Repurposing the anti-dementia drug memantine, (a dualalpha7-nAChR NMDAR antagonist) as an anti-cancer agent in human squamous cell lung cancer

Purpose of the study : Memantine is a drug used in clinical practice to combat dementia associated with mild-to-moderate Alzheimer's disease. Traditionally, memantine is an NMDAR receptor antagonist, but published reports show that it has multiple molecular targets apart from NMDAR. Nicotinic acetylcholine receptors (nAChRs) are a class of ion-channel receptors which mediate the bioactivity of nicotine. Published reports reveal that memantine functions as an antagonist to a particular kind of nAChR, namely the alpha-7-nicotinic receptor (alpha7-nAChR). The binding affinity of memantine for alpha7-nAChRs is stronger than its affinity for the NMDAR receptor. Squamous cell lung carcinoma (LUSC) is a type of non-small cell lung cancer (NSCLC) that typically develops in one of the air passages (bronchi) of the lungs. The primary objective of our research project was to repurpose the drug memantine as a growth-inhibitory agent in LUSCs. Experimental procedures . Data from the TCGA atlas show that the alpha7-nAChR is overexpressed on patient-isolated LUSC tumors relative to matched normal tissue. Our research has shown that the alpha7-nAChR is upregulated in LUSC tissues and LUSC cell lines relative to normal lung epithelial cells. It is well known that almost 30% of LUSC patients continue to smoke after diagnosis, and many LUSC patients are exposed to nicotine via smoking-cessation devices like patches and gums. Therefore, we decided to evaluate the antiproliferative activity of memantine on nicotine-induced LUSC cells. Proliferating Cell Nuclear Antigen (PCNA) ELISA assays revealed that memantine robustly inhibited nicotine-induced proliferation of LUSCs. The growth-inhibitory activity of memantine was further confirmed in chicken chorioallantoic membrane (CAM) model systems of LUSC. Additionally, the anti-tumor activity of memantine was measured in two independent mice models, namely the cell derived xenograft (CDX) mouse model and the patient derived xenograft (PDX) mouse model. Finally, siRNA methodology was used to delineate the signaling pathways underlying the anti-proliferative activity of memantine in LUSC. Results: Memantine potently inhibited nicotine-induced proliferation across a panel of human LUSC cell lines. The presence of memantine induced cell cycle arrest (at G1/S phase) in nicotine-treated LUSC cells and the anti-proliferative activity of memantine was also observed in chicken CAM models of LUSC. Finally, the administration of memantine via dietary methods decreased nicotine-induced growth of LUSC tumors in both CDX and PDX tumors in immunodeficient mice models. Depletion of the alpha7-nAChR expression by siRNA methodology abrogated the anti-proliferative activity of memantine in human LUSC cells. Conclusions: The drug memantine could be repurposed as a potent anti-cancer drug for the treatment of LUSC.