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000132562 0247_ $$2doi$$a10.1126/scitranslmed.aaf7444
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000132562 037__ $$aDKFZ-2018-00240
000132562 041__ $$aeng
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000132562 1001_ $$00000-0003-4937-4161$$aStafford, William C$$b0
000132562 245__ $$aIrreversible inhibition of cytosolic thioredoxin reductase 1 as a mechanistic basis for anticancer therapy.
000132562 260__ $$aWashington, DC$$bAAAS$$c2018
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000132562 520__ $$aCancer 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.
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000132562 7001_ $$aPeng, Xiaoxiao$$b1
000132562 7001_ $$aOlofsson, Maria Hägg$$b2
000132562 7001_ $$aZhang, Xiaonan$$b3
000132562 7001_ $$00000-0001-5728-0398$$aLuci, Diane K$$b4
000132562 7001_ $$aLu, Li$$b5
000132562 7001_ $$00000-0002-3170-9333$$aCheng, Qing$$b6
000132562 7001_ $$00000-0002-1395-8416$$aTrésaugues, Lionel$$b7
000132562 7001_ $$00000-0002-6444-3121$$aDexheimer, Thomas S$$b8
000132562 7001_ $$00000-0002-3896-7909$$aCoussens, Nathan P$$b9
000132562 7001_ $$00000-0001-5963-8197$$aAugsten, Martin$$b10
000132562 7001_ $$aAhlzén, Hanna-Stina Martinsson$$b11
000132562 7001_ $$aOrwar, Owe$$b12
000132562 7001_ $$00000-0003-3993-0021$$aÖstman, Arne$$b13
000132562 7001_ $$aStone-Elander, Sharon$$b14
000132562 7001_ $$aMaloney, David J$$b15
000132562 7001_ $$00000-0001-7955-1451$$aJadhav, Ajit$$b16
000132562 7001_ $$aSimeonov, Anton$$b17
000132562 7001_ $$00000-0002-4952-445X$$aLinder, Stig$$b18
000132562 7001_ $$00000-0002-4807-6114$$aArnér, Elias S J$$b19
000132562 773__ $$0PERI:(DE-600)2518839-2$$a10.1126/scitranslmed.aaf7444$$gVol. 10, no. 428, p. eaaf7444 -$$n428$$peaaf7444 -$$tScience translational medicine$$v10$$x1946-6242$$y2018
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