Remote ischemic conditioning protects against anthracycline cardiotoxicity without impairing its antitumor activity.

Abstract

Anthracyclines remain a cornerstone of treatment for many cancer types; however, their cardiotoxic potential leads to cardiac dysfunction in a substantial proportion of patients, ultimately compromising long-term quality of life. Few strategies have proven effective in preventing anthracycline-induced cardiotoxicity (AIC). Among them, remote ischemic conditioning (RIC) has emerged as one of the most promising, having shown robust cardioprotective potential in preclinical studies and currently being evaluated in clinical trials. However, it remains unclear whether this intervention, while protecting the heart, could also inadvertently protect tumors from the cytotoxic effects of anthracyclines, thereby reducing their antitumor efficacy. In this study, we investigated whether RIC protects against AIC in a tumor-bearing mouse model, allowing simultaneous assessment of both cardiac and tumoral responses. Cutaneous tumors were induced in CD1 mice using a DMBA/TPA protocol, followed by five weekly intraperitoneal injections of doxorubicin (5 mg/kg). Mice bearing tumors were randomized to receive doxorubicin alone or in combination with weekly RIC (three cycles of 5 min hindlimb ischemia/reperfusion). Longitudinal echocardiography was used to assess cardiac function, while tumor growth, survival, and body weight were monitored throughout the protocol. Doxorubicin treatment reduced overall survival, inhibited tumor growth, and induced left ventricular systolic dysfunction and cardiac atrophy compared with untreated controls. RIC preserved left ventricular ejection fraction, partially attenuated early left ventricular atrophy, and showed a trend towards improved survival, without attenuating the antitumor efficacy of doxorubicin, as tumor suppression remained comparable between treatment groups. These findings demonstrate that RIC preserves cardiac systolic function during anthracycline chemotherapy in tumor-bearing mice without impairing the antitumor efficacy of the drug. The results support RIC as a simple, safe, and low-cost non-pharmacological strategy to mitigate AIC with potential translational relevance for oncology patients.