A Biophysical Systems Approach to Identifying the Pathways of Acute and Chronic Doxorubicin Mitochondrial Cardiotoxicity

• DOI: 10.1371/journal.pcbi.1005214
• Publication Date: 2016-11-21T18:40:56Z
• Authors: Bernardo L. de Ol...; Steven Niederer
• Keywords: Cardiotoxicity; Mitochondrial toxicity

The clinical use of the anthracycline doxorubicin is limited by its cardiotoxicity which associated with mitochondrial dysfunction. Redox cycling, DNA damage and electron transport chain inhibition have been identified as potential mechanisms toxicity. However, relative roles each these proposed are still not fully understood. purpose this study to identify pathways independently or in combination responsible for A state art mathematical model mitochondria including citric acid cycle, ROS production scavenging systems was extended incorporating a novel representation repair. In silico experiments were performed quantify contributions toxicity dysfunction during acute chronic stages Simulations predict that redox cycling has minor role cardiotoxicity. Electron main pathway supratherapeutic doses, being lethal at concentrations higher than 200μM. Direct principal therapeutic leading progressive irreversible long term