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Prepublished online as a Blood First Edition Paper on June 12, 2003; DOI 10.1182/blood-2003-03-0869.
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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)
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