Anti‐angiogenic activity of memantine, a dual α7‐nAChR/ NMDAR antagonist, in human squamous cell lung cancer

Abstract

Squamous cell lung cancer (SCC‐L) bears a strong etiological association with smoking habits. Nicotine, the addictive component of cigarettes, promotes angiogenesis in lung cancer via the α7‐nicotinic acetylcholine receptor (α7‐nAChR) subunit on human lung endothelial cells. Our published data shows that nicotine upregulates the expression of α7‐nAChR in SCC‐L cell lines. Therefore, we conjectured that α7‐nAChR‐antagonists should display potent anti‐angiogenic and anti‐tumor activity in SCC‐Ls. Memantine is a dual α7‐nAChR/NMDAR antagonist, which is used in the clinic for the treatment of patients suffering from mild‐to‐moderate Alzheimer's disease. Receptor binding assays have shown that the affinity of Memantine for α7‐nAChR is greater than NMDAR. Tumor‐associated endothelial cells are biochemically and morphologically distinct from normal pulmonary endothelial cells. We observed that SCC‐L associated endothelial cells (STACE) and human microvascular endothelial cells of the lung (HMEC‐Ls) expressed robust levels of α7‐nAChR and NMDAR‐1 and NMDAR‐1. Our results indicate that memantine attenuated nicotine‐induced angiogenesis in HMEC‐L. Most interestingly, the levels of α7‐nAChR in tumor‐associated endothelial cells was greater than normal lung endothelial cells. The anti‐angiogeneic activity of memantine was mediated by the α7‐nAChR (and not by NMDARs) on lung endothelial cells. Furthermore, the α7‐nAChR antagonist memantine displayed potent anti‐angiogenic activity in chicken chorioallantoic membrane (CAM) model. Our studies show that α7‐nAChR antagonists may be useful anti‐tumor agents relevant for the treatment of human lung cancer.Support or Funding InformationFunding for our study was supported by an NIH R15‐AREA Grant (2R15CA161491‐02), Edwards Cancer Center Pilot grant, Cabell Huntington Hospital, Marshall University. This work was supported in part by the West Virginia IDeA Network of Biomedical Research Excellence (WV‐INBRE) grant GM103434(PI: Dr. G. Rankin). A NASA Undergraduate Fellowship was also given to NAN.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.