Dataset Information

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.

SUBMITTER: Ichikawa Y

PROVIDER: S-EPMC3904631 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation.

Ichikawa Yoshihiko Y Ghanefar Mohsen M Bayeva Marina M Wu Rongxue R Khechaduri Arineh A Naga Prasad Sathyamangla V SV Mutharasan R Kannan RK Naik Tejaswitha Jairaj TJ Ardehali Hossein H

The Journal of clinical investigation 20140102 2

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 ...[more]

PMID: 24382354

Similar Datasets

Project description:In several cancers, the efflux and resistance against doxorubicin (DOX), an effective anticancer drug, are associated with cellular iron deficiency and overexpression of the mitochondrial exporter ABCB8. Conversely, decreased ABCB8 expression and disrupted iron homeostasis in the heart have been implicated in DOX-associated cardiotoxicity. While studies have demonstrated that altered iron status can modulate the susceptibility to DOX cardiotoxicity, the exact molecular mechanisms have not been clearly understood. Here, we hypothesized that iron stores influence cardiac ABCB8 expression and consequently cardiac retention and toxicity of DOX. First, we found that ABCB8 deficiency in cardiomyocytes decreased DOX efflux, increased DOX-induced toxicity, and decreased cell viability. Conversely, intracellular DOX retention and toxicity were ameliorated by ABCB8 overexpression. To determine if altered cardiac iron status modifies ABCB8 expression, we treated cardiomyocytes with high iron or iron chelators. Western blot and qPCR analyses revealed that ABCB8 levels were decreased in iron overload and increased in iron deficiency. Subsequently, DOX retention and toxicity were increased in cardiomyocytes with iron overload, whereas iron deficiency ameliorated these effects. Next, we validated our results using a mouse model of hereditary hemochromatosis (HH), a genetic iron overload disorder. HH mice exhibited decreased ABCB8 expression and increased DOX retention and toxicity. These changes were abolished by the treatment of HH mice with a low-iron diet. Finally, cardiac-specific overexpression of ABCB8 in HH mice prevented cardiac DOX accumulation and abrogated DOX-induced cardiotoxicity without altering iron overload in the heart. Together, our results demonstrate that ABCB8 mediates DOX efflux and that iron regulates DOX retention and toxicity by altering cardiac ABCB8 expression. Our study identifies a novel role of iron in DOX-induced cardiotoxicity and suggests potential therapeutic intervention for DOX and anthracycline-based cancer pharmacology.

Dataset Information

Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation.

Publications

Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets