New Developments in Anthracycline-Induced Cardiotoxicity

Abstract

Anthracyclines are among the most effective anticancer drugs ever developed. Unfortunately, their clinical use is severely limited by the development of a progressive dose-dependent cardiomyopathy that irreversibly evolves toward congestive heart failure, usually refractory to conventional therapy. The pathophysiology of anthracycline-induced cardiomyopathy remains controversial and incompletely understood. The current thinking is that anthracyclines are toxic per se but gain further cardiotoxicity after one-electron reduction with ROS overproduction or two-electron reduction with conversion to C-13 alcohol metabolites. ROS overproduction can probably be held responsible for anthracycline acute cardiotoxicity, but not for all the aspects of progressive cardiomyopathy. Intramyocardial formation of secondary alcohol metabolites might play a key role in promoting the progression of cardiotoxicity toward end-stage cardiomyopathy and congestive heart failure. In this review we also discuss recent developments in: a) the molecular mechanisms underlying anthracycline-induced cardiotoxicity; b) the role of cytosolic NADPH-dependent reductases in anthracycline metabolism; c) the influence of genetic polymorphisms on cardiotoxicity outcome; d) the perspectives on the most promising strategies for limiting or preventing anthracycline-induced cardiotoxicity, focusing on controversial aspects and on recent data regarding analogues of the natural compounds, tumor-targeted formulations and cardioprotective agents.

Anthracycline-Related Cardiomyopathy After Childhood Cancer: Role of Polymorphisms in Carbonyl Reductase Genes—A Report From the Children's Oncology Group

“…7,8 Development of cardiomyopathy correlates with myocardial accumulation of anthracycline alcohol metabolites. 9,10 Variability in the formation of these metabolites could influence the risk of cardiomyopathy.…”

“…9,10 Variability in the formation of these metabolites could influence the risk of cardiomyopathy. 7 Synthesis of cardiotoxic alcohol metabolites is catalyzed by myocardial cytosolic carbonyl reductases (CBRs). 7,11 In humans, two monomeric CBRs (CBR1 and CBR3) are encoded for by genes located on chromosome 21.…”

The Citrus Flavanone Naringin Enhances Antioxidant Status in the Albino Rat Liver Treated with Doxorubicin

“…Doxorubicin has been known to generate highly reactive free radicals in the mitochondria of cells and presence of iron further aggravates the problem [10]. The DOX produces quinone-hydroquinone containing anthracyclines, which are redox active and therefore undergo both one-electron and two-electron reductions by a wide variety of chemical and enzymatic reducing agents [2,11,12]. The one-electron reduction of DOX casues the formation of semiquinone free radicals or other reactive species that could exert antitumor action either by alkylating DNA, by causing DNA strand scission, or by inducing lipid peroxidation [13].…”

Anthracycline Treatment and Ventricular Remodeling in Left Ventricular Assist Device Patients

“…Intramyocardial formation of secondary alcohol metabolites might play a key role in promoting the development of end-stage HF. [21][22][23] Additional pathogenetic mechanisms currently under investigation include apoptosis, iron metabolism interference, and calcium dysregulation. 24,25 Pathology.…”