Hindawi Publishing Corporation Oxidative Medicine and Cellular Longevity Volume 2012, Article ID 619185, 7 pages doi:10.1155/2012/619185 Research Article Desferrioxamine Attenuates Doxorubicin-Induced Acute Cardiotoxicity through TFG-β/Smad p53 Pathway in Rat Model Othman A. Al-Shabanah, Abdulaziz M. Aleisa, Mohamed M. Hafez, Salim S. Al-Rejaie, Abdulaziz A. Al-Yahya, Saleh A. Bakheet, Mohamed M. Al-Harbi, and Mohamed M. Sayed-Ahmed Department of Pharmacology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia Correspondence should be addressed to Othman A. Al-Shabanah, shabanah@ksu.edu.sa Received 1 November 2011; Revised 14 February 2012; Accepted 14 February 2012 Academic Editor: Ersin Fadillioglu Copyright © 2012 Othman A. Al-Shabanah et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Interaction of doxorubicin DOX with iron and the consequent generation of reactive oxygen species (ROS) is a major player in DOX-induced cardiomyopathy. Accordingly, this study has been initiated to investigate the preventive effect of the iron chelator, desferrioxamine (DFX), against DOX-induced acute cardiotoxicity in rats. Male Wistar albino rats were divided into four groups and were injected intraperitoneally (I.P.) with normal saline, a single dose of DOX (15 mg/kg), a single dose of DFX (250 mg/kg) and a combined treatment with DFX (250 mg/kg) 30 min prior to a single dose of DOX, (15 mg/kg). A single dose of DOX signifi- cantly increased mRNA expression of TGF-β, Smad2, Smad4, CDKN2A and p53 and significantly decreased Samd7 and Mdm2 mRNA expression levels. Administration of DFX prior to DOX resulted in a complete reversal of DOX-induced alteration in cardiac enzymes and gene expression to normal levels. Data from this study suggest that (1) DOX induces its acute cardiotoxicity secondary to increasing genes expression of TGF-β/Smad pathway. (2) DOX increases apoptosis through upregulation of CDKN2A and p53 and downregulation of Mdm2 gene expression. (3) The preventive effect of DFX against DOX-induced cardiotoxicity is mediated via the TGF-β1/Smad pathway. 1. Introduction Doxorubicin (DOX) is a potent anthracycline chemothera- peutic agent used to treat a wide variety of human malignan- cies [1]. However, its clinical use is limited by a significant DOX-induced cardiotoxicity which can progress to heart failure [2–4]. The mechanism by which DOX-induced cardi- otoxicity has not been fully understood yet; however, several mechanisms have been proposed. The mechanisms include increased oxidative stress [5], alteration of myocardial ener- gy metabolism [6], altered molecular signaling [7], pro- grammed cell death [4] and iron-dependent oxidative dam- age to biological macromolecules [8]. One of the mechanism explained DOX-induced cardiotoxicity is the formation of free radical-mediated myocytes damage. Iron (Fe) is a crit- ical biogenic element necessary as oxidation-reduction catal- ysis and bioenergetics in all living cells. However, this- metal plays a crucial role in the formation of reactive oxygen species (ROS) [9]. There are two main pathways by which Fe may promote ROS formation in DOX-exposed cells, one of them is the formation of DOX-Fe complexes. The iron chelator, desferrioxamine (DFX), is used in the treatment of iron overload status and prevents interaction of DOX with iron, thus preventing DOX-induced damage in cultured heart cells [10]. ROS have been proposed as contributing to the deterioration of cardiac function in patients with both is- chemic and nonischemic cardiomyopathies [11]. Transforming growth factor-β1 (TGF-β1) is formed mainly by cardiac myofibroblast and fibroblast and is con- tributed to cardiac fibrosis development, hypertrophy, and apoptosis [12]. Previous report showed that TGF-β1 gene expression is increased in the left ventricular myocardium of patients with idiopathic hypertrophic cardiomyopathy or di- lated cardiomyopathy and in animals after myocardial infarc- tion [13]. ROS have been shown to play important roles in the development of apoptosis under various pathological