title: Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation.
abstract: Doxorubicin is an effective anticancer drug with known cardiotoxic side effects. It has been hypothesized that doxorubicin-dependent cardiotoxicity occurs through ROS production and possibly cellular iron accumulation. Here, we found that cardiotoxicity develops through the preferential accumulation of iron inside the mitochondria following doxorubicin treatment. In isolated cardiomyocytes, doxorubicin became concentrated in the mitochondria and increased both mitochondrial iron and cellular ROS levels. Overexpression of ABCB8, a mitochondrial protein that facilitates iron export, in vitro and in the hearts of transgenic mice decreased mitochondrial iron and cellular ROS and protected against doxorubicin-induced cardiomyopathy. Dexrazoxane, a drug that attenuates doxorubicin-induced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicin-induced cardiac damage. Finally, hearts from patients with doxorubicin-induced cardiomyopathy had markedly higher mitochondrial iron levels than hearts from patients with other types of cardiomyopathies or normal cardiac function. These results suggest that the cardiotoxic effects of doxorubicin develop from mitochondrial iron accumulation and that reducing mitochondrial iron levels protects against doxorubicin-induced cardiomyopathy.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Ichikawa
authors.forename: Mohsen
authors.initials: M
authors.lastname: Ghanefar
authors.forename: Marina
authors.initials: M
authors.lastname: Bayeva
authors.forename: Rongxue
authors.initials: R
authors.lastname: Wu
authors.forename: Arineh
authors.initials: A
authors.lastname: Khechaduri
authors.forename: Sathyamangla V
authors.initials: SV
authors.lastname: Naga Prasad
authors.forename: R Kannan
authors.initials: RK
authors.lastname: Mutharasan
authors.forename: Tejaswitha Jairaj
authors.initials: TJ
authors.lastname: Naik
authors.forename: Hossein
authors.initials: H
authors.lastname: Ardehali
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002316:Cardiotonic Agents / Q000737:chemistry; D003433:Crosses, Genetic; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003676:Deferoxamine / Q000737:chemistry; D064730:Dexrazoxane / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000009:adverse effects*; D004452:Echocardiography; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics; D006801:Humans; D007501:Iron / Q000378:metabolism*; D015227:Lipid Peroxidation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species; D059005:Topoisomerase II Inhibitors / Q000737:chemistry
chemical_list: C571883:ABCB8 protein, mouse; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D002316:Cardiotonic Agents; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D059005:Topoisomerase II Inhibitors; D064730:Dexrazoxane; D004317:Doxorubicin; D007501:Iron; D004250:DNA Topoisomerases, Type II; D003676:Deferoxamine