Inhibition of both of these systems effectively kills cancer cells, but such broad inhibition of antioxidant activity also kills normal cells, which is highly unwanted in a clinical setting. We therefore evaluated targeting of the TXN pathway alone and, more specifically, selective inhibition of the cytosolic selenocysteine-containing enzyme TXN reductase 1 (TXNRD1). TXNRD1 inhibitors were discovered in a large screening effort and displayed increased specificity compared to pan-TXNRD inhibitors, such as auranofin, that also inhibit the mitochondrial enzyme TXNRD2 and additional targets. For our lead compounds, TXNRD1 inhibition correlated with cancer cell cytotoxicity, and inhibitor-triggered conversion of TXNRD1 from an antioxidant to a pro-oxidant enzyme correlated with corresponding increases in cellular production of H2O2In mice, the most specific TXNRD1 inhibitor, here described as TXNRD1 inhibitor 1 (TRi-1), impaired growth and viability of human tumor xenografts and syngeneic mouse tumors while having little mitochondrial toxicity and being better tolerated than auranofin. These results display the therapeutic anticancer potential of irreversibly targeting cytosolic TXNRD1 using small molecules and present potent and selective TXNRD1 inhibitors. Given the pronounced up-regulation of TXNRD1 in several metastatic malignancies, it seems worthwhile to further explore the potential benefit of specific irreversible TXNRD1 inhibitors for anticancer therapy.

---

Contributing Institute(s):

1. Vaskuläre Onkologie und Metastasierung (A190)

Research Program(s):

1. 311 - Signalling pathways, cell and tumor biology (POF3-311) (POF3-311)

Appears in the scientific report 2018

---

Database coverage:
; BIOSIS Previews ; IF >= 15 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

---