Disclosing the effect of doxorubicin and mitoxantrone on cardiac mitochondrial proteome: an in vivo approach using a murine model

The number of cancer survivors has increased considerably due to the current therapies. Nevertheless, the cardiac side effects in these patients are still a concern. Our goal was to study the effects of doxorubicin (DOX) and mitoxantrone (MTX) on the molecular mechanisms harbored in the heart of male mice. Six intraperitoneal administrations were given to the animals. DOX- and MTX-treated animals received a total cumulative dose of 9 and 6 mg/kg, respectively. Whole cardiac tissue and corresponding enriched mitochondrial fractions were analyzed by immunoblot and enzymatic techniques. Additionally, enriched mitochondrial fractions were studied by mass spectrometry-based proteomics. From this analysis 693 different proteins were identified, assigned to the biological processes “small molecule metabolic process”, “oxidation -reduction process” and “carboxylic acid metabolic process” . The distribution analysis of the mitochondrial proteome data showed clustering among the conditions. Indeed, MTX treatment presented less similarities with control. Moreover, DOX and MTX promoted a decrease on mitochondrial density. Metabolic adaptations were noticed, more evident for DOX. Concomitantly, metabolic adaptations were noticed, more evident in the heart of DOX treated mice. Indeed, increased GAPDH-to-ATP and ETFDH-to-ATP ratios were observed. Thus, more than differences in cardiac mitochondrial proteome, these drugs seem to decrease this organelle density. Our goal to study the effects of DOX and MTX on the cardiac mitochondrial proteome remodeling of adult male CD-1 mice. GeLC-MS/MS: combines one dimensional SDS-PAGE with liquid chromatography-tandem mass spectrometry Statistical analysis was performed with GraphPad Prism (version 6.0.1). Experimental groups were compared using ordinary one-way ANOVA followed by Turkey’s multiple comparisons test ( p < 0.05). Results are presented as significantly increased ( ), decreased ( ) or no significantly different ( ) related to the control group. Results are presented as significantly increased ( ), decreased ( ) or no significantly different ( ) related to the control group. increased GAPDH/ATP-B ETFDH/ATP-B ratios compared Results are presented as significantly increased ( ), decreased ( ) or no significantly different ( ) related to the control group.