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dc.contributor.authorRadenkovic, Filip
dc.contributor.authorHolland, Olivia
dc.contributor.authorVanderlelie, Jessica J
dc.contributor.authorPerkins, Anthony V
dc.date.accessioned2018-02-04T22:46:55Z
dc.date.available2018-02-04T22:46:55Z
dc.date.issued2017
dc.identifier.issn0006-2952
dc.identifier.doi10.1016/j.bcp.2017.09.009
dc.identifier.urihttp://hdl.handle.net/10072/368834
dc.description.abstractAuranofin 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.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherElsevier
dc.relation.ispartofpagefrom42
dc.relation.ispartofpageto52
dc.relation.ispartofjournalBiochemical Pharmacology
dc.relation.ispartofvolume146
dc.subject.fieldofresearchBiochemistry and cell biology
dc.subject.fieldofresearchPharmacology and pharmaceutical sciences
dc.subject.fieldofresearchPharmacology and pharmaceutical sciences not elsewhere classified
dc.subject.fieldofresearchcode3101
dc.subject.fieldofresearchcode3214
dc.subject.fieldofresearchcode321499
dc.titleSelective inhibition of endogenous antioxidants with Auranofin causes mitochondrial oxidative stress which can be countered by selenium supplementation
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.facultyGriffith Health, School of Medical Science
gro.hasfulltextNo Full Text
gro.griffith.authorPerkins, Anthony V.
gro.griffith.authorVanderlelie, Jessica J.
gro.griffith.authorRadenkovic, Filip
gro.griffith.authorHolland, Olivia J.


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