Aspalathin reverts doxorubicin-induced cardiotoxicity through increased autophagy and decreased expression of p53/mTOR/p62 signaling

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dc.contributor.authorJohnson, Rabiaen_ZA
dc.contributor.authorShabalala, Samukelisiween_ZA
dc.contributor.authorLouw, Johanen_ZA
dc.contributor.authorKappo, Abidemi Paulen_ZA
dc.contributor.authorMuller, Christo John Fredericken_ZA
dc.date.accessioned2018-01-22T12:39:15Z
dc.date.available2018-01-22T12:39:15Z
dc.date.issued2017-11-01
dc.descriptionCITATION: Johnson, R., et al. 2017. Aspalathin reverts doxorubicin-induced cardiotoxicity through increased autophagy and decreased expression of p53/mTOR/p62 signaling. Molecules, 22(10):1589, doi:10.3390/molecules22101589.
dc.descriptionThe original publication is available at http://www.mdpi.com
dc.description.abstractENGLISH ABSTRACT: Doxorubicin (Dox) is an effective chemotherapeutic agent used in the treatment of various cancers. Its clinical use is often limited due to its potentially fatal cardiotoxic side effect. Increasing evidence indicates that tumour protein p53 (p53), adenosine monophosphate-activated protein kinase (AMPK), nucleoporin p62 (p62), and the mammalian target of rapamycin (mTOR) are critical mediators of Dox-induced apoptosis, and subsequent dysregulation of autophagy. Aspalathin, a polyphenolic dihydrochalcone C-glucoside has been shown to activate AMPK while decreasing the expression of p53. However, the role that aspalathin could play in the inhibition of Dox-induced cardiotoxicity through increased autophagy flux remained unexplored. H9c2 cardiomyocytes and Caov-3 ovarian cancer cells were cultured in Dulbecco’s Modified Eagle’s medium and treated with or without Dox for five days. Thereafter, cells exposed to 0.2 µM Dox were co-treated with either 20 µM Dexrazozane (Dexra) or 0.2 µM aspalathin (ASP) daily for 5 days. Results obtained showed that ASP mediates its cytoprotective effect in a p53-dependent manner, by increasing the Bcl-2/Bax ratio and decreasing apoptosis. The latter effect was diminished through ASP-induced activation of autophagy-related genes (Atgs) with an associated decrease in p62 through induction of AMPK and Fox01. Furthermore, we showed that ASP was able to potentiate this effect without decreasing the anti-cancer efficacy of Dox, as could be observed in Caov-3 ovarian cancer cells. Taken together, the data presented in this study provides a credible mechanism by which ASP co-treatment could protect the myocardium from Dox-induced cardiotoxicity.en_ZA
dc.description.urihttp://www.mdpi.com/1420-3049/22/10/1589
dc.description.versionPublisher's version
dc.format.extent14 pages : illustrationsen_ZA
dc.identifier.citationJohnson, R., et al. 2017. Aspalathin reverts doxorubicin-induced cardiotoxicity through increased autophagy and decreased expression of p53/mTOR/p62 signaling. Molecules, 22(10):1589; doi:10.3390/molecules22101589
dc.identifier.issn1420-3049 (online)
dc.identifier.otherdoi:10.3390/molecules22101589
dc.identifier.urihttp://hdl.handle.net/10019.1/103070
dc.language.isoen_ZAen_ZA
dc.publisherMDPI
dc.rights.holderAuthors retain copyright
dc.subjectCancer -- Pathogenesisen_ZA
dc.subjectDoxorubicinen_ZA
dc.subjectChemotherapyen_ZA
dc.subjectOxidative stressen_ZA
dc.subjectApoptosisen_ZA
dc.titleAspalathin reverts doxorubicin-induced cardiotoxicity through increased autophagy and decreased expression of p53/mTOR/p62 signalingen_ZA
dc.typeArticleen_ZA
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