Abstract 14143: Curcumin Prevents Doxorubicin-Induced Cardiotoxicity Through Phosphorylated Bcl-2-Regulated Autophagy
Background: The Cardiac complications of Doxorubicin (DOX), a commonly used anticancer agent, are one of the issues awaiting solution in clinical medicine. A natural compound, curcumin (Cur), has shown potent anticancer efficacy in various types of cancers and is also known to protect against cardiac hypertrophy. However, its effect on cardiomyopathy caused by DOX treatment is unclear.
Method and Results: Male 8-week-old C57Bl mice(n=200) were randomized to 1 of 4 groups treated with phosphate-buffered saline (PBS), Cur, DOX, or a combination of DOX and Cur. DOX treatment caused severe cardiac dysfunction and markedly higher mortality than PBS treatment (Fig). The number of cardiac myocytes that underwent apoptosis was much higher and fibrotic areas were remarkable in DOX-treated mice than in PBS-treated mice. These cardiotoxic effects of DOX were significantly ameliorated in combination with Cur. Investigation with GFP-LC3 transgenic mice showed that Cur induced autophagy and reduced apoptosis in the heart. Studies with rat neonatal cardiac myocytes with DOX only or DOX and Cur treatment showed that Cur induced autophagy and suppressed DOX-induced apoptosis evaluated by TUNEL-positive cell count as well as cleavage of poly (ADP-ribose) polymerase 1 (PARP1). The PI3K inhibitor 3MA decreased the cardioprotective effect of Cur. Immunoblot analysis showed that Cur decreased the c-Jun N-terminal protein kinase (JNK) phosphorylation level, resulting in reduction of the phosphorylated Bcl-2 level, thereby stabilizing the Bcl-2-Beclin1 complex. The JNK inhibitor SP600125 abolished these effects. Finally, Cur induced autophagy and reduced DOX-induced cardiomyocyte apoptosis.
Conclusion: Cur protects cardiomyocyte from DOX-induced cardiotoxicity via stabilization of the JNK1-mediated Bcl-2-Beclin1 complex. The cardiac autophagy pathway will be a novel therapeutic target for DOX-induced cardiotoxicity.
- © 2012 by American Heart Association, Inc.