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.

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

“…In view of the important role of a7 nAChRs, both in terms of their expression levels and their relevance for downstream biologic pathways to which they are associated, it was proposed that specific a7 nAChR antagonists such as toxins might be of use in cancer treatment (Alama et al, 2011;Pillai and Chellappan, 2012;Brown et al, 2012).…”

Nicotine and lung cancer

“…[92] Separate studies also demonstrate that nicotine-induced angiogenesis can be prevented with inhibition of the α7nAChR in mice containing SCLC xenografts. [93] Data also suggest that inhibition of COX-2 may prevent the angiogenic effects of nicotine. [82] NNK also increases angiogenesis and VEGF production.…”

Inhibition of Cholinergic Signaling Causes Apoptosis in Human Bronchioalveolar Carcinoma

“…Immunohistochemical staining of VAChT, ChAT in human BAC tissue microarray and normal lung TMA Human BAC tissue microarray (TMA) slides (Abnova) were deparaffinized and rehydrated as described previously (19,20). The immunostaining was conducted using Vectastain ABC Kit (Vector Laboratories) following the manufacturer's protocol.…”