{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T16:57:56Z","timestamp":1773421076870,"version":"3.50.1"},"reference-count":45,"publisher":"American Society of Hematology","issue":"7","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2003,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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)<\/jats:p>","DOI":"10.1182\/blood-2003-03-0869","type":"journal-article","created":{"date-parts":[[2003,6,17]],"date-time":"2003-06-17T00:34:45Z","timestamp":1055810085000},"page":"2574-2580","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":148,"title":["Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin"],"prefix":"10.1182","volume":"102","author":[{"given":"Carlos J.","family":"Miranda","sequence":"first","affiliation":[{"name":"From the Ho\u0302pital Notre-Dame and the Ho\u0302pital Saint-Luc, Centre Hospitalier de l'Universite\u0301 de Montre\u0301al, Montre\u0301al, 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."}]},{"given":"Hortence","family":"Makui","sequence":"additional","affiliation":[{"name":"From the Ho\u0302pital Notre-Dame and the Ho\u0302pital Saint-Luc, Centre Hospitalier de l'Universite\u0301 de Montre\u0301al, Montre\u0301al, 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."}]},{"given":"Ricardo J.","family":"Soares","sequence":"additional","affiliation":[{"name":"From the Ho\u0302pital Notre-Dame and the Ho\u0302pital Saint-Luc, Centre Hospitalier de l'Universite\u0301 de Montre\u0301al, Montre\u0301al, 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."}]},{"given":"Marc","family":"Bilodeau","sequence":"additional","affiliation":[{"name":"From the Ho\u0302pital Notre-Dame and the Ho\u0302pital Saint-Luc, Centre Hospitalier de l'Universite\u0301 de Montre\u0301al, Montre\u0301al, 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."}]},{"given":"Jeannie","family":"Mui","sequence":"additional","affiliation":[{"name":"From the Ho\u0302pital Notre-Dame and the Ho\u0302pital Saint-Luc, Centre Hospitalier de l'Universite\u0301 de Montre\u0301al, Montre\u0301al, 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."}]},{"given":"Hajatollah","family":"Vali","sequence":"additional","affiliation":[{"name":"From the Ho\u0302pital Notre-Dame and the Ho\u0302pital Saint-Luc, Centre Hospitalier de l'Universite\u0301 de Montre\u0301al, Montre\u0301al, 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."}]},{"given":"Richard","family":"Bertrand","sequence":"additional","affiliation":[{"name":"From the Ho\u0302pital Notre-Dame and the Ho\u0302pital Saint-Luc, Centre Hospitalier de l'Universite\u0301 de Montre\u0301al, Montre\u0301al, 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."}]},{"given":"Nancy C.","family":"Andrews","sequence":"additional","affiliation":[{"name":"From the Ho\u0302pital Notre-Dame and the Ho\u0302pital Saint-Luc, Centre Hospitalier de l'Universite\u0301 de Montre\u0301al, Montre\u0301al, 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."}]},{"given":"Manuela M.","family":"Santos","sequence":"additional","affiliation":[{"name":"From the Ho\u0302pital Notre-Dame and the Ho\u0302pital Saint-Luc, Centre Hospitalier de l'Universite\u0301 de Montre\u0301al, Montre\u0301al, 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."}]}],"member":"234","reference":[{"key":"2020021223043106300_REF1","doi-asserted-by":"crossref","unstructured":"Jain D. 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