Exploring the aging effect of the anticancer drugs doxorubicin and mitoxantrone on cardiac mitochondrial proteome using a murine model

• Type: Article in International Scientific Journal
• Date: 2021

Authors

Sofia Reis Brandão (Author) Other; Ana Reis-Mendes (Author) Other; Pedro Domingues (Author) Other; José Alberto Duarte (Author) FADEUP; Maria Lourdes Bastos (Author) Other; Félix Carvalho (Author) FFUP; Rita Ferreira (Author) Other; Vera Marisa Costa (Author) Other

Journal

Title: Toxicology

Vol. 459

Pages: 152852/1-152852/14

ISSN: 0300-483X

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 0 Citations

Scientific classification

FOS: Social sciences

Other information

Authenticus ID: P-00V-6XY

DOI: 10.1016/j.tox.2021.152852

Abstract (EN): Current cancer therapies are successfully increasing the lifespan of cancer patients. Nevertheless, cardiotoxicity is a serious chemotherapy-induced adverse side effect. Doxorubicin (DOX) and mitoxantrone (MTX) are cardiotoxic anticancer agents, whose toxicological mechanisms are still to be identified. This study focused on DOX and MTX's cardiac mitochondrial damage and their molecular mechanisms. As a hypothesis, we also sought to compare the cardiac modulation caused by 9 mg/kg of DOX or 6 mg/kg of MTX in young adult mice (3 months old) with old control mice (aged control, 18-20 months old) to determine if DOX- and MTX-induced damage had common links with the aging process. Cardiac homogenates and enriched mitochondrial fractions were prepared from treated and control animals and analyzed by immunoblotting and enzymatic assays. Enriched mitochondrial fractions were also characterized by mass spectrometry-based proteomics. Data obtained showed a decrease in mitochondrial density in young adults treated with DOX or MTX and aged control, as assessed by citrate synthase (CS) activity. Furthermore, aged control had increased expression of the peroxisome proliferator-activated receptor. coactivator 1 alpha (PGC1 alpha) and manganese superoxide dismutase (MnSOD). Regarding the enriched mitochondrial fractions, DOX and MTX led to downregulation of proteins related to oxidative phosphorylation, fatty acid oxidation, amino acid metabolic process, and tricarboxylic acid cycle. MTX had a greater impact on malate dehydrogenase (MDH2) and pyruvate dehydrogenase E1 component subunit alpha (PDHA1). No significant proteomic changes were observed in the enriched mitochondrial fractions of aged control when compared to young control. To conclude, DOX and MTX promoted changes in several mitochondrial-related proteins in young adult mice, but none resembling the aged phenotype.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 14