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 free-radical 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 free-radical 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 Ca2+ 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.
Mordente
A
A
Institute of Biological Chemistry, Catholic University School of Medicine, Rome, Italy. a.mordente@uniserv.ccr.rm.cnr.it
Meucci
E
E
Martorana
G E
GE
Giardina
B
B
Minotti
G
G
D018943:Anthracyclines / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D003600:Cytosol / Q000201:enzymology*; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D005609:Free Radicals / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006801:Humans; D007501:Iron / Q000378:metabolism; D008954:Models, Biological; D009206:Myocardium / Q000201:enzymology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D018943:Anthracyclines; D005609:Free Radicals; D004317:Doxorubicin; D007501:Iron; D010088:Oxidoreductases