Daunorubicin therapy is associated with upregulation of E3 ubiquitin ligases in the heart.
Daunorubicin (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.
Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa.
Balindiwe J N
BJ
Sishi
Dirk J
DJ
Bester
Anita
A
Wergeland
Benjamin
B
Loos
Anne K
AK
Jonassen
Jacques
J
van Rooyen
Anna-Mart
AM
Engelbrecht
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D000071186:Beclin-1; D053148:Caspase 3 / Q000378:metabolism; D003630:Daunorubicin / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D009124:Muscle Proteins / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D015398:Signal Transduction; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D053148:Caspase 3; D003630:Daunorubicin; D008869:Microtubule-Associated Proteins; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases; D046988:Proteasome Endopeptidase Complex; D044843:SKP Cullin F-Box Protein Ligases; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C512829:Becn1 protein, rat; C526109:Anxa3 protein, rat; C486692:Fbxo32 protein, rat; C499086:Trim63 protein, rat