Human Heart Cytosolic Reductases and Anthracycline Cardiotoxicity

Anthracyclines are a class of antitumor drugs widely used for the treatment of a variety of malignancy, including leukemias, lymphomas, sarcomas, and carcinomas. Different mechanisms have been proposed for anthracycline antitumor effects including freeradical generation, DNA intercalation/binding, activation of signaling pathways, inhibition of topoisomerase II and apoptosis. A life‐threatening form of cardiomyopathy hampers the clinical use of anthracyclines. According to the prevailing hypothesis, anthracyclines injure the heart by generating damaging free radicals through iron‐catalyzed redox cycling. Although the “iron and freeradical hypothesis” can explain some aspects of anthracycline acute toxicity, it is nonetheless disappointing when referred to chronic cardiomyopathy. An alternative hypothesis implicates C‐13 alcohol metabolites of anthracyclines as mediators of myocardial contractile dysfunction (“metabolite hypothesis”). Hydroxy metabolites are formed upon two‐electron reduction of the C‐13 carbonyl group in the side chain of anthracyclines by cytosolic NADPH‐dependent reductases. Anthracycline alcohol metabolites can affect myocardial energy metabolism, ionic gradients, and Ca 2+ movements, ultimately impairing cardiac contraction and relaxation. In addition, alcohol metabolites can impair cardiac intracellular iron handling and homeostasis, by delocalizing iron from the [4Fe‐4S] cluster of cytoplasmic aconitase. Chronic cardiotoxicity induced by C‐13 alcohol metabolite might be primed by oxidative stress generated by anthracycline redox cycling (“unifying hypothesis”). Putative cardioprotective strategies should be aimed at decreasing C‐13 alcohol metabolite production by means of efficient inhibitors of anthracycline reductases, as short‐chain coenzyme Q analogs and chalcones that compete with anthracyclines for the enzyme active site, or by developing novel anthracyclines less susceptible to reductive metabolism.