Abstract LB099: The inhibitory effect of pemetrexed disodium heptahydrate on the growth of A549 cells

Background: Pemetrexed disodium heptahydrate (pemetrexed) is currently used for the treatment of patients with advanced non-small cell lung cancer (NSCLC). More than 30% of lung cancer cases involve KRAS mutations. In this study, we examined the anticancer ability of pemetrexed in KRAS-dependent A549 lung cancer cells. Methods: A549 cells were treated with pemetrexed for 72 h and then evaluated by a TUNEL assay, ROS assay and Western blotting. Results: The apoptotic effect of pemetrexed was observed through increased levels of cleaved caspase-9 (Asp 315), cleaved caspase-3 (Asp 175) and cleaved PARP. Furthermore, pemetrexed increased ROS-mediated DNA damage and enhanced the proapoptotic Bax protein expression, leading to the loss of mitochondrial membrane potential (MMP). The increased expression of the β-galactosidase protein was correlated with the induction of cellular senescence. Significantly, pemetrexed induced cytotoxicity without inhibiting the RAS/RAF/MEK/ERK signaling pathway, while pemetrexed induced autophagy, which activated the AMPK/mTOR signaling pathway. Conclusion: Taken together, these findings indicate that, in addition to apoptosis, pemetrexed-induced autophagy and cellular senescence, providing a promising direction for the development of KRAS-targeted therapy. Citation Format: Md Mohiuddin, Hideharu Kimura, Takashi Sone, Satoshi Watanabe, Hiroki Matsuoka, Keigo Saeki, Nanao Terada, Miki Abo, Kazuo Kasahara. The inhibitory effect of pemetrexed disodium heptahydrate on the growth of 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 LB099.