Recombinant human interleukin-1 receptor antagonist protects mice against acute doxorubicin-induced cardiotoxicity

Abstract

Doxorubicin is a potent anticancer drug which is widely used in the treatments of a variety of solid and hematopoietic tumors, but its use is limited by its cardiotoxicity and dose-dependent congestive heart failure. After finding a close connection between Interleukin-1 family and doxorubicin-induced cardiotoxicity, we assumed that recombinant human interleukin-1 receptor antagonist (rhIL-1Ra), the natural antagonist of interleukin-1, might have a protective role in doxorubicin-induced cardiotoxicity. In this report, Balb/c mice were intraperitoneally injected with doxorubicin (18 mg/kg) followed by injections of 1mg/kg rhIL-1Ra 4h later, and consecutive daily injections of rhIL-1Ra on the following 4 days (1mg/kg/day). We found that rhIL-1Ra significantly decreased malondialdehyde in cardiac tissue and prevented doxorubicin-associated cardiac troponin I elevations in serum, especially at day 14 after doxorubicin treatment. Importantly, rhIL-1Ra diminished doxorubicin-induced microstructural damages of cardiac tissue and rescued doxorubicin-caused reduction of cardiac functions exemplified by ejection fraction and fraction shortening. Our results reveal a potential role of rhIL-1Ra in protecting mice against doxorubicin-induced cardiac injuries and lead to a conclusion that this protein may be a potential candidate agent that inhibits cardiomyocyte-toxicity in doxorubicin-exposed patients.