Marshall Digital Scholar

Title

MG624, an a7-nAChR Antagonist, Inhibits Angiogenesis via the Egr-1/FGF2 Pathway

Authors

Kathleen C. Brown, Marshall University
Jamie K. Lau, Marshall UniversityFollow
Aaron M. Dom, Marshall UniversityFollow
Theodore R. Witte, Marshall UniversityFollow
Haitao Luo
Clayton M. Crabtree, Marshall University
Yashoni H. Shah
Brandon S. Shiflett, Marshall UniversityFollow
Aileen J. Marcelo, Marshall UniversityFollow
Nancy A. Proper, Marshall UniversityFollow
W. Elaine Hardman, Marshall UniversityFollow
Richard D. Egleton, Marshall UniversityFollow
Yi Charlie Chen
Elsa I. Mangiarua, Marshall UniversityFollow
Piyali Dasgupta, Marshall UniversityFollow

Document Type

Article

Publication Date

3-2012

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.

Comments

This article first appeared in Volume 15, Number 1 of Angiogenesis, and is reprinted with permission. The final publication is available at http://www.springerlink.com

© 2012 Springer, Part of Springer Science+Business Media

Recommended Citation

Brown KC, Lau JK, Dom AM, Witte TR, Luo H, Crabtree CM, Shah YH, Shiflett BS, Marcelo AJ, Proper NA, Hardman WE, Egleton RD, Chen YC, Mangiarua EI, Dasgupta P. MG624, an α7-nAChR antagonist, inhibits angiogenesis via the Egr-1/FGF2 pathway. Angiogenesis. 2012 Mar; 15(1): 99-114.