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  • Selective inhibition of endogenous antioxidants with Auranofin causes mitochondrial oxidative stress which can be countered by selenium supplementation

    Author(s)
    Radenkovic, Filip
    Holland, Olivia
    Vanderlelie, Jessica J
    Perkins, Anthony V
    Griffith University Author(s)
    Perkins, Anthony V.
    Vanderlelie, Jessica J.
    Radenkovic, Filip
    Holland, Olivia J.
    Year published
    2017
    Metadata
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    Abstract
    Auranofin is a thiol-reactive gold (I)-containing compound with potential as a chemotherapeutic. Auranofin has the capacity to selectively inhibit endogenous antioxidant enzymes thioredoxin reductase (TrxR) and glutathione peroxidase (GPx), resulting in oxidative stress and the initiation of a pro-apoptotic cascade. The effect of Auranofin exposure on TrxR and GPx, and the potential for cellular protection through selenium supplementation was examined in the non-cancerous human cell line Swan-71. Auranofin exposure resulted in a concentration dependent differential inhibition of selenoprotein antioxidants. Significant ...
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    Auranofin is a thiol-reactive gold (I)-containing compound with potential as a chemotherapeutic. Auranofin has the capacity to selectively inhibit endogenous antioxidant enzymes thioredoxin reductase (TrxR) and glutathione peroxidase (GPx), resulting in oxidative stress and the initiation of a pro-apoptotic cascade. The effect of Auranofin exposure on TrxR and GPx, and the potential for cellular protection through selenium supplementation was examined in the non-cancerous human cell line Swan-71. Auranofin exposure resulted in a concentration dependent differential inhibition of selenoprotein antioxidants. Significant inhibition of TrxR was observed at 20 nM Auranofin with inhibition of GPx from 10 µM. Significant increases in reactive oxygen species (ROS) were associated with antioxidant inhibition at Auranofin concentrations of 100 nM (TrxR inhibition) and 10 µM (TrxR and GPx inhibition), respectively. Evaluation of mitochondrial respiration demonstrated significant reductions in routine and maximal respiration at both 100 nM and 10 μM Auranofin. Auranofin treatment at concentrations of 10 μM and higher concentrations resulted in a ∼68% decrease in cellular viability and was associated with elevations in pro-apoptotic markers cytochrome c flux control factor (FCFc) at concentration of 100 nM and mitochondrial Bax at 10 μM. The supplementation of selenium (100 nM) prior to treatment had a generalized protective affect through the restoration of antioxidant activity with a significant increase in TrxR and GPx activity, a significant reduction in ROS and associated improvement in mitochondrial respiration and cellular viability (10 µM ∼48% increase). Selenium supplementation reduced the FCFc at low doses of Auranofin (<10 μM) however no effect was noted on either FCFc or Bax at concentrations above 10 μM. The inhibition of antioxidant systems in non-cancerous cells by Auranofin is strongly dose dependent, and this inhibition can be altered by selenium exposure. Therefore, Auranofin dose and the selenium status of patients are important considerations in the therapeutic use of Auranofin as an agent of chemosensitization.
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    Journal Title
    Biochemical Pharmacology
    Volume
    146
    DOI
    https://doi.org/10.1016/j.bcp.2017.09.009
    Subject
    Biochemistry and cell biology
    Pharmacology and pharmaceutical sciences
    Pharmacology and pharmaceutical sciences not elsewhere classified
    Publication URI
    http://hdl.handle.net/10072/368834
    Collection
    • Journal articles

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