An angiotensin system inhibitor (Losartan) potentiates anti-tumor efficacy of cisplatin in a murine model of non-small cell lung cancer

Objective Previous studies have demonstrated synergistic anti-tumor effects of angiotensin system inhibition (ASI) combined with cisplatin therapy in pancreatic cancer. This study examines whether synergistic anti-tumor effects occur with combination ASI and cisplatin treatment in lung cancer, and whether ASI-induced changes in epithelial-mesenchymal transition play a role in the mechanism of this anti-tumor phenomenon. Methods A set of lung cancer cell lines representing a spectrum of epithelial to mesenchymal phenotypes were identified and characterized. Response of EMT markers to losartan was characterized. Cell culture models of lung cancer were next treated with losartan, cisplatin, or combination of both. Markers of epithelial-mesenchymal transition or surrogates of other signaling pathways (AKT, Stat3, PD-L1), and cell viability were quantified. Findings were confirmed in both allogenic and syngeneic in vivo murine flank tumor models. Results Losartan treatment significantly increased E-cadherin and reduced Vimentin in human lung cancer cell lines. Combination treatment with losartan and cisplatin 1) enhanced epithelial markers, 2) reduced mesenchymal markers, 3) inhibited pro-mesenchymal signaling mediators, and 4) reduced cell viability. Findings were confirmed in vivo in a murine flank tumor model with transition from mesenchymal to epithelial phenotype and reduced tumor size following combination losartan and cisplatin treatment. Conclusions Combination losartan and cisplatin treatment attenuates the EMT pathway and enhances the cytotoxic effect of chemotherapy with in vitro and in vivo models of NSCLC. This study suggests an important role for ASI therapy in the treatment of lung cancer.