Interaction of tobacco-specific toxicants with the neuronal α7 nicotinic acetylcholine receptor and its associated mitogenic signal transduction pathway: potential role in lung carcinogenesis and pediatric lung disorders

Schüller, Hildegard M.; Jull, Brian A.; Sheppard, Barbara J.; Plummer, Howard K.

doi:10.1016/s0014-2999(00)00094-7

Cited by 106 publications

(81 citation statements)

References 48 publications

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“…For example, the pulmonary neuroendocrine cells are an important source of GRP in the normal organism. These cells function as hypoxia-sensitive chemoreceptors and in situations of pathologic chronic hypoxia, as found in chronic bronchitis, emphysema, and several smokingassociated lung disorders, there is a marked increase in the number of GRP-producing endocrine cells (Johnson and Georgieff, 1989;Sissons and Gosney, 1990;Schuller et al, 2000). Our experimental data indicate that GRP expression is not regulated by hypoxia in lung cancer cells, thus defining GRP as a member of the small but growing class of angiogenic factors whose expression is not part of the tumor survival response to low oxygen tension environments (Michiels et al, 1998;Safronova et al, 2003;Lockwood et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Gastrin-releasing peptide (GRP) induces angiogenesis and the specific GRP blocker 77427 inhibits tumor growth in vitro and in vivo

et al. 2005

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Angiogenesis is becoming a major target for antitumor therapies, and identifying new angiogenic factors and their specific inhibitors may provide new avenues for tumor management. Here we identify gastrin-releasing peptide (GRP) as a new angiogenic molecule that is secreted by tumors and acts directly upon GRP receptors in the endothelial cells. Addition of GRP increases endothelial cell migration and cord formation in vitro, and induces angiogenesis in an in vivo assay. We have recently identified a small molecule GRP blocker, compound 77427. This inhibitor significantly reduced endothelial cell cord formation in vitro and angiogenesis in vivo. Conversely, when applied to VEGF-induced angiogenesis, the small molecule did not have any effect, demonstrating its specificity. Furthermore, this GRP blocker was able to reduce lung tumor cell growth in vitro as demonstrated by MTT and clonogenic assays. When applied to a xenograft model with lung cancer cells, compound 77427 reduced tumor volume to undetectable sizes, although when the treatment was suspended, tumors began to grow again at normal rates. Our collective observations indicate that GRP is a new angiogenic peptide and that its inhibition offers an attractive tool to reduce tumor burden.

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Section: Discussionmentioning

confidence: 99%

Gastrin-releasing peptide (GRP) induces angiogenesis and the specific GRP blocker 77427 inhibits tumor growth in vitro and in vivo

et al. 2005

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“…Previous studies identified α7 nicotinic acetylcholine receptor (nAChR) as the principal receptor subtype mediating effects of tobacco products and pure nicotine on epithelial cells (Cattaneo et al, 1997;Codignola et al, 1994;Schuller, 1989;Schuller et al, 2000;SchullerOrloff, 1998;Schuller et al, 2003). We have demonstrated that α7 nAChR is essential for a sustained turnover of the mucocutaneous epithelium in humans (Arredondo et al, 2002).…”

Section: Introductionmentioning

confidence: 87%

Receptor-mediated tobacco toxicity: Alterations of the NF-κB expression and activity downstream of α7 nicotinic receptor in oral keratinocytes

et al. 2007

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To gain a mechanistic insight into nicotinic receptor-dependent morbidity of tobacco products in the oral cavity, we studied effects of exposures of normal human oral keratinocytes (KCs) for 24 h to environmental tobacco smoke (ETS) vs. equivalent concentration of pure nicotine. The exposed KCs showed a multifold increase of nuclear factor-κB (NF-κB) at the mRNA and protein levels, which could be significantly (p<0.05) diminished by α-bungarotoxin or transfection with anti-α7 small interfering RNA. An increased protein-binding activity of NF-κB also could be prevented by blocking α7 signaling. The use of pathway inhibitors demonstrated that the Ras/Raf-1/MEK1/ERK steps mediated α7-dependent upregulation of NF-κB. Thus, exposure of KCs to tobacco may lead to the pathobiologic effects via an intracellular signaling pathway downstream of α7 that proceeds through the Ras/Raf-1/MEK1/ERK steps leading to upregulated expression and transactivation of NF-κB.

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“…[1][2][3] The adverse effects of nicotine on the cardiovascular system are numerous. 4 As nAChRs are ubiquitous in both the peripheral and central nervous system, a broadly affecting anticholinergic that can cross the blood-brain barrier and act specifