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J. Biol. Chem., Vol. 281, Issue 16, 10990-11001, April 21, 2006

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Defective One- or Two-electron Reduction of the Anticancer Anthracycline Epirubicin in Human Heart

RELATIVE IMPORTANCE OF VESICULAR SEQUESTRATION AND IMPAIRED EFFICIENCY OF ELECTRON ADDITION^*

Emanuela Salvatorelli¹, Simone Guarnieri¹, Pierantonio Menna¹, Giovanni Liberi, Antonio M. Calafiore^¶2, Maria A. Mariggiò, Alvaro Mordente^||, Luca Gianni^**, and Giorgio Minotti³

From the Center of Excellence on Aging and Department of Cardiac Surgery, G. d'Annunzio University School of Medicine, 66013 Chieti, ^¶Unit of Cardiac Surgery, European Hospital, 00148 Rome, ^||Institute of Biochemistry and Clinical Biochemistry, Catholic University School of Medicine, 00168 Rome, and ^**Unit of Medical Oncology, Istituto Nazionale Tumori, 20133 Milan, Italy

One-electron quinone reduction and two-electron carbonyl reduction convert the anticancer anthracycline doxorubicin to reactive oxygen species (ROS) or a secondary alcohol metabolite that contributes to inducing a severe form of cardiotoxicity. The closely related analogue epirubicin induces less cardiotoxicity, but the determinants of its different behavior have not been elucidated. We developed a translational model of the human heart and characterized whether epirubicin exhibited a defective conversion to ROS and secondary alcohol metabolites. Small myocardial samples from cardiac surgery patients were reconstituted in plasma that contained clinically relevant concentrations of doxorubicin or epirubicin. In this model only doxorubicin formed ROS, as detected by fluorescent probes or aconitase inactivation. Experiments with cell-free systems and confocal laser scanning microscopy studies of H9c2 cardiomyocytes suggested that epirubicin could not form ROS because of its protonation-dependent sequestration in cytoplasmic acidic organelles and the consequent limited localization to mitochondrial one-electron quinone reductases. Accordingly, blocking the protonation-sequestration mechanism with the vacuolar H⁺-ATPase inhibitor bafilomycin A1 relocalized epirubicin to mitochondria and increased its conversion to ROS in human myocardial samples. Epirubicin also formed 60% less alcohol metabolites than doxorubicin, but this was caused primarily by its higher K_m and lower V_max values for two-electron carbonyl reduction by aldo/keto-reductases of human cardiac cytosol. Thus, vesicular sequestration and impaired efficiency of electron addition have separate roles in determining a defective bioactivation of epirubicin to ROS or secondary alcohol metabolites in the human heart. These results uncover the molecular determinants of the reduced cardiotoxicity of epirubicin and serve mechanism-based guidelines to improving antitumor therapies.

Received for publication, July 29, 2005 , and in revised form, December 12, 2005.

^* This work was supported by Associazione Italiana Ricerca sul Cancro, Ministero dell' Universitá e Ricerca Scientifica e Tecnologica (MIUR), Cofin 2004, FIRB RBNE 014HJ3-002, and Center of Excellence on Aging at the University of Chieti. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² Present address: Department of Cardiac Surgery, University of Catania School of Medicine, 95124 Catania, Italy.

³ To whom correspondence should be addressed: G. d'Annunzio University School of Medicine, Ce.S.I., Rm. 412, Via dei Vestini, 66013 Chieti, Italy. Tel.: 39-0871-541391; Fax: 39-0871-541480, E-mail: gminotti{at}unich.it.

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