Acute and chronic effects of anti-cancer agents on cardiac mitochondrial function

Abstract

Cardiotoxicity resulting from the agents used to treat neoplastic disorders is becoming increasingly clinically relevant as cancer survival rates improve. Mitochondria are a common target and potential mediator of this toxicity. Healthy mitochondrial function is integral to both the life and death of cardiomyocytes and alterations in mitochondrial function are increasingly recognised in patients presenting with cardiomyopathy. This PhD project examined the acute and chronic effects of anti-cancer agents on the heart with a specific focus on cardiac mitochondrial function.

A rat model of DOX-induced cardiomyopathy was utilised to examine the chronic effect of doxorubicin (DOX) on cardiac mitochondria. DOX-treated rats showed progressive cardiac decline with a significant reduction in ejection fraction and marked mitochondrial morphological changes. RNA sequencing of left ventricular tissue revealed that the most significantly decreased transcript levels were those related to mitochondrial function. Twenty-four hour DOX treatment of freshly isolated adult rat ventricular cardiomyocytes resulted in a significant decrease in maximal respiratory capacity and a significant increase in mitochondrial-related transcript levels. In the Langendorff-perfused rat heart DOX infusion resulted in acute progressive concentration-dependent mitochondrial membrane potential (m) dissipation. Infusion of the tyrosine kinase inhibitors sunitinib or SU14813 was also found to result in a slight dissipation of the m in the isolated rat heart.

This study demonstrates that the effects of DOX on cardiac mitochondrial function are both acute and chronic and contribute significantly to the pathogenesis of DOX-induced cardiomyopathy. Overall, these findings demonstrate that mitochondrial dysfunction plays a significant role in the development of anti-cancer agent induced-cardiomyopathy and highlights mitochondria as a novel target for cardioprotection.