Abstract 16765: Cardiotoxic Effects of Doxorubicin are Alleviated through Reduction in Mitochondiral Iron
Background: Doxorubicin (DOX) is an effective anticancer drug with cardiotoxic side effects. The mechanism for its cardiotoxicity has been hypothesized to occur through reactive oxygen species (ROS) production and possibly cellular iron accumulation. We had previously shown that mitochondrial ATP-biding cassette protein-B8 (ABCB8) plays a role in mitochondrial iron homeostasis and export, and its genetic deletion leads to cardiomyopathy with mitochondrial iron accumulation. We hypothesized that a reduction in mitochondrial iron levels through ABCB8 overexpression or by iron chelators would attenuate the cardiotoxic effects of DOX.
Results: DOX treatment of neonatal rat cardiomyocytes (NRCM) resulted in preferential accumulation of iron inside the mitochondria, while ABCB8 overexpression and reduction in mitochondrial iron in NRCM exerted protective effects against DOX. To confirm the in vitro data, we generated cardiac-specific ABCB8 transgenic (TG) mice. Treatment with multiple intraperitoneal injections of DOX resulted in a significant decrease in cardiac systolic function as well as disruption of mitochondrial morphology in non-transgenic (NTG) mice, while ABCB8 TG mice displayed preserved cardiac function and mitochondrial morphology. Tissue lipid peroxidation (a marker of cellular oxidative stress) was increased in NTG mice compared to ABCB8 TG, while cardiac mitochondrial DNA content and mRNA levels of key regulators of mitochondrial biogenesis were decreased. Dexrazoxane, a drug that attenuates DOX-induced cardiotoxicity, decreases mitochondrial iron levels and reverses DOX-induced cardiac damage in wild type mice. However, a potent but mitochondria-impermeable chelator deferoxamine offered no protection. Finally, hearts from patients with DOX-induced cardiomyopathy displayed significantly higher mitochondrial iron levels.
Conclusions: These results suggest that the cardiotoxic effects of DOX develop from mitochondrial iron accumulation and that reducing mitochondrial iron levels protects against DOX-induced cardiomyopathy.
- © 2012 by American Heart Association, Inc.