The Protective And Mechanism Of Sanyang Blood Stasis On Bone Marrow And Myocardial Injury Induced By Doxorubicin

The protective effect of SYKT in doxorubicin induced myelosuppression and carditoxicityObjectives:Doxorubicin (DOX) is an antineoplastic drug widely used for the treatment of various types of cancer; however, it can induce severe side effects, such as myelosuppression and cardiotoxicity. Sanyang Xuedai (SYKT) is a natural medicine originating from an ancient prescription of the Dai nationality in Southwest China. With eight Chinese herbal medicines, including sanguis draconis, radix et rhizoma notoginseng, radix et rhizoma glycyrrhizae and radix angelicae sinensis as the primary ingredients, SYKT has been reported to possess numerous biological functions. The present study investigated whether SYKT can confer protection against DOX-induced myelosuppression and cardiotoxicity, and explored the potential mechanism involved.Methods: Mice were treated with DOX, SYKT or a combination of the two;hematopoietic functions were assessed by measuring the number of peripheral blood cells, cluster of differentiation CD34+/CD44+ bone marrow cells and apoptotic cells.Myocardial enzymes, including aspartate aminotransferase, lactate dehydrogenase,creatine kinase (CK) and its isoform CK-MB,were assessed using a biochemical analyzer. The apoptotic rate of cardiomyocytes was assessed using flow cytometry. Histopathological analysis was conducted using hematoxylin-eosin staining. Intracellular reactive oxygen species (ROS) production was evaluated using a dichlorofluorescein intensity assay.Results: The mice treated with DOX exhibited a reduced survival rate, reduced peripheral blood and CD34+/CD44+ cell counts, elevated myocardial enzymes and apoptotic indices in bone marrow cells and cardiomyocytes, all of which were effectively prevented by SYKT co-administration. Furthermore, bone marrow cells and myocytes from mice treated with DOX demonstrated increased dichlorofluorescein intensity, which was attenuated by SYKT. Notably, SYKT did not interfere with the effects of DOX on tumor volume or the induction of tumor cell apoptosis in tumor-bearing mice. The present study indicated that SYKT may counteract DOX-induced myelosuppression and cardiotoxicity through inhibiting ROS-mediated apoptosis.Conclusions: The present results demonstrated that SYKT may prevent DOX-induced myelosuppression and cardiotoxicity without impairing its antitumor efficacy,through a mechanism involving the inhibition of ROS-mediated apoptosis.Therefore, the present study suggested that SYKT co-administration may be considered a potential solution to counteract the myelosuppressive and cardiotoxic action of DOX.The mechanism of protective role of SYKT against doxorubicin induced cardiotoxicityObjectives: In spite of tremendous demand for the development and implementation of effective therapeutic strategies, limitations are still associated with doxorubicin-induced cardiotoxicity. Sanyang Xuedai (SYKT) has been shown to possess a multitude of biological functions. The purpose of the present study was to explore whether SYKT plays any protective role against doxorubicin-induced cardiotoxicity; and if so, what molecular mechanism it utilizes for its protective action.Methods: Mice primary myocardial cells in vitro were identified and puritied by CTnI immunofluorescence staining. The p53, p38 and JNK activation in myocardial cells were detected by western blot, PFT - ?, SB203580, SP600125 were served as the specific inhibitors of p53, p38 and JNK,and were set as positive control of SYKT.Mitochondria was extracted with cell mitochondria cytoplasm separation kits,cytoplasm and mitochondrial protein were extracted respectively, the expression of Bax and cytochrome C in myocardial cell cytoplasm and mitochondria were detected by western blot. Through Rhodamine 123 staining and FCM and CLSM to detect the change of myocardial cell mitochondrial membrane potential. Caspase-3 and PARP that apoptosis related proteins of myocardial cell were detected by western blot.Results: In mouse cardiomyocytes, doxorubicin administration activated the proapoptotic p53, p38 and JNK MAPKs, Bax translocation, disrupted mitochondrial membrane potential, precipitated mitochondrion mediated caspase-dependent apoptotic signalling and reduced viability of cardiomyocytes. And joint SYKT,expression of activated p53, p38 and JNK decreased, Bax transposition was abated,the mitochondrial membrane potential was stabilised, release of cytochrome C was reduced. The expression of apoptosis related proteins caspase 3 and PARP were reduced. Finally, the myocardial cell apoptosis was suppressed obviously. Contrast with the positive control (PFT -?, SB203580, SP600125), the effection of SYKT was exact, prompt that SYKT can protect myocardial through inhibit activation of apoptosis pathway about p53 and MAPKs.Conclusions: Combining all, our results suggest that doxorubicin induces cardiac apoptosis via the activation of JNK-p38 and p53-mediated signalling pathways.SYKT can effectively and extensively counteract this action of doxorubicin, and may potentially protect the heart and cardiomyocytes from the severe doxorubicin-induced cardiovascular burden.