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 a cytoprotective effect on the heart. To investigate the cardioprotective efficacy of HNG alone or in combination with DRZ against Dox-induced
cardiotoxicity, 80 adult male mice were randomly divided into 8 groups to receive the following treatments via
intraperitoneal injection: saline dailym HNG (5 mg/kg) daily, DRZ (60 mg/kg) weekly, Dox (3 mg/kg) weekly, DRZ + HNG, Dox + HNG, Dox + DRZ, and Dox + HNG + DRZ. Echocardiograms were performed before and at 4, 8, and 9.5 wk after the beginning of treatment. All mice were euthanized
at 10 wk. 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 the 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. NEW & NOTEWORTHY
Doxorubicin (Dox) is commonly used for treating a wide range of human
cancers. However, cumulative dosage-dependent carditoxicity often limits its clinical applications. We demonstrated in this study that treating young adult male mice with synthetic
humanin analog enhanced the cardiac protective effect of
dexrazoxane against chemotherapeutic agent Dox-induced cardiac dysfunction. Thus,
humanin analog can potentially serve as an adjuvant to
dexrazoxane in more effectively preventing Dox-induced cardiac dysfunction and
cardiomyopathy.