Drug-induced mitochondrial dysfunction and cardiotoxicity

Abstract

Mitochondria has essential role in myocardial tissue homeostasis, thus deterioration in mitochondrial function eventually leads to cardiomyocyte and endothelial cell death and consequent cardiovascular dysfunction. Several chemical compounds and drugs have been known to modulate directly or indirectly cardiac mitochondrial function which can account both for the toxicological and pharmacological properties of these substances. In many cases toxicity problems appear only in the presence of additional cardiovascular disease conditions or develop months/years following the exposure making the diagnosis difficult. Cardiotoxic agents affecting mitochondria include several widely used anticancer drugs (anthracyclines - (Doxorubicin/Adriamycin), cisplatin, trastuzumab (Herceptin), arsenic trioxide (Trisenox), mitoxantrone (Novantrone), imatinib (Gleevec), and bevacizumab (Avastin), sunitinib (Sutent) and sorafenib (Nevaxar)), antiviral compound azidothymidine (AZT, Zidovudine) and several oral antidiabetics (e.g. rosiglitazone (Avandia)). Illicit drugs such as alcohol, cocaine, methamphetamine, ecstasy, and synthetic cannabinoids (spice, K2) may also induce mitochondria-related cardiotoxicity. Mitochondrial toxicity develops due to various mechanisms, involving interference with the mitochondrial respiratory chain (e.g. uncoupling), or due to inhibition of the important mitochondrial enzymes (oxidative phosphorylation, Szent-Gyorgyi-Krebs cycle, mitochondrial DNA replication, ADP/ATP translocator). The final phase of mitochondrial dysfunction induces loss of mitochondrial membrane potential, increase in mitochondrial oxidative/nitrative stress, eventually culminating into cell death. This review aims to discuss the mechanisms of mitochondrion-mediated cardiotoxicity of commonly used drugs and some potential cardioprotective strategies to prevent these toxicities.