Reducing doxorubicin cardiotoxicity in rats with mammary tumors by dantrolene.

Abstract

e12013 Background: Doxorubicin (DOX), widely used in breast cancer, is known for its cardiotoxicity. Preventing DOX-cardiotoxicity without affecting its antitumor efficacy has not been successful. DOX-cardiotoxicity results from oxidative stress that increases intracellular calcium levels by promoting the release of Ca2+ from sarcoplasmic reticulum (SR) and impairing Ca2+ clearance in cardiomyocytes. Dantrolene (DNT), a postsynaptic muscle relaxant inhibits the release of Ca2+ from SR by inhibiting the ryanodine receptor (RYR). The aim of this study was to examine the effect of DNT on cardiotoxicity and anti-tumor efficacy of DOX in a rat model of breast cancer. Methods: Female F344 rats with implanted MatBIII breast cancer cells were randomized into 3 groups of 12 rats/group and were treated as follows: “DOX” group was injected i.p. with DOX 2x week for 3 weeks (cumulative dose 12 mg/kg); “DNT” group received daily DNT (5mg/kg/day) by oral gavage; and “DOX+DNT” group was treated with DOX 2x week for 3 weeks and daily DNT (5mg/kg). The presence of cardiac alterations was examined by echocardiography before and after the experiment. Body weight, tumor size and volume were measured at sacrifice. H&E stainings of the hearts and tumors was examined. Blood glutathione (GSH) levels were determined. Results: Mortality in the groups of rats treated with DOX alone, DNT+DOX and DNT was 40%, 16% and 0%, respectively. Histopathologic analysis of hearts of the surviving rats showed reduced DOX induced cardiotoxicity in the group treated with DOX+DNT as shown by reduced interstitial edema, cytoplasmic vacuolization and myofibrilar dysruption, compared to DOX only treated hearts. DNT significantly increased cardiac output and stroke volume, and improved the decline of left ventricle ejection fraction (LVEF) induced by DOX by 50%. Also, reduced breast tumor volumes with increased tumor necrosis was observed in rats treated with DOX+DNT compared to DOX alone. Rats treated with DNT lost less body weight and had a higher blood GSH levels. Conclusions: These data indicate that DNT is able to provide protection against DOX cardiotoxicity while maintaining its antitumor efficacy. Further preclinical studies are needed to determine the optimal dosing of DNT.