Schisandrin B Prevents Doxorubicin-induced Chronic Cardiotoxicity And Enhances Its Anticancer Activity In Vivo

Cancer has become the world's leading cause of death for human beings. Cancer chemotherapy is one of the most effective and widely used approaches for malignant tumors therapy. Anthracycline anticancer agents are the first-line drugs used in the clinical treatments of various solid tumors and leukemia, but these drugs could cause a considerable number of patients with severe myocardial damage. To mitigate the cardiotoxicity of anthracycline antibiotics without compromising their anticancer activities is still an issue to be solved. We previously demonstrated that schisandrin B (Sch B) could protect against doxorubicin (Dox)-induced acute cardiotoxicity via enhancing cardiomyocytic glutathione redox cycling that could attenuate oxidative stress generated from Dox. In this study, we attempted to prove if Sch B could also protect against Dox-induced chronic cardiotoxicity, a more clinically relevant issue, without compromising its anticancer activity. Rat was given intragastrically either vehicle or Sch B (50 mg/kg) two hours prior to i.p. Dox (2.5mg/kg) weekly over a 5-week period with a cumulative dose of Dox 12.5mg/kg. At the 6th and 12th week after last dosing, rats were subjected to cardiac function measurement, and left ventricles were processed for histological and ultrastructural examination. Dox anticancer activities enhanced by Sch B was evaluated by growth inhibition of 4T1, a breast cancer cell line, in vitro and in vivo. Pretreatment with Sch B significantly attenuated Dox-induced loss of cardiac function and damage of cardiomyocytic structure. Sch B substantially enhanced Dox cytotoxicities toward 4T1 in vitro. Although we did not observe this enhancement against the implanted 4T1 primary tumor, the spontaneous metastasis to lung was significantly reduced in combined treatment group than Dox alone group. In conclusion, Sch B is capable of protecting Dox-induced acute and chronic cardiotoxicity and enhancing its anticancer activity. To the best of our knowledge, Sch B is the only molecule ever proved to function as a cardioprotective agent as well as a chemotherapeutic sensitizer, which is potentially applicable for cancer treatment.