doxorubicin-induced cardiotoxicity

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Since the discovery of doxorubicin (DOX) as a potential anticancer agent, different types of human cancers have been successfully treated. Objective: To review the state-of-art regarding the mechanisms of DOX-induced cardiotoxicity, especially focusing on mitochondria, and to describe strategies aimed at preventing such toxicity. The present review can help on the development of new strategies to counteract DOX toxicity focusing on the mitochondria as the target.

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    ISSN (electronic): 1916-6958

    2010; Volume 1; Number 2 (May-August): 39-53

    Editor

    Alejandro A. NAVA-OCAMPO, Toronto, Canada

    Editorial Board

    Mara ALONSO SPILSBURY Mxico DF, Mxico S. Satheesh ANAND Newark, USA Anglica M. BELLO Toronto, Canada Nicholas BODOR Gainesville, USA Roberto CANAPARO Torino, Italy Antonio CAPPUCCIO Roma, Italy Francisca Cla F. DE SOUSA Fortaleza, Brazil Dermot COX Dublin, Ireland Jerome DEL CASTILLO Montreal, Canada Miguel GONZLEZ LOZANO Mxico DF, Mxico

    Bhushan KAPUR Toronto, Canada Ram Chandra GUPTA Lucknow, India Rade INJAC Ljubljana, Slovenia Tarun JHA Kolkata, India Anisur R KHUDA-BUKHSH Kalyani, India Hyung Sik KIM Seoul, Korea Carlos R. V. KIFFER So Paulo, Brazil Ricard MARCOS Bellaterra, Spain Daniel MOTA ROJAS Mxico DF, Mxico Ruta MUCENIECE Riga, Latvia

    Nekka FAHIMA Montreal, Canada Kayode OGUNGBENRO Manchester, United Kingdom Paulo J. OLIVEIRA Coimbra, Portugal Sadi S. OZDEM Antalya, Turkey Ramiro RAMREZ NECOECHEA, Mxico DF, Mxico Mahendra Pratap SINGH, Lucknow, India Diana STEMPAK, Toronto, Canada Yoo-Hun SUH, Seoul, Korea Bourama TONI, Petersburg, USA E. Yadira VELZQUEZ ARMENTA, Toronto, Canada Liu XINMIN, Beijin, PR China Yin-Di ZHANG, Nanjing, PR China

    Consulting Technical Editor Matt CULHAM, Toronto, Canada

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    The Journal of Theoretical & Experimental Pharmacology is an open-access journal published electronically by PremiumReasons, located in Toronto, Ontario, Canada. Published manuscripts are peer-reviewed by scientists with proven reputation in their field. Substantial efforts are made to publish only those manuscripts that properly justified the aim of the study, used appropriate methods, adequately summarized the results, and provided a sufficient analysis of the literature in comparison to the findings of the study. However, manuscripts published by the journal represent the sole opinion of the authors. PremiumReasons, the Editor or the Editorial Board of the Journal of Theoretical & Experimental Pharmacology cannot assume any responsibility for the procedures, methods, chemical compounds, drugs, doses, statements of facts, or opinions expressed in the manuscripts, or any involuntary or intentional failure to disclose conflicts of interests. In addition, selected manuscripts may discuss investigational drugs or unlabeled uses of approved medications, or use of devices that had not been yet approved by regulatory agencies. All rights are reserved, and other than private or academic use, no part of the publication may be reproduced, stored, transmitted, or disseminated in any form or by any means for commercial purposes without prior written permission from the publisher. For a complete guide of our publications, publishing programs, permissions, or any other information, you are invited to visit our website at www.premiumreasons.com or to contact us by e-mail to: services@premiumreasons.com. Finally, in order to promote and encourage environmental awareness, PremiumReasons invites the readers of the Journal of Theoretical & Experimental Pharmacology to use the electronic version of the manuscripts rather than printing hard copies of the documents.

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    ISSN 1916-6958

    2010; Volume 1 (Number 2): Pages 39-53

    REVIEW ARTICLE

    Pharmacological strategies to counteract doxorubicin-induced cardiotoxicity: the role of mitochondria

    Gonalo C. PEREIRA and Paulo J. OLIVEIRA*

    Center for Neurosciences and Cell Biology, Department of Zoology, University of Coimbra, Portugal

    *Corresponding author: pauloliv@ci.uc.pt

    ABSTRACT Since the discovery of doxorubicin (DOX) as a potential anticancer agent, different types of human cancers have been successfully treated. However, the use of the drug leads to an irreversible and dose-dependent cumulative cardiotoxicity thus restraining the treatment efficacy. Previous studies pointed out mitochondrial dysfunction as the main mechanism for drug cardiotoxicity, although the story still remains incomplete. Several approaches have been proposed in order to prevent DOX selective cardiotox-icity, some of which specifically target mitochondria. The present review performs a brief overview of the mitochon-drial targets of DOX toxicity and the pharmacological strategies designed to decrease it, with a special focus on agents that act on mitochondria. This review is thus di-vided in to three main sections: a) the effects of DOX on mitochondrial physiology and bioenergetics as well as the consequences at the myocyte level; b) non-pharmacological strategies already demonstrated to coun-teract DOX-induced cardiotoxicity and, c) damage-preventing approaches involving mitochondria and their mechanism. Our objective was to review the state-of-art regarding the mechanisms of DOX-induced cardiotoxicity, especially focusing on mitochondria, and to describe strategies aimed at preventing such toxicity. The present review can help on the development of new strategies to counteract DOX toxicity focusing on the mitochondria as the target.

