| Objective:Doxorubicin is one of the commonly used anthraquinones antineoplastic agents with high efficiency.However,doxorubicin-induced cardiotoxicity is the mainly adverse effect in clinic.The purpose of this study was to investigate the cardioprotective effects of PNS against doxorubicin-induced cardiotoxicity and its possible influence on the anti-tumor activity of doxorubicin. This work will provide scientific basis for the potentially clinical application of PNS to overcome the negative side effects of doxorubicin.Method:1)An acute cardiotoxicity model was induced by a single dose of doxorubicin (15 mg·kg-1,i.p.).The effects of PNS on the cardiac toxicity of doxorubicin were evaluated by cardiac function,serum levels of dehydrogenase(LDH),creatine kinase (CK)and creatine kinase isoenzyme(CKMB),activities of antioxidant enzymes and contents of ATP/ADP/AMP in heart tissue,and Histopathological examination.2)The inhibitory effect of doxorubicin on cadiocyte H9C2 viability and the protective effect of PNS was measured in vitro.Intracellular reactive oxygen free radicals and mitochondrial membrane potential was revealed by fluorescent probes Carboxy-H2DCFDA and JC-1,respectively.3)And the effect of PNS on the antitumor efficacy,of DOX was also examined using tumor-bearing mice and three cancer cell lines,namely MCF-7,K562 and KB in vitro.Results:1)After 72 h of doxorubicin treatment,cardiac function in mice was significantly declined.And serum levers of LDH,CK,CKMB were greatly elevated. Morphological changes,for example myocardial rupture,deformation and atrophia of myocardial mitochondria,dissolution of myocardial fibers in DOX-treated animals were observed.In PNS(100 mg·kg-1)pretreated group,the value of LVSP,+dp·dt-1max and -dp·dt-1maxwere higher than DOX group for 19.8%,49.5%and 54.9% respectively;the values of LDH,CK and CKMB were lower than DOX group for 44.2%,39.5%and 36.0%;the adenylate energy charge was higher than DOX group for 29.4%;and a significant reduction in the morphological changes in heart structure was also observed.PNS appeared dose-dependent protective effects at the range of 25～100 mg·kg-1.The activities of SOD,CAT and GSH-px elevated 17.6%,32.1%, 17.0%respectively,compared with DOX-treated group.These results indicated the protective effect of PNS on DOX-induced cardiotoxicity.2)Based on MTT assay,viability of the H9C2 cells decreased for 20%as 10μM doxorubicin treated for 24 h.Pretreatment with PNS(6.25～100 mg·L-1)increased cell viability.Notoginsenoside R1 and ginsenoside Rg3 showed the most marked protective effects.Rg3 inhibited the increase of intra-cell ROS and decrease of the mitochondrial membrane potential induced by doxorubicin.However,PNS could not scavenge superoxide anion free radical generated by xanthine-xanthine oxidase system.3)Treated with doxorubicin(2 mg·kg-1,i.p.)every other day,the mice S180 sarcoma were inhibited for 49.6%.Co-administration of PNS(25,50,100 mg·kg-1, i.g.)everyday resulted inhibitory effect of 45.8～61.2%,with no significant difference compared with doxorubicin-treatment alone.At the range of 6.25～100 mg·L-1,PNS appeared no influence on the inhibitory effects of doxorubicin on the growth of human tumor cell(KB,MCF-7,K562).Conclusion:Our study demonstrated the protective effect of saponins from Panax notoginseng against DOX-induce cardiotoxicity without compromising the antitumor activity of DOX.We therefore suggest that PNS could be a novel cardioprotective agent that may be used clinically to help offset the negative side effects of DOX. |
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