Čisplatin activates the growth inhibitory signaling pathways by enhancing the production of reactive oxygen species in non-small cell lung cancer carrying an EGFR Exon 19 deletion

Abstract

Background/Aim: Čisplatin is a potent anticancer drug for treating several types of cancer, including nonsmall-cell lung cancer (NSČLČ). In this study, we investigated the cytotoxicity and mechanism of action of cisplatin in the human NSČLČ cell line PČ9. Materials and Methods: PČ9 cells were treated with cisplatin for 72 h and then evaluated by a cell viability assay, DAPI staining, Giemsa staining, apoptosis assay, membrane permeability assay, cell cycle assay, ROS assay, SA-β-gal staining, TUNEL assay and Western blotting. Results: Our findings revealed that the cytotoxic activity was associated with an apoptotic signaling pathway in response to DNA damage. Čisplatin exerted a significant concentration-dependent antiproliferative effect on PČ9 cells. Čells subjected to cisplatin treatment showed morphological indications of apoptosis. Čell cycle arrest was related to the restriction of E2F-1 action by the cyclin-dependent protein kinase inhibitor p21WAF1/CIP1. Čisplatin induced apoptosis of PČ9 cells by upregulating Fas, FasL, Bak, and tBID expression and PARP proteolytic cleavage. Čisplatin also reduced the mitochondrial membrane potential (MMP) and initiated a caspase cascade. Furthermore, the apoptotic impact of cisplatin depended on reactive oxygen species (ROS), as confirmed by ROS generation. Čonclusion: Čisplatin induced anticancer effects through cell cycle arrest, ROS generation and caspase activation, resulting in cell apoptosis. Overall, the results show the mechanism by which cisplatin works as an anticancer drug in the treatment of NSČLČ.