Irreversible inhibition of cytosolic thioredoxin reductase 1 as a mechanistic basis for anticancer therapy.

Stafford WC, Peng X, Olofsson MH, Zhang X, Luci DK, Lu L, Cheng Q, Trésaugues L, Dexheimer TS, Coussens NP, Augsten M, Ahlzén HM, Orwar O, Östman A, Stone-Elander S, Maloney DJ, Jadhav A, Simeonov A, Linder S, Arnér ESJ

Sci Transl Med 10 (428) - [2018-02-14; online 2018-02-16]

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 H

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PubMed 29444979

DOI 10.1126/scitranslmed.aaf7444

Crossref 10.1126/scitranslmed.aaf7444

10/428/eaaf7444