    Key words Doxorubicin; Heart; Mechanism of action; Mitochondria; Prevention; Toxic potential

    RSUM La dcouverte de la doxorubicine (DOX) comme agent anticancreux potentiel a permis de traiter avec succs diffrents types de cancers humains. Lutilisation rpte de cette mdication cause cependant une cardiotoxicit dose-dpendante et irrversible qui limite son usage th-rapeutique. Des tudes prcdentes ont identifi une dysfonction mitochondriale comme mcanisme principal de cette cardiotoxicit, mais ce nest quune partie de lhistoire. Diffrentes approches ont t proposes pour prvenir cette toxicit slective, certaines visant spcifi-quement les mitochondries. Cet article effectue une brve revue des cibles mitochondriales de toxicit de la DOX et des stratgies pharmacologiques conues pour la rduire, avec un accent sur les molcules agissant sur les mito-chondries. Cette revue est divise en trois sections: a) les effets de la DOX sur la physiologie et la bionergtique mitochondriale, et leurs consquences au niveau des myo-cytes; b) les stratgies non-pharmacologiques contrecar-rant la cardiotoxicit induite, et c) les approches prven-tives impliquant les mitochondries et leur mcanisme. Lobjectif tait la revue du state-of-art concernant les mcanismes de la cardiotoxicit induite par la DOX avec un accent sur les mitochondries et la description des stra-tgies visant prvenir cette toxicit. Cette revue devrait aider dvelopper de nouvelles stratgies pour contrecar-rer cette toxicit en mettant laccent sur les mitochondries.

    Mots cls Doxorubicine; Cur; Mcanisme daction; Mitochondries; Prvention; Potentiel toxique

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    RESUMEN Desde el descubrimiento de la doxorubicina (DOX) como un posible compuesto anticancergeno, diferentes tipos de cncer han sido tratados exitosamente. Sin embargo, el uso de este frmaco puede conducir a una cardiotoxicidad irreversible, dosis-dependiente y acumulativa, limitando su eficacia teraputica. Estudios anteriores propusieron a la disfuncin mitocondrial como el principal mecanismo de cardiotoxicidad; sin embargo, an son necesarios ms estudios. Se han propuesto varias alternativas para preve-nir la cardiotoxicidad selectiva de DOX, algunas dirigidas especficamente a la mitocondria. Este artculo revisa en forma breve la toxicidad mitocondrial inducida por DOX y propone estrategias farmacolgicas orientadas a dismi-nuirla, en especial con agentes que actan a nivel mito-condrial. Esta revisin se divide en tres secciones princi-pales: a) los efectos de DOX en la fisiologa mitocondrial y su bioenergtica as como las consecuencias a nivel del miocito; b) la descripcin de estrategias no farmacolgi-cas para contrarrestar la cardiotoxicidad de la DOX, y c) acciones preventivas del dao que involucran a la mito-condria en su mecanismo de accin. Nuestro objetivo fue revisar el conocimiento actual de los mecanismos de car-diotoxicidad inducida por DOX y su prevencin, enfocados en forma particular en la mitocondria. Esta revisin puede ayudar en el desarrollo de nuevas estrategias para contra-rrestar la toxicidad mitocondrial inducida por DOX.

    Palabras clave Doxoribicina; Corazn; Mecanismo de accin; Mitocondria; Prevencin; Toxicidad potencial

    INTRODUCTION Doxorubicin (DOX, Adriamycin) (Figure 1) is an anth-racycline antibiotic discovered and isolated from Streptomyces peucetius in the early 1960s [1]. Pre-sently, it is one of the most important antineoplastic agents used against a broad spectrum of cancer types, such as lymphomas, leukemias and solid tu-mors. The anticancer activity of DOX is explained by its ability to bind and/or intercalate the DNA double strand causing a stereochemical disorder and thus inhibiting the synthesis of DNA, RNA, and proteins, eventually leading to cell death [2].

    Despite the potent antineoplastic activity of DOX, its clinical use is restrained by an irreversible and dose-dependent cumulative cardiotoxicity. Acute effects may arise immediately after treatment and are clini-cally characterized by arrhythmias, hypotension, pericarditis, diastolic functional impairment (first) and systolic function alterations (later) [3].

    The reported effects are transient and disappear as soon as the patient discontinues the treatment. However, chronic effects, which are characterized by progressive left ventricular dysfunction, lead to irre-

    versible heart failure and are therefore more se

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