Anti‐angiogenic Activity of Nicotinic Receptor Antagonists in Lung Cancer

Small cell lung cancer (SCLC) is a highly angiogenic tumor with a dismal survival rate. Cisplatin‐based therapies are initially effective in SCLC. However, the tumor relapses and subsequently becomes resistant to cisplatin‐based therapies. Pilot clinical trials have shown that the combination of cisplatin with an anti‐angiogenic agent can improve therapeutic response of small cell lung cancer patients. A unique feature of SCLC is that it occurs almost exclusively in smokers. Nicotine, the addictive component of cigarettes, can promote angiogenesis in lung cancer. We show that nicotine stimulates angiogenesis in human retinal microvascular endothelial cells (HRMECs) and human lung microvascular endothelial cells (HMECLs). The proangiogenic effects of nicotine were mediated via the α7‐nAChR subunit. We conjectured that α7‐nAChR antagonists should attenuate nicotine‐induced angiogenesis and be useful for the therapy of angiogenesis‐related diseases. Our results show that the α7‐nAChR antagonist memantine displays potent anti‐angiogenic activity in the Matrigel model and chicken chorioallantoic membrane (CAM) model. Another α7‐nAChR antagonist MG624 also inhibited nicotine‐induced angiogenesis in lung endothelial cells. Our studies show that α7‐nAChR antagonists may be useful for novel combination therapies in human SCLC.