Abstract
Cardiac side effects are a major drawback of anticancer therapies, often requiring the use of low and less effective doses or even discontinuation of the drug. Among all the drugs known to cause severe cardiotoxicity are anthracyclines that, though being the oldest chemotherapeutic drugs, are still a mainstay in the treatment of solid and hematological tumors. The recent expansion of the field of Cardio-Oncology, a branch of cardiology dealing with prevention or treatment of heart complications due to cancer treatment, has greatly improved our knowledge of the molecular mechanisms behind anthracycline-induced cardiotoxicity (AIC). Despite excessive generation of reactive oxygen species was originally believed to be the main cause of AIC, recent evidence points to the involvement of a plethora of different mechanisms that, interestingly, mainly converge on deregulation of mitochondrial function. In this review, we will describe how anthracyclines affect cardiac mitochondria and how these organelles contribute to AIC. Furthermore, we will discuss how drugs specifically targeting mitochondrial dysfunction and/or mitochondria-targeted drugs could be therapeutically exploited to treat AIC.
Highlights
Advances in cancer therapy resulted in marked improvements in patient survival, with anthracyclines (ANTs) probably being the most potent antineoplastic therapeutics available for the clinical practice, and still representing one of the pillars in the treatment of different tumors
It has been demonstrated that β-oxidation, the main process used by the healthy heart to generate energy, is inhibited upon DOX treatment through the down-modulation of carnitine palmitoyltransferase 1 (CPT-1), while glycolysis is increased by 50% within few hours as a compensatory response
Perhexiline is another drug acting on metabolism that was originally thought as an antianginal medication and its usage was declined for several side effects, including hepatotoxicity and neurotoxicity [114]
Summary
Advances in cancer therapy resulted in marked improvements in patient survival, with anthracyclines (ANTs) probably being the most potent antineoplastic therapeutics available for the clinical practice, and still representing one of the pillars in the treatment of different tumors. It was demonstrated that early treatments with the angiotensin converting enzyme I (ACE-I) enalapril, either alone or in combination with carvedilol, are able to fully or partially recover LVEF in 82% of patients manifesting signs of cardiotoxicity within the first year after the end of ANT treatment [13] These regimens are far from optimal for AIC treatment, and this is probably due to the fact that the mechanisms involved in this specific type of cardiomyopathy are different to those underlying other types of cardiac disease, like ischemic, post-infectious, and idiopathic dilated cardiomyopathies [22]. ANT-mediated ATP depletion (as described in the previous paragraph) reduces the mitochondrial membrane potential and causes MTP opening, further dysregulating Ca2+ homeostasis [45]
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