Department of Pharmacology, Physiology, and Toxicology, Joan C. Edwards School of Medicine, Marshall University, 1700 3rd Avenue, Huntington, WV 25755, USA.
Angiogenesis. 2012 Mar;15(1):99-114. doi: 10.1007/s10456-011-9246-9. Epub 2011 Dec 25.
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.
小细胞肺癌（SCLC）与吸烟有很强的病因学关联。虽然香烟烟雾是由大约 4000 种化合物组成的混合物，但尼古丁是香烟烟雾中的成瘾成分。几项趋同研究表明，尼古丁通过内皮细胞上的α7-烟碱型乙酰胆碱受体（α7-nAChR）促进肺癌中的血管生成。因此，我们推测α7-nAChR 拮抗剂可能会减弱尼古丁诱导的血管生成，并且对治疗人类 SCLC 有用。我们的研究首次探讨了小分子α7-nAChR 拮抗剂 MG624 在几种血管生成实验模型中的抗血管生成活性。我们观察到 MG624 能有效地抑制原代人肺微血管内皮细胞（HMEC-Ls）的增殖。此外，MG624 在 Matrigel、大鼠主动脉环和大鼠视网膜外植体实验中表现出强大的抗血管生成活性。通过两种体内模型，即鸡胚绒毛尿囊膜模型和裸鼠模型，评估了 MG624 的抗血管生成活性。在这两种实验模型中，MG624 均抑制了人 SCLC 肿瘤的血管生成。最重要的是，MG624 的给药在小鼠中没有引起任何毒性副作用、昏睡或不适。MG624 通过抑制 HMEC-Ls 中尼古丁诱导的 FGF2 水平发挥抗血管生成作用。MG624 降低了 HMEC-Ls 中尼古丁诱导的早期生长反应基因 1（Egr-1）水平，并减少了 FGF2 启动子上的 Egr-1 水平。因此，这一过程降低了 FGF2 水平和血管生成。我们的研究结果表明，MG624 的抗血管生成作用可能有助于人类 SCLC 的抗血管生成治疗。
