Humanin analog enhances the protective effect of dexrazoxane against doxorubicin-induced cardiotoxicity

Abstract

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.

Sodium nitrate co-supplementation does not exacerbate low dose metronomic doxorubicin-induced cachexia in healthy mice

“…SN co-supplementation elicited a protective effect by preventing the induction of myocardial fibrosis. The increase in fibrotic tissue prevalence in the heart is a consistent hallmark of DOX-induced cardiotoxicity [52][53][54][55][56] , and our data demonstrate this precedes DOX-induced myocardial toxicity. Surprisingly, SN co-supplementation increased left ventricular wall thickness compared to both the VEH and DOX control group.…”

FNDC5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via activating AKT

“…To investigate the therapeutic effect of irisin, mice were subcutaneously infused with either saline or irisin (12 nmol/kg/ day) for 14 days from the 6th day before DOX injection via osmotic minipumps (Alzet model 2004, Alza Corp) as previously described [29,30]. In addition, mice were intraperitoneally injected with a weekly dose of 60 mg/kg DEX for two times, with the first injection at the 6th day before DOX injection, and the second one at the second day after DOX treatment [31].…”

“…All these mice were observed daily and the survival rate was calculated every week. To compare the effect of irisin and DEX in chronic model, mice with irisin protection were pretreated with irisin (12 nmol/kg/day) for 6 days and lasting for another 6 weeks, whereas mice with DEX administration were intraperitoneally injected with a weekly dose of 60 mg/kg DEX for seven times [29][30][31]. Considering the fact that long-term use of high-doses of DEX resulted in severe side effects, we then investigated whether combined use of DEX with irisin (6 nmol/kg/day) could decrease the usage of DEX.…”

Drug Development and the Use of Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Disease Modeling and Drug Toxicity Screening

“…Several drug families, mainly chemotherapeutics, while having a desired cytotoxic effect responsible for the anti-cancer efficacy, can cause apoptosis, necrosis or both [ 67 , 68 , 69 ]. For example, anthracyclines represented by doxorubicin cause cardiomyocyte loss by inducing apoptosis, demonstrated in cultured cardiomyocytes including iPSC-CMs and experimental animals such as mice and rats [ 62 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ]. Several groups showed that doxorubicin-induced apoptosis is mediated by the generation of reactive oxygen species (ROS) [ 75 , 76 , 83 , 84 ].…”