Abstract 4711: PRMT5 selective inhibitor enhances therapeutic efficacy of cisplatin in lung adenocarcinoma cells

Abstract

Abstract Background: Lung cancer is the most common cancer globally, with an estimate of more than 2 million new cases every year. Protein arginine methyltransferase 5 (PRMT5) is an enzyme that is identified to be involved in multiple cellular events, including gene expression regulation transcriptional regulation and cell division. It has been shown that PRMT5 is highly expressed in cancers including lung adenocarcinoma, hepatocellular carcinoma, and melanoma, raising evidence that PRMT5 might be involved in tumorigenesis. The aim of this study is to examine the potential selective anti-neoplastic activity of AMI-1 and cisplatin on lung adenocarcinoma. Experimental methods: The effect of AMI-1 and subsequent PRMT5 activity inhibition on lung adenocarcinoma (A549 cell line) behavior with the standard chemotherapeutic agent, cisplatin was assessed, by measuring cell viability using MTT assay, PMRT5/β-catenin protein levels via Western Blotting, the extent of cell migration through wound healing assay, and survival of cancer cells by performing cell cycle progression and Annexin-V staining assays along with both drugs combination potential toxicity that was evaluated in human bronchial epithelial cells (HBEC). Results and Discussions: Combination treatment with 10 µM AMI-1 and IC50 of Cisplatin (23.4 µM) significantly reduced viable cell percentages at 24 and 48 hours. Treatment with both drugs at 48 hours led to a decreased cells migration rate. G2/M arrest in A549 cells was evident at 24 hours of AMI-1 addition, which was reinforced after drugs combined treatment. Furthermore, 48 hours of both drug administration hindered the ability of A549 cells to recycle again as they G1 occupying cells percentage was increased after 48 hours of combination treatment. There was a minor cell death induction after 48 hours of treatment with both drugs. Western blot analysis showed that there was no evidence change in total PRMT5 and β-catenin protein levels. Nevertheless, there was a reduction in demethylation Histone 4, a PRMT5- downstream target, after 48 hours treatment with AMI-1 alone or in combination with Cisplatin. Interestingly, as combination approach increased anti-survival effect on lung cancer cells, it exhibited cyto-protective abilities on normal epithelial cells. Conclusion: This study shows a novel selective antitumor activity of AMI-1 and cisplatin in adenocarcinoma cells. Citation Format: Khuloud Bajbouj, Rakhee Ramakrishnan, Ahmed M.H.Ihmaid, Suhaib Al Haj Ali, Abdulla Alalool, Reem Abdullah, Maha Saber-Ayad, Qutayba Hamid. PRMT5 selective inhibitor enhances therapeutic efficacy of cisplatin in lung adenocarcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4711.