Auranofin, a thioredoxin reductase inhibitor, causes platelet death through calcium overload.
Taylor & Francis
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Harper, M. (2019). Auranofin, a thioredoxin reductase inhibitor, causes platelet death through calcium overload.. Platelets, 30 (1), 98-104. https://doi.org/10.1080/09537104.2017.1378809
Platelets are central to normal haemostasis and must be tightly controlled to prevent thrombosis. However, drug treatments that also affect platelets could lead to unwanted side effects on haemostasis or thrombosis. In this study, the effect of auranofin on platelets was tested. Auranofin, a gold-based thioredoxin reductase (TRXR) inhibitor, has been previously used in arthritis. Recently auranofin and other inhibitors of the thioredoxin system have been proposed as novel anti-cancer therapies. TRXR is an important part of the antioxidant defences in many cells that maintain intracellular proteins in their reduced state. TRXR activity in platelets could be completely inhibited by auranofin. Auranofin-treated platelets showed several features of cell death, including an inability to aggregate in response to thrombin, leakage of cytosolic lactate dehydrogenase, and surface exposure of procoagulant phosphatidylserine. Auranofin increased platelet reactive oxygen species production and intracellular calcium concentration. DTT, a sulfydyl reducing agent, and BAPTA-AM, which chelates intracellular calcium, prevented auranofin-induced phosphatidylserine exposure. These data suggest that TRXR is an important part of the platelet antioxidant defence. TRXR inhibition by auranofin triggers oxidative stress and disrupts intracellular calcium homeostasis, leading to platelet necrosis. The use of auranofin or other TRXR inhibitors could therefore lead to unwanted side effects.
Blood Platelets, Humans, Calcium, Reactive Oxygen Species, Auranofin, Caspases, Cell Death, Oxidation-Reduction, Oxidative Stress, Homeostasis, Thioredoxin-Disulfide Reductase, Biomarkers
Isaac Newton Trust/ Wellcome Trust ISSF/University of Cambridge Joint Research Grant.
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External DOI: https://doi.org/10.1080/09537104.2017.1378809
This record's URL: https://www.repository.cam.ac.uk/handle/1810/268139