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Prepublished online as a Blood First Edition Paper on June 12, 2003; DOI 10.1182/blood-2003-03-0869. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-03-0869v1 102/7/2574    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Miranda, C. J. Articles by Santos, M. M. Search for Related Content PubMed PubMed Citation Articles by Miranda, C. J. Articles by Santos, M. M. Related Collections Neoplasia Red Cells Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 October 2003, Vol. 102, No. 7, pp. 2574-2580 NEOPLASIA Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin Carlos J. Miranda, Hortence Makui, Ricardo J. Soares, Marc Bilodeau, Jeannie Mui, Hajatollah Vali, Richard Bertrand, Nancy C. Andrews, and Manuela M. Santos From the Hôpital Notre-Dame and the Hôpital Saint-Luc, Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada; Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada; UnIGENe, Instituto de Biologia Molecular e Celular, Porto, Portugal; and Howard Hughes Medical Institute, Department of Pediatrics, Harvard Medical School, Children's Hospital, Boston, MA. The clinical use of doxorubicin (DOX), an anthracycline chemotherapeutic agent, is limited by cardiotoxicity. The possible involvement of iron in DOX-induced cardiotoxicity became evident from studies in which iron chelators were shown to be cardioprotective. Iron overload is found in hereditary hemochromatosis, a genetic disorder prevalent in individuals of European descent. We hypothesized that Hfe deficiency may increase susceptibility to DOX-induced toxicity. Acute cardiotoxicity and iron changes were studied after treatment with DOX in Hfe knock-out (Hfe-/-) mice and wild-type mice. DOX-induced iron metabolism changes were intensified in Hfe-/- mice, which accumulated significantly more iron in the heart, liver, and pancreas, but less in the spleen compared with wild-type mice. In addition, Hfe-deficient mice exhibited significantly greater sensitivity to DOX-induced elevations in serum creatine kinase and aspartate aminotransferase. Increased mortality after chronic DOX treatment was observed in Hfe-/- mice and Hfe+/-mice compared with wild-type mice. DOX-treated Hfe-/- mice had a higher degree of mitochondrial damage and iron deposits in the heart than did wild-type mice. These data demonstrate that Hfe deficiency in mice increases susceptibility to DOX-induced cardiotoxicity and suggest that genetic mutations related to defects in iron metabolism may contribute to its cardiotoxicity in humans. (Blood. 2003;102:2574-2580) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. V. Barry, S. E. Lipshultz, and S. E. Sallan Anthracycline-induced Cardiotoxicity: Natural History, Risk Factors, and Prevention ASCO Educational Book, January 1, 2008; 2008(1): 448 - 453. [Abstract] [Full Text] [PDF] G. S. Panjrath, V. Patel, C. I. Valdiviezo, N. Narula, J. Narula, and D. Jain Potentiation of Doxorubicin Cardiotoxicity by Iron Loading in a Rodent Model J. Am. Coll. Cardiol., June 26, 2007; 49(25): 2457 - 2464. [Abstract] [Full Text] [PDF] X. Xu, H. L. Persson, and D. R. Richardson Molecular Pharmacology of the Interaction of Anthracyclines with Iron Mol. Pharmacol., August 1, 2005; 68(2): 261 - 271. [Abstract] [Full Text] [PDF] L Valenti, D Conte, A Piperno, P Dongiovanni, A L Fracanzani, M Fraquelli, A Vergani, C Gianni, L Carmagnola, and S Fargion The mitochondrial superoxide dismutase A16V polymorphism in the cardiomyopathy associated with hereditary haemochromatosis J. Med. Genet., December 1, 2004; 41(12): 946 - 950. [Abstract] [Full Text] [PDF]

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