title: Drug-induced cardiac mitochondrial toxicity and protection: from doxorubicin to carvedilol.
abstract: Mitochondria have long been involved in several cellular processes beyond its role in energy production. The importance of this organelle for cardiac tissue homeostasis has been greatly investigated and its impairment can lead to cell death and consequent organ failure. Several compounds have been described in the literature as having direct effects on cardiac mitochondria which can provide a mechanistic explanation for their toxicological or pharmacological effects. The present review describes one classic example of drug-induced cardiac mitochondrial toxicity and another case of drug-induced mitochondrial protection. For the former, we present the case for doxorubicin, an anticancer agent whose treatment is associated with a cumulative and dose-dependent cardiomyopathy with a mitochondrial etiology. Following this, we present the case of carvedilol, a β-blocker with intrinsic antioxidant activity, which has been described to protect cardiac mitochondria from oxidative injury. The final part of the review integrates information from the previous chapters, demonstrating how carvedilol can contribute to reduce doxorubicin toxicity on cardiac mitochondria. The two referred examples result in important take-home messages: a) drug-induced cardiac mitochondrial dysfunction is an important contributor for drug-associated organ failure, b) protection of mitochondrial function is involved in the beneficial impact of some clinically-used drugs and c) a more accurate prediction of toxic vs. beneficial effects should be an important component of drug development by the pharmaceutical industry.
authors: Center for Neuroscience and Cell Biology, Department of Life Sciences, University of Coimbra, Portugal.
authors: Gonçalo C
authors: GC
authors: Pereira
authors: Ana M
authors: AM
authors: Silva
authors: Cátia V
authors: CV
authors: Diogo
authors: Filipa S
authors: FS
authors: Carvalho
authors: Pedro
authors: P
authors: Monteiro
authors: Paulo J
authors: PJ
authors: Oliveira
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000009:adverse effects / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000494:pharmacology; D002227:Carbazoles / Q000009:adverse effects / Q000494:pharmacology*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control; D002316:Cardiotonic Agents / Q000009:adverse effects / Q000494:pharmacology; D000077261:Carvedilol; D004317:Doxorubicin / Q000009:adverse effects* / Q000494:pharmacology; D006801:Humans; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011412:Propanolamines / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D000319:Adrenergic beta-Antagonists; D000903:Antibiotics, Antineoplastic; D002227:Carbazoles; D002316:Cardiotonic Agents; D011412:Propanolamines; D000077261:Carvedilol; D004317:Doxorubicin