Mitochondrial Determinants of Anti-Cancer Drug-Induced Cardiotoxicity

Abstract

Mitochondria are key organelles for the maintenance of myocardial tissue homeostasis, playing a pivotal role in adenosine triphosphate (ATP) production, calcium signaling, redox homeostasis, and thermogenesis, as well as in the regulation of crucial pathways involved in cell survival. On this basis, it is not surprising that structural and functional impairments of mitochondria can lead to contractile dysfunction, and have been widely implicated in the onset of diverse cardiovascular diseases, including ischemic cardiomyopathy, heart failure, and stroke. Several studies support mitochondrial targets as major determinants of the cardiotoxic effects triggered by an increasing number of chemotherapeutic agents used for both solid and hematological tumors. Mitochondrial toxicity induced by such anticancer therapeutics is due to different mechanisms, generally altering the mitochondrial respiratory chain, energy production, and mitochondrial dynamics, or inducing mitochondrial oxidative/nitrative stress, eventually culminating in cell death. The present review summarizes key mitochondrial processes mediating the cardiotoxic effects of anti-neoplastic drugs, with a specific focus on anthracyclines (ANTs), receptor tyrosine kinase inhibitors (RTKIs) and proteasome inhibitors (PIs).

Keywords: anticancer therapy; cardiotoxicity; heart failure; mitochondrial function.

Figure 1

Schematic representation of major events leading to mitochondrial dysfunction during ANT (DOX)-induced cardiotoxicity. ANT: anthracycline; DOX: doxorubicin; ROS: reactive oxygen species; RNS: reactive nitrogen species; ERS: endoplasmic reticulum stress; Top2β: topoisomerase 2β; ETC: electron transport chain; mtDNA: mitochondrial DNA.

Figure 2

Schematic representation of mitochondrial dynamics alterations induced by ANT (DOX) leading to cardiotoxicity. ANT: anthracycline; DOX: doxorubicin; ROS: reactive oxygen species; MFN1: mitofusin-1; MFN2: mitofusin-2; OPA1: optic atrophy 1; DRP1: dynamin-related protein 1; Midivi-1: mitochondrial division inhibitor-1; mPTP: mitochondrial permeability transition pore; cyt c: cytochrome c.

Figure 3

Proposed mechanism of cardiac mitochondrial alterations secondary to PIs and RTKIs exposure. PIs: Proteasome inhibitors; RTKIs: Receptor tyrosine kinase inhibitors; ETC: electron transport chain; ROS: reactive oxygen species; mPTP: mitochondrial permeability transition pore; cyt c: cytochrome c.