Memantine, the dual α7‐nAChR/NMDAR antagonist displays potent anti‐angiogenic activity in lung cancer

Abstract

Non‐small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) bear 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 in human lung endothelial cells. Therefore, we conjectured that α7‐nAChR‐antagonists should display potent anti‐angiogenic and antitumor activity in lung cancers. 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. Here we show that memantine attenuates nicotine‐induced angiogenesis in human microvascular endothelial cells of the lung (HMEC‐Ls). Most interestingly, the levels of α7‐nAChR in tumor‐associated endothelial cells was greater than normal lung endothelial cells. The anti‐angiogenetic 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 the 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 the an NIH R15‐AREA Grant (2R15CA161491‐02), WVU‐MU Health Partnership Grant and by ACTSI Grant from Marshall University