title: Drug-induced mitochondrial dysfunction and cardiotoxicity.
abstract: Mitochondria has an 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 directly or indirectly modulate 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), 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 inhibition of the important mitochondrial enzymes (oxidative phosphorylation, Szent-Györgyi-Krebs cycle, mitochondrial DNA replication, ADP/ATP translocator). The final phase of mitochondrial dysfunction induces loss of mitochondrial membrane potential and an 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.
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland; Cardiometabolic Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary;
authors.forename: Zoltán V
authors.initials: ZV
authors.lastname: Varga
authors.affiliation: Cardiometabolic Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary; Pharmahungary Group, Szeged, Hungary; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Ferdinandy
authors.affiliation: Department of Intensive Care Medicine BH 08-621-University Hospital Medical Center, Lausanne, Switzerland.
authors.forename: Lucas
authors.initials: L
authors.lastname: Liaudet
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland; pacher@mail.nih.gov.
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects*; D000998:Antiviral Agents / Q000009:adverse effects*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000378:metabolism; D066126:Cardiotoxicity / Q000209:etiology / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D013287:Illicit Drugs / Q000009:adverse effects*; D008929:Mitochondria, Heart / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000209:etiology* / Q000378:metabolism; D018384:Oxidative Stress
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D007004:Hypoglycemic Agents; D013287:Illicit Drugs
keywords: cardiomyopathy; drug development; heart; heart failure; reactive oxygen species; toxicology