Schisandrin B Prevents Doxorubicin-Induced Chronic Cardiotoxicity and Enhances Its Anticancer Activity In Vivo

Abstract

BackgroundTo 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.MethodologyRat was given intragastrically either vehicle or Sch B (50 mg/kg) two hours prior to i.p. Dox (2.5 mg/kg) weekly over a 5-week period with a cumulative dose of Dox 12.5 mg/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 activity enhanced by Sch B was evaluated by growth inhibition of 4T1, a breast cancer cell line, and S180, a sarcoma cell line, in vitro and in vivo.Principal FindingsPretreatment with Sch B significantly attenuated Dox-induced loss of cardiac function and damage of cardiomyocytic structure. Sch B substantially enhanced Dox cytotoxicities toward S180 in vitro and in vivo in mice, and increased Dox cytotoxcity against 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.ConclusionSch B is capable of protecting Dox-induced 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.

Comparative Study of the Protective Effect of Metformin and Sitagliptin against Doxorubicin-Induced Cardiotoxicity in Rats

“…The results of the present study are in agreement with Xu [21] who showed weight loss, [22] who demonstrated significant reduction in systolic blood pressure [23] Different cellular mechanisms may explain doxorubicin-induced cardiac toxicity as increase intracellular iron accumulation causing increased oxidative stress [29], preventing the repair of damaged DNA strands [30], changes in vascular endothelium-derived vasoactive mediators (endothelin-1 and cardiac nitric oxide) [31] and alteration of cardiac-specific gene expression including struc tural, metabolic and enzyme activities [32].…”

Salvianolic Acid B Prevents Arsenic Trioxide-Induced CardiotoxicityIn Vivoand Enhances Its Anticancer ActivityIn Vitro

“…These results were also observed in several other antioxidant studies [7, 26]. Although the mechanism is still elusive, we speculate that it may be due to the functionally contradictory effects of some proteins critical for apoptotic signaling in different cell types induced by ATO, such as the proapoptotic effects of c-Jun-NH2-kinase (JNK) activation in ATO-induced ovarian cancer cells [27] in contrast to the antiapoptotic effects on JNK activation in some other cell lines [28, 29].…”

Isorhamnetin Protects against Doxorubicin-Induced Cardiotoxicity In Vivo and In Vitro

“…Excessive production of ROS is identified as a contributor to the damage of nuclear DNA, changes in calcium handling, restrain from cell survival and protein synthesis, disruption of sarcomere stability, and eventual cardiomyocyte death [32]. Due to their phenolic hydroxy structure, flavonoid compounds can act as strong natural antioxidants via combining directly with ROS and activating the antioxidant defense systems [33]. The present study was primarily designed to examine the potent protective effect of isorhamnetin on Dox-induced oxidative stress.…”