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  • Stafford, William C.Karolinska Institutet,Karolinska Inst, Sweden; Obl Therapeut AB, Sweden (författare)

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

  • Artikel/kapitelEngelska2018

Förlag, utgivningsår, omfång ...

  • AMER ASSOC ADVANCEMENT SCIENCE,2018
  • printrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:liu-145449
  • https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-145449URI
  • https://doi.org/10.1126/scitranslmed.aaf7444DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:137630431URI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • 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
  • 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.

Ämnesord och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Peng, XiaoxiaoKarolinska Inst, Sweden; AstraZeneca, Sweden (författare)
  • Olofsson, Maria HaggKarolinska Inst, Sweden; VLVBio AB, Sweden (författare)
  • Zhang, XiaonanKarolinska Institutet,Karolinska Inst, Sweden (författare)
  • Luci, Diane K.NIH, MD 20892 USA (författare)
  • Lu, LiKarolinska Univ Hosp, Sweden (författare)
  • Cheng, QingKarolinska Institutet,Karolinska Inst, Sweden (författare)
  • Tresaugues, LionelKarolinska Inst, Sweden; Novum, Sweden (författare)
  • Dexheimer, Thomas S.NIH, MD 20892 USA; Michigan State Univ, MI 48824 USA (författare)
  • Coussens, Nathan P.NIH, MD 20892 USA; NIH, MD 20892 USA (författare)
  • Augsten, MartinKarolinska Inst, Sweden; Amcure GmbH, Germany; German Canc Res Ctr, Germany (författare)
  • Martinsson Ahlzen, Hanna-StinaKarolinska Inst, Sweden; Karolinska Univ Hosp, Sweden (författare)
  • Orwar, OweObl Therapeut AB, Sweden; Karolinska Inst, Sweden (författare)
  • Ostman, ArneKarolinska Institutet,Karolinska Inst, Sweden; Univ Bergen, Norway (författare)
  • Stone-Elander, SharonKarolinska Institutet,Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden (författare)
  • Maloney, David J.NIH, MD 20892 USA; Inspyr Therapeut Inc, CA 91362 USA (författare)
  • Jadhav, AjitNIH, MD 20892 USA (författare)
  • Simeonov, AntonNIH, MD 20892 USA (författare)
  • Linder, StigLinköpings universitet,Avdelningen för läkemedelsforskning,Medicinska fakulteten,Karolinska Inst, Sweden(Swepub:liu)stili13 (författare)
  • Arner, Elias S. J.Karolinska Inst, Sweden (författare)
  • Karolinska InstitutetKarolinska Inst, Sweden; Obl Therapeut AB, Sweden (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Science Translational Medicine: AMER ASSOC ADVANCEMENT SCIENCE10:4281946-62341946-6242

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