Targeting acetylcholine: a novel strategy for treating lung adenocarcinoma

Lung cancer remains one of the deadliest cancers, both in terms of the incidence and mortality rates. Although a combination therapy comprising immune checkpoint inhibitors and chemotherapy has become the standard therapy for driver gene-negative lung adenocarcinoma, its efficacy is yet to be further improved. Additionally, new treatment methods still need to be developed. Acetylcholinesterase (AChE) has emerged as a potential therapeutic target in various cancers. However, its role in lung adenocarcinoma remains poorly understood.

This study aims to investigate the role of AChE in the progression of lung adenocarcinoma and to design and synthesize small-molecule compounds targeting AChE for exploring their potential as novel therapeutic agents.

AChE is significantly overexpressed in lung adenocarcinoma. Therefore, we synthesized two novel AChE inhibitors and characterized them by nuclear magnetic resonance and high-resolution mass spectrometry. Subsequently, two inhibitors were added to lung adenocarcinoma A549 and H1975 cells to detect changes in their biological behaviors such as cell proliferation, apoptosis, cell cycle, and colony-formation ability. Simultaneously, a mouse transplant tumor model was constructed and an AChE inhibitor was injected intraperitoneally to observe changes in the volume and weight of the mouse transplant tumor.

Our AChE inhibitors showed significant cytotoxicity against A549 and H1975 cells. They can effectively inhibit cell proliferation, induce apoptosis, prevent cell cycle progression, and reduce colony-formation ability. The mouse transplant tumor model confirmed that they can inhibit cell proliferation. The tumor volume and weight were significantly reduced in the intraperitoneal injection inhibitor group. Notably, the inhibitor did not cause pathological damage to normal organs.

Our novel AChE inhibitors can potentially be used to treat lung adenocarcinoma and to develop a promising new direction for future lung adenocarcinoma treatments.