Abstract 14200: Iron Accumulation in the Mitochondria, but not Other Cellular Compartments, Mediates Cardiotoxic Effects of Doxorubicin

Background: Doxorubicin (DOX) is an effective anticancer drug with a side-effect of severe but mechanistically uncharacterized cardiotoxicity. Here, we report that toxic effects of DOX result from iron accumulation specifically inside the mitochondria, and that reduction in mitochondrial iron through facilitation of export or pharmacologic chelation protects the heart against DOX damage. Results: DOX treatment of neonatal rat cardiomyocytes (NRCM) and wild-type (WT) mice significantly increased mitochondrial iron levels, while nuclear and cytosolic iron content remained unchanged. Moreover, mitochondrial, but not cytosolic, iron levels were significantly elevated in the hearts of human patients with DOX cardiomyopathy compared to non-myopathic hearts or hearts with other causes of cardiomyopathy. To test if mitochondrial iron accumulation is the cause for DOX cardiotoxicity, we took genetic and pharmacologic approaches. Reduction in mitochondrial iron levels through genetic overexpression of ATP-binding cassette B8 (ABCB8), a protein that facilitates mitochondrial iron export, was protective against DOX toxicity in vitro and in vivo. Importantly, non-transgenic (NTG) mice displayed significant decrease in cardiac systolic function, disruption of mitochondrial morphology, increased tissue lipid peroxidation (a marker of oxidative stress), and higher mortality rates after DOX treatment, while these parameters were preserved in DOX-treated ABCB8 TG littermates. For the pharmacologic approach, we showed that deferoxamine (DFO), a strong iron chelator, reduced nuclear and cytosolic, but not mitochondrial iron levels, while dexrazoxane (DXZ), the only FDA approved drug for DOX-mediated cardiotoxicity that has mild iron chelator properties, preferentially reduced mitochondrial iron with little to no effect on iron in other cellular compartments. Consistently, we showed that DFO conferred no protection against DOX toxicity in WT mice, while DXZ significantly attenuated DOX-induced damage to the heart. Conclusions: We establish that cardiotoxic effects of DOX are mediated by preferential iron accumulation in the mitochondria, and that targeted reduction in mitochondrial iron protects against DOX-induced cardiomyopathy.