Abstract LB100: Pemetrexed disodium heptahydrate and cisplatin have distinctive growth inhibitory effects in monotherapy and combination therapy on A549 cells

Abstract

Abstract Background: Cisplatin combined with pemetrexed disodium heptahydrate (pemetrexed) is considered the standard treatment for patients with advanced, non-squamous, non-small-cell lung cancer (NSCLC). However, its individual growth inhibitory effects on KRAS-dependent A549 human lung cancer cells as monotherapy and combination therapy are not well understood. The aim of this study was to compare the effects of cisplatin (CDDP) and pemetrexed (PEM) on A549 cells as monotherapy and combination therapy.Methods: For in vitro studies, A549 cells were exposed to cisplatin and pemetrexed as monotherapy and combination therapy for 72 h. The results were then evaluated by a cell viability assay, apoptosis assay, ROS assay, TUNEL assay and Western blotting.Results: Our results revealed that cisplatin monotherapy was the most potent growth inhibitor; cisplatin plus pemetrexed combination therapy had an intermediate effect; and pemetrexed monotherapy induced a minimal growth inhibitory effect in the A549 cell line, which was observed by the inhibition of the RAS/RAF/MEK/ERK signaling pathway. Furthermore, apoptotic effects were examined according to ROS-mediated DNA damage and increased levels of cleaved caspase-3, cleaved caspase-9 and cleaved PARP. Interestingly, cisplatin monotherapy was the primary eliminator of cellular senescence; combination therapy with cisplatin plus pemetrexed had an intermediate eliminator effect, while pemetrexed monotherapy increased cellular senescence in A549 cells, which was assessed by the expression of the β-galactosidase protein. The results of Western blotting of proteins in the AMPK/mTOR signaling pathway indicated that the highest inducer of autophagy was pemetrexed monotherapy, while combination therapy with cisplatin plus pemetrexed had an intermediate inhibitory effect on autophagy. Cisplatin monotherapy showed the strongest autophagy inhibitory activity.Conclusion: In light of these findings, cisplatin monotherapy showed the most potent anticancer effects, suggesting that cisplatin monotherapy may be more effective than pemetrexed monotherapy or cisplatin plus pemetrexed combination therapy in A549 cells. Citation Format: Md Mohiuddin, Hideharu Kimura, Takashi Sone, Satoshi Watanabe, Hiroki Matsuoka, Keigo Saeki, Nanao Terada, Miki Abo, Kazuo Kasahara. Pemetrexed disodium heptahydrate and cisplatin have distinctive growth inhibitory effects in monotherapy and combination therapy on A549 cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB100.