title: MG624, an α7-nAChR antagonist, inhibits angiogenesis via the Egr-1/FGF2 pathway.
abstract: Small cell lung cancer (SCLC) demonstrates a strong etiological association with smoking. Although cigarette smoke is a mixture of about 4,000 compounds, nicotine is the addictive component of cigarette smoke. Several convergent studies have shown that nicotine promotes angiogenesis in lung cancers via the α7-nicotinic acetylcholine receptor (α7-nAChR) on endothelial cells. Therefore, we conjectured that α7-nAChR antagonists may attenuate nicotine-induced angiogenesis and be useful for the treatment of human SCLC. For the first time, our study explores the anti-angiogenic activity of MG624, a small-molecule α7-nAChR antagonist, in several experimental models of angiogenesis. We observed that MG624 potently suppressed the proliferation of primary human microvascular endothelial cells of the lung (HMEC-Ls). Furthermore, MG624 displayed robust anti-angiogenic activity in the Matrigel, rat aortic ring and rat retinal explant assays. The anti-angiogenic activity of MG624 was assessed by two in vivo models, namely the chicken chorioallantoic membrane model and the nude mice model. In both of these experimental models, MG624 inhibited angiogenesis of human SCLC tumors. Most importantly, the administration of MG624 was not associated with any toxic side effects, lethargy or discomfort in the mice. The anti-angiogenic activity of MG624 was mediated via the suppression of nicotine-induced FGF2 levels in HMEC-Ls. MG624 decreased nicotine-induced early growth response gene 1 (Egr-1) levels in HMEC-Ls, and reduced the levels of Egr-1 on the FGF2 promoter. Consequently, this process decreased FGF2 levels and angiogenesis. Our findings suggest that the anti-angiogenic effects of MG624 could be useful in anti-angiogenic therapy of human SCLCs.
authors.affiliation: Department of Pharmacology, Physiology, and Toxicology, Joan C. Edwards School of Medicine, Marshall University, 1700 3rd Avenue, Huntington, WV 25755, USA.
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Brown
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Lau
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Dom
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Witte
authors.forename: Haitao
authors.initials: H
authors.lastname: Luo
authors.forename: Clayton M
authors.initials: CM
authors.lastname: Crabtree
authors.forename: Yashoni H
authors.initials: YH
authors.lastname: Shah
authors.forename: Brandon S
authors.initials: BS
authors.lastname: Shiflett
authors.forename: Aileen J
authors.initials: AJ
authors.lastname: Marcelo
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Proper
authors.forename: W Elaine
authors.initials: WE
authors.lastname: Hardman
authors.forename: Richard D
authors.initials: RD
authors.lastname: Egleton
authors.forename: Yi Charlie
authors.initials: YC
authors.lastname: Chen
authors.forename: Elsa I
authors.initials: EI
authors.lastname: Mangiarua
authors.forename: Piyali
authors.initials: P
authors.lastname: Dasgupta
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002645:Chickens; D015536:Down-Regulation / Q000187:drug effects; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000166:cytology; D051379:Mice; D008819:Mice, Nude; D055806:Microvessels / Q000166:cytology / Q000187:drug effects; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009538:Nicotine / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D018733:Nicotinic Antagonists; D000644:Quaternary Ammonium Compounds; D011978:Receptors, Nicotinic; D013267:Stilbenes; D064569:alpha7 Nicotinic Acetylcholine Receptor; D016222:Fibroblast Growth Factor 2; C118602:triethyl-(beta-4-stilbenoxyethyl)ammonium; D009538:Nicotine