Daunorubicin therapy is associated with upregulation of E3 ubiquitin ligases in the heart

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dc.contributor.authorSishi B.J.N.
dc.contributor.authorBester D.J.
dc.contributor.authorWergeland A.
dc.contributor.authorLoos B.
dc.contributor.authorJonassen A.K.
dc.contributor.authorvan Rooyen J.
dc.contributor.authorEngelbrecht A.-M.
dc.date.accessioned2012-04-12T08:21:19Z
dc.date.available2012-04-12T08:21:19Z
dc.date.issued2012
dc.description.abstractDaunorubicin (DNR) and doxorubicin (DOX) are two of the most effective anthracycline drugs known for the treatment of systemic neoplasms and solid tumors. However, their clinical use is hampered due to profound cardiotoxicity. The mechanism by which DNR injures the heart remains to be fully elucidated. Recent reports have indicated that DOX activates ubiquitin proteasome-mediated degradation of specific transcription factors; however, no reports exist on the effect of DNR on the E3 ubiquitin ligases, MURF-1 (muscle ring finger 1) and MAFbx (muscle atrophy F-box). The aim of this study was to investigate the effect of DNR treatment on the protein and organelle degradation systems in the heart and to elucidate some of the signalling mechanisms involved. Adult rats were divided into two groups where one group received six intraperitoneal injections of 2 mg/kg DNR on alternate days and the other group received saline injections as control. Hearts were excised and perfused on a working heart system the day after the last injection and freeze-clamped for biochemical analysis. DNR treatment significantly attenuated cardiac function and increased apoptosis in the heart. DNR-induced cardiac cytotoxicity was associated with upregulation of the E3 ligases, MURF-1 and MAFbx and also caused significant increases in two markers of autophagy, beclin-1 and LC3. These changes observed in the heart were also associated with attenuation of the phosphoinositide 3-kinase/Akt signalling pathway. © 2012 by the Society for Experimental Biology and Medicine.
dc.identifier.citationExperimental Biology and Medicine
dc.identifier.citation237
dc.identifier.citation2
dc.identifier.citation219
dc.identifier.citation226
dc.identifier.issn15353702
dc.identifier.other10.1258/ebm.2011.011106
dc.identifier.urihttp://hdl.handle.net/10019.1/20564
dc.subjectAntracyclines
dc.subjectAutophagy
dc.subjectCardiotoxicity
dc.subjectDaunorubicin
dc.subjectUbiquitin ligases
dc.titleDaunorubicin therapy is associated with upregulation of E3 ubiquitin ligases in the heart
dc.typeArticle
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