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.