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

Stafford, William C. (författare)
Karolinska Institutet,Karolinska Inst, Sweden; Obl Therapeut AB, Sweden,Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE 171 77 Stockholm, Sweden.;Oblique Therapeutics AB, SE 413 46 Gothenburg, Sweden.
Peng, Xiaoxiao (författare)
Karolinska Inst, Sweden; AstraZeneca, Sweden,Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE 171 77 Stockholm, Sweden.
Olofsson, Maria Hagg (författare)
Karolinska Inst, Sweden; VLVBio AB, Sweden,Department of Oncology-Pathology, Karolinska Institutet, SE 171 77 Stockholm, Sweden.
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Zhang, Xiaonan (författare)
Karolinska Institutet,Karolinska Inst, Sweden,Department of Oncology-Pathology, Karolinska Institutet, SE 171 77 Stockholm, Sweden.
Luci, Diane K. (författare)
NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892–4874, USA.
Lu, Li (författare)
Karolinska Univ Hosp, Sweden,Karolinska Experimental Research and Imaging Center, Karolinska University Hospital, SE 171 76 Stockholm, Sweden.
Cheng, Qing (författare)
Karolinska Institutet,Karolinska Inst, Sweden,Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE 171 77 Stockholm, Sweden.
Tresaugues, Lionel (författare)
Karolinska Inst, Sweden; Novum, Sweden,Division of Biophysics, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE 171 77 Stockholm, Sweden.
Dexheimer, Thomas S. (författare)
NIH, MD 20892 USA; Michigan State Univ, MI 48824 USA,NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892–4874, USA.
Coussens, Nathan P. (författare)
NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892–4874, USA.
Augsten, Martin (författare)
Karolinska Inst, Sweden; Amcure GmbH, Germany; German Canc Res Ctr, Germany,Department of Oncology-Pathology, Karolinska Institutet, SE 171 77 Stockholm, Sweden.
Martinsson Ahlzen, Hanna-Stina (författare)
Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden,Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE 171 77 Stockholm, Sweden.
Orwar, Owe (författare)
Obl Therapeut AB, Sweden; Karolinska Inst, Sweden,Oblique Therapeutics AB, SE 413 46 Gothenburg, Sweden.;Department of Physiology and Pharmacology, Karolinska Institutet, SE 171 77 Stockholm, Sweden.
Ostman, Arne (författare)
Karolinska Institutet,Karolinska Inst, Sweden; Univ Bergen, Norway,Department of Oncology-Pathology, Karolinska Institutet, SE 171 77 Stockholm, Sweden.;University of Bergen, Postboks 7804, N-5020 Bergen, Norway.
Stone-Elander, Sharon (författare)
Karolinska Institutet,Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden,Department of Neuroradiology, Positron Emission Tomography Radiochemistry, Karolinska University Hospital, SE 171 76 Stockholm, Sweden.;Department of Clinical Neurosciences, Karolinska Institutet, SE 171 77 Stockholm, Sweden.
Maloney, David J. (författare)
NIH, MD 20892 USA; Inspyr Therapeut Inc, CA 91362 USA,NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892–4874, USA.
Jadhav, Ajit (författare)
NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892–4874, USA.
Simeonov, Anton (författare)
NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892–4874, USA.
Linder, Stig (författare)
Linköpings universitet,Avdelningen för läkemedelsforskning,Medicinska fakulteten,Karolinska Inst, Sweden,Department of Oncology-Pathology, Karolinska Institutet, SE 171 77 Stockholm, Sweden.;Division of Drug Research, Department of Medicine and Health, Linköping University, SE 581 83 Linköping, Sweden.
Arner, Elias S. J. (författare)
Karolinska Inst, Sweden,Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE 171 77 Stockholm, Sweden.
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 (creator_code:org_t)
AMER ASSOC ADVANCEMENT SCIENCE, 2018
2018
Engelska.
Ingår i: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 10:428
Relaterad länk:
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • 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

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

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