Pathophysiology of anthracycline cardiotoxicity Donato Mele a , Carlo G. Tocchetti b , Pasquale Pagliaro c , Rosalinda Madonna d , Giuseppina Novo e , Alessia Pepe f , Concetta Zito g , Nicola Maurea h and Paolo Spallarossa i Anthracyclines (ANTs) are powerful drugs that have reduced the mortality of cancer patients. However, their use is limited by the development of cardiotoxicity (CTX), which is dose dependent and may lead to left ventricular dysfunction and heart failure. Although various strategies have been suggested to reduce the negative effects of ANTs, CTX is still an important unresolved clinical issue. This may be due at least partly to the incomplete characterization of the molecular and cellular mechanisms of ANT-induced CTX. In addition, although various forms of cardiac damage have been demonstrated with the use of these drugs in experimental studies, it is not yet clear how these translate to the clinical setting. Appropriate characterization of potential candidates for ANT-based therapies is essential to decide whether to administer these drugs. Hopefully, new information from genetic profiling will help to identify patients who are at high risk of developing CTX. J Cardiovasc Med 2016, 17 (suppl 1):e3–e11 Keywords: anthracyclines, cancer, cardiotoxicity a Cardiology Unit, University Hospital of Ferrara, b Department of Translational Medical Sciences, Division of Internal Medicine, Federico II University, Naples, c Department of Clinical and Biological Sciences, University of Turin, Orbassano, d Cardiology, Center of Excellence on Aging, ‘G. d’Annunzio’ University, Chieti, e Chair and Division of Cardiology, University of Palermo, Palermo, f U.O.C. Magnetic Resonance Imaging, Fondazione G. Monasterio C.N.R., Pisa, g U.O.C. Cardiology Intensive Unit, A.O.U. Policlinico ‘G. Martino’, University of Messina, Messina, h Division of Cardiology, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘‘Fondazione Giovanni Pascale’’ –IRCCS, Naples, Italy and i Clinic of Cardiovascular Diseases, IRCCS San Martino IST, Genoa, Italy Correspondence to Donato Mele, MD, Cardiology Unit, University Hospital of Ferrara, Ferrara, Italy Tel: +39 532 239058; fax: +39 532 239048; e-mail: donatomele@libero.it Received 27 January 2016 Introduction Anthracyclines (ANTs) are widely used and effective chemotherapeutic agents. They are currently utilized for the treatment of many malignancies including lym- phomas, leukemias, and sarcomas, and for both early and advanced breast cancer. Unfortunately, these drugs also induce cardiotoxic effects, which have been recog- nized since the 1960s. 1 ANT-related cardiotoxicity (CTX) may lead to the development of cardiomyopathy (CMP) and heart failure, 2 which limits the administration of the drugs, and consequently limits the treatment of malignant disease. Several efforts have been made to understand the mech- anisms underlying ANT-related CTX, to generate mol- ecules to decrease the CTX, to set up strategies to reduce the development of cardiac dysfunction and for the early recognition of myocardial damage due to CTX. However, CTX remains a relevant problem for all of the ANTs. General characteristics of anthracyclines The ANTs (or anthracycline antibiotics) are a class of drugs composed of an aglycone and a sugar. 3 The agly- cone is a tetracyclic ring structure containing an anthra- quinone chromophore and a short side-chain with a carbonyl group at C-13. The sugar, called daunosamine, is attached by a glycosidic bond to C-7 of the tetracyclic ring (Fig. 1). Daunorubicin, the first ANT compound to be charac- terized, was isolated from Streptomyces peucetius, a soil bacterium. Doxorubicin (also known as Adriamy- cin) is a hydroxyl derivative of daunorubicin. Various chemical modifications have been introduced in these two molecules to obtain new ANTs. Idarubicin is a semisynthetic derivative of daunorubicin, charac- terized by the absence of a methoxy group at C-4 in ring D of the tetracyclic structure (Fig. 2); this gives the compound a high lipophilicity, which results in an increased rate of cellular uptake compared with other ANTs. Epirubicin is a semisyn- thetic derivative of doxorubicin obtained by an axial-to-equatorial epimerization of the hydroxyl group at C-4 in daunosamine (Fig. 2). Valrubicin is a semisynthetic analog, and mitoxantrone is a synthetic analog, of doxorubicin. Notably, mitoxantrone is a substituted aglyconic anthraquinone, with no dauno- samine (Fig. 2). In an effort to reduce CTX, specific formulations of ANTs have been generated with the encapsulation of these drugs by nonpegylated or pegylated liposomes (in the latter case with an additional polyethylene glycol layer). A lower proportion of ANTs administered in the liposomal form (especially in the pegylated liposomes) is delivered to the cardiomyocytes compared with the nonliposomal form. Supplement submission 1558-2027 ß 2016 Italian Federation of Cardiology. All rights reserved. DOI:10.2459/JCM.0000000000000378 © 2016 Italian Federation of Cardiology. All rights reserved.