Pharmacological senolysis reduces doxorubicin-induced cardiotoxicity and improves cardiac function in mice

Many anticancer agents used in clinics induce premature senescence in healthy tissues generating accelerated aging processes and adverse side-effects in patients. Cardiotoxicity is a well-known limiting factor of anticancer treatment with doxorubicin (DOX), a very effective anthracycline widely used as antitumoral therapy in clinical practice, that leads to long-term morbidity and mortality. DOX exposure severely affects the population of cardiac cells in both mice and human hearts by inducing premature senescence, which may represent the molecular basis of DOX-induced cardiomyopathy. Here, we demonstrate that senescence induction in the heart contributes to impaired cardiac function in mice upon DOX treatment. Concomitant elimination of senescent cells with the senolytic Navitoclax in different formulations produces a significant decrease in senescence and cardiotoxicity markers together with the restoration of the cardiac function in mice followed by echocardiography. These results evidence the potential clinical use of senolytic therapies to alleviate cardiotoxicities induced in chemotherapy-treated patients.

Automated summary

Many anticancer drugs can cause premature aging in healthy tissues, resulting in accelerated aging processes and adverse effects in patients. Cardiotoxicity is a major limiting factor in the use of doxorubicin as a cancer treatment, leading to long-term morbidity and mortality. In this study, it was demonstrated that induction of senescence in the heart contributes to impaired cardiac function in mice treated with doxorubicin. Elimination of senescent cells using the senolytic Navitoclax significantly reduced senescence and cardiotoxicity markers, and restored cardiac function in mice. These results suggest the potential clinical use of senolytic therapies to alleviate cardiotoxicities induced by chemotherapy.