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Anti‐angiogenic activity of alpha7‐nicotinic receptor antagonists in human small cell lung cancer
Author(s) -
Thornhill Brent A,
Brown Kathleen C,
Lau Jamie K,
Dom Aaron M,
Witte Theodore R,
Hardman W Elaine,
Luo Haitao,
Chen Yi C,
Dasgupta Piyali
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1087.14
Subject(s) - angiogenesis , nicotine , pharmacology , methyllycaconitine , chorioallantoic membrane , cancer research , nicotinic agonist , lung cancer , matrigel , endothelial stem cell , chemistry , medicine , nicotinic acetylcholine receptor , receptor , biology , biochemistry , in vitro
Small cell lung cancer (SCLC), a highly angiogenic tumor displays a 90% association with smoking. Nicotine promotes angiogenesis in lung cancer via alpha7‐nicotinic acetylcholine receptors (α7‐nAChRs). We conjectured that α7‐nAChR antagonists should suppress nicotine‐induced angiogenesis and may have potential applications for the therapy of SCLC. Here we show that the synthetic α7‐nAChR antagonist MG624 suppresses nicotine‐induced proliferation of human microvascular endothelial cells from the lung (HMEC‐L). MG624 displayed potent anti‐angiogenic activity in the Matrigel, rat aortic ring, and chicken chorioallantoic membrane models and in human SCLC tumors xenografted in athymic mice. The administration of MG624 did not cause any discomfort, gross toxicity or lethargy in mice. Chromatin immunprecipitation assays show that MG624 decreases the recruitment of Egr‐1 on FGF2 promoter thereby decreasing its transcription and suppressing nicotine‐induced angiogenesis. Currently, our laboratory is testing the anti‐angiogenic activity of other well characterized α7‐nAChR antagonists like MLA and COG. Our results suggest that α7‐nAChR based anti‐angiogenic agents may be useful for the therapy of human SCLC.