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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 617-630 |
| Number of pages | 14 |
| Journal | Journal of Clinical Investigation |
| Volume | 124 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 3 2014 |
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ASJC Scopus subject areas
- Medicine(all)
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Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. / Ichikawa, Yoshihiko; Ghanefar, Mohsen; Bayeva, Marina; Wu, Rongxue; Khechaduri, Arineh; Naga Prasad, Sathyamangla V.; Mutharasan, R Kannan; Jairaj Naik, Tejaswitha; Ardehali, Hossein.
In: Journal of Clinical Investigation, Vol. 124, No. 2, 03.02.2014, p. 617-630.Research output: Contribution to journal › Article
TY - JOUR
T1 - Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation
AU - Ichikawa, Yoshihiko
AU - Ghanefar, Mohsen
AU - Bayeva, Marina
AU - Wu, Rongxue
AU - Khechaduri, Arineh
AU - Naga Prasad, Sathyamangla V.
AU - Mutharasan, R Kannan
AU - Jairaj Naik, Tejaswitha
AU - Ardehali, Hossein
PY - 2014/2/3
Y1 - 2014/2/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84893845965&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84893845965&partnerID=8YFLogxK
U2 - 10.1172/JCI72931
DO - 10.1172/JCI72931
M3 - Article
C2 - 24382354
AN - SCOPUS:84893845965
VL - 124
SP - 617
EP - 630
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 2
ER -