Humanin Analogue (HNG) Enhances the Protective Effect of Dexrazoxane against Doxorubicin-induced Cardiotoxicity

The chemotherapeutic effect of Doxorubicin (Dox) is limited by cumulative dose-dependent cardiotoxicity in cancer survivors. Dexrazoxane (DRZ) is approved to prevent Dox-induced cardiotoxicity. Humanin and its synthetic analog HNG have cytoprotective effect on the heart. To investigate the cardioprotective efficacy of HNG alone or in combination with DRZ against Dox-induced cardiotoxicity, eighty adult male mice were randomly divided into 8 groups to receive the following treatments via intraperitoneal injection: saline daily; HNG (5mg/kg) daily; DRZ (60mg/kg) weekly; Dox (3mg/kg) weekly; DRZ+HNG, Dox+HNG; Dox+DRZ and Dox+HNG+DRZ. Echocardiogram was performed before and at 4, 8 and 9.5 weeks after beginning of treatment. All mice were euthanized at 10 weeks. In the absence of Dox, HNG, DRZ or DRZ+HNG had no adverse effect on the heart. Dox treatment caused decreases in ejection fraction and cardiac mass, and increases in cardiomyocyte apoptosis and intracardiac fibrosis. HNG or DRZ alone blunted the Dox-induced decrease in left ventricle posterior wall thickness and modestly ameliorated Dox-induced decrease in ejection fraction. HNG+DRZ significantly ameliorated Dox-induced decreases in ejection function, cardiac fibrosis, and cardiac mass. Using a targeted analysis for the mitochondrial gene array and protein expression in heart tissues, we demonstrated that HNG+DRZ reversed DOX-induced altered transcripts that were biomarkers of cardiac damage and uncoupling protein 2. We conclude that HNG enhances the cardiac protective effect of DRZ against Dox-induced cardiotoxicity. HNG+DRZ protects mitochondria from Dox-induced cardiac damage and blunts the onset of cardiac dysfunction. Thus, HNG may be an adjuvant to DRZ in preventing Dox-induced cardiotoxicity.