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Irreversible inhibition of cytosolic thioredoxin reductase 1 as a mechanistic basis for anticancer therapy
Karolinska Inst, Sweden; Obl Therapeut AB, Sweden.
Karolinska Inst, Sweden; AstraZeneca, Sweden.
Karolinska Inst, Sweden; VLVBio AB, Sweden.
Karolinska Inst, Sweden.
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2018 (English)In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 10, no 428, article id eaaf7444Article in journal (Refereed) Published
Abstract [en]

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 H2O2. In 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.

Place, publisher, year, edition, pages
AMER ASSOC ADVANCEMENT SCIENCE , 2018. Vol. 10, no 428, article id eaaf7444
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:liu:diva-145449DOI: 10.1126/scitranslmed.aaf7444ISI: 000424970500001PubMedID: 29444979OAI: oai:DiVA.org:liu-145449DiVA, id: diva2:1192903
Note

Funding Agencies|Karolinska Institutet; Swedish Research Council; Swedish Cancer Society; Radiumhemmets forskningsfonder; Barncancerfonden; Swedish Foundation for Strategic Research; Knut and Alice Wallenberg Foundations; NIH Intramural Research Program; NIH [5R03MH090846]; National Center for Advancing Translational Sciences; Molecular Libraries Initiative of the NIH Roadmap for Medical Research [U54MH084681]; Oblique Therapeutics AB

Available from: 2018-03-23 Created: 2018-03-23 Last updated: 2019-06-28

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Linder, Stig
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