Doxorubicin cardiotoxicity is associated with mitochondria-accumulating iron

Doxorubicin accumulates within the mitochondria of cardiomyocytes and this accumulation promotes mitochondrial production of reactive oxygen species (ROS) and the accumulation of iron, according to new research.

Doxorubicin is widely used as a component of chemotherapy regimens; however, the use of doxorubicin is associated with severe cardiotoxicity. It is unclear exactly how doxorubicin promotes cardiotoxicity, but it has been proposed that doxorubicin-associated cardiomyopathy develops as the result of reactive oxygen species (ROS) production and iron accumulation.

This study on the cardiotoxicity of doxorubicin was reported in the Journal of Clinical Investigation (2014; doi:10.1172/JCI72931) by Hossein Ardehali, MD, PhD, and colleagues at Northwestern University in Chicago, Illinois. In a mouse model of doxorubicin-associated cardiotoxicity, overexpression of a protein that enhances mitochondrial iron transport reduced mitochondrial iron, reduced ROS, and protected the animals from doxorubicin-induced cardiomyopathy.

Treatment of animals with dexrazoxane, which attenuates doxorubicin-induced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicin-induced cardiac damage. Though dexrazoxane is FDA-approved to treat cardiomyopathy induced by doxorubicin, it is rarely used in the clinic and is not recommended by the European Medicines Agency. The authors explained that these concerns exist because of the multiple side effects of dexrazoxane and because of concerns that it may reduce the antineoplastic efficacy of doxorubicin by inhibiting topoiserase-2-alpha. The authors suggest that understanding how dexrazoxane is cardioprotective is critical to develop new treatments for the toxicity of doxorubicin.

Furthermore, heart samples from patients undergoing doxorubicin therapy revealed higher levels of mitochondrial iron in patients with cardiomyopathies compared with patients without cardiac complications.

These data suggest that therapies that limit mitochondrial iron accumulation have the potential to limit doxorubicin-associated cardiotoxicity. The authors stated that “our findings strongly suggest the need for development of novel iron chelators that can effectively and preferentially reduce mitochondrial iron.” They found that reducing iron levels in the mitochondria was effective in reversing the cardiomyopathy induced by doxorubicin.

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