Anti-Lung Cancer Effect Of Combination Of Topotecan And Crizotinib

Lung cancer is a malignant disease with a high mortality rate.Non-small-cell lung carcinoma is the most common subtype of lung cancer,accounting for about 85%of the incidence of lung cancer,although there are many treatments for non-small-cell lung carcinoma,but for the majority of non-small-cell lung carcinoma patients,chemotherapy remains the mainstay of treatment,and the biggest problem with chemotherapy is its inevitable toxicity and poor targeting.The combination therapy for non-small-cell lung carcinoma is effective and has obvious advantages.The aim of this study was to investigate the effects of Topotecan(a chemotherapeutic drug)and Crizotinib(a targeted drug)on non-small-cell lung carcinoma and its potential mechanism.Topotecan,a well established anticancer drug,has been shown to be effective against small-cell carcinoma and has been poorly studied in non-small-cell lung carcinoma,ALK is a small molecule targeted drug for patients with advanced non small cell disease who are ALK positive.The cells in this study,non-small-cell lung carcinoma H1975 and HCC827,are both EGFR mutants,simultaneously expands the treatment scope and the anti-tumor spectrum,"the old medicine new use" is a new medicine discovery important way,will Topotecan(the chemotherapy medicine)and the Crizotinib(the targeted medicine)joint medication,to further explore the effect of combination therapy on non-small-cell lung carcinoma and its potential mechanism of action.The effects of Topotecan and Crizotinib on(1)the proliferation of NSCLC;(2)the apoptosis of NSCLC were investigated in vitro;(3)evaluation of the effect of ROS and mitochondrial membrane potential in non-small cell lung cancer(NSCLC);(4)analysis of the e ffect of signal pathway in NSCLC.In addition,the effect of Topotecan combined with Crizotinib on H1975 xenografted tumor model mice and the related tissue protein signaling pathway of xenografted tumor model mice were further studied.The results showed that Topotecan combined with Crizotinib had a significant synergistic effect on non-small-cell lung carcinoma at the cellular level and the synergistic mechanism was further studied by DAP I staining,the observation of morphological changes indirectly reflected the synergistic effect of Topotecan and Crizotinib on inducing cell apoptosis,and the combined use of Topotecan and Crizotinib could promote the accumulation of ROS and decrease mitochondrial membrane potential in cell water,these results suggest that apoptosis may play a potential role in the synergistic inhibition of tumor cell proliferation.The results of quantitative analysis showed that the combination of the two drugs could obviously promote the apoptosis of tumor cells and inhibit the proliferation of tumor cells.Topotecan combined with Crizotinib could down-regulate the expression of p-AKT,p-JNK,p-ERKand p-38 protein,which showed that topotecan combined with Crizotinib could inhibit the proliferation of lung cancer cells through multiple signaling pathways,in vivo animal experiments further proved that Topotecan combined with Crizotinib had a significant effect on inhibiting the proliferation of tumor cells,the inhibitory rate was more than 80%,and the effect was obviously stronger than that of the two single drug groups.These data showed that Topotecan combined with Crizotinib had a good synergistic effect.Therefore,the combination of Topotecan(a chemotherapeutic drug)and Crizotinib(a targeted drug)is a potential candidate for the treatment of non-small-cell lung carcinoma.