Losartan Improves The Efficacy Of Cisplatin In The Treatment Of Lung Cancer

Objective Lung cancer is currently the highest global morbidity and mortality rate of malignant tumors.Chemotherapy,represented by cisplatin,is the one of most important treatment for lung cancer.But the weakness of conventional chemotherapy drugs represented by cisplatin,such as poor specificity and strong dosage dependence,makes it necessary to further study the methods to improve the therapeutic effect of treatment for lung cancer.Methods Firstly,we systematically review and analyze the data of patients with Stage IIIA lung cancer from the Divion of Thoracic Surgery at Massachusetts General Hospital,from Jan 2009 to Sep 2015.We compared the differences in prognosis between patients who had used angiotensin System inhibitors(ASI+)and those who had not use angiotensin System inhibitors(ASI-),as well as the differences in related clinicopathological features.Secondly,in cell experiments,we chose 5 lung cancer cell lines(each cell represents one cancer statu,based on epithelial and mesenchymal characteristics),H441(E),H358(i E),H1299(i M),SW1573(M)and mice lung cancer cell line TC-1.Immunofluorescence was used to detect the expression of angiotensin II type 1 receptor on the surface of lung cancer tissue and cells.Angiotensin II,Losartan and cisplatin were used to stimulate lung cancer cells respectively,and conbination of losartan and cisplatin stimulated lung cancer cells,and the proliferation,protein,and RNA were detected by MTT,Western Blot and RT-q PCR respectively.We also tested the migration of lung cancer cells stimulated by different concentrations of losartan with scratch experiments.Furtherly,SW1573 was injected into Sprague-Dawley Rat lung tissue to build 3D lung cancer model.Losartan and/or cisplatin was used to stimulate 3D lung cancer model,and the biological activity of SW1573 was detected.Finally,for the vivo expreiment,SW1573 was injected in to flank nude mice and TC-1 was injected into flank C57BL/6 mice.The volume and weight of tumor in mice,the tumor volume and body weight change of mice,and the finial tumor size and weight of mice,were recorded.The protein and RNA of key indicators were dected by Western Blot and RT-q PCR respectively.Results We found that patients with lung cancer in stage IIIA who used Losartan had a better prognosis.We selected 4 human lung cancer cell lines and one mice lung cancer cell line which express angiotensin II type 1 receptor.Angiotensin II,Losartan and cisplatin can inhibit the proliferation of lung cancer alone,and more importantly,combined with losartan and cisplatin inhibit more for the proliferation of lung cancer cell lines than cisplatin alone.Losartan significantly inhibits the migration of lung cancer cell lines.The results of 3D lung cancer model were consistent with those of conventional cell experiments.In the model of mice lung cancer,we found that the inhibitory effect of losartan on tumor progression was weak when used alone,but the combination of Losartan and cisplatin was more significant in inhibiting the progression of tumor than using the two reagents alone,which showed that the tumor was smaller and lighter.In cell experiments and animal experiments,we use Western Blot and RTq PCR to detect the key indicators change and found that losartan can increase the expression of E-cadherin,but down-regulate the expression of vimentin?IL-6,AKT,P-AKT,Stat3,P-Stat3,PD-L1,and Zeb1.Conclusion Losartan can significantly inhibit the progression of lung cancer and also can improve the therapeutic effect of cisplatin on lung cancer,this process is accompanied by the inhibition of epithelial-mesenchymal transition,as well as downregulating IL-6,AKT,and PD-L1.This study will provide an important way for improving the effect of traditional chemotherapy treatment for lung cancer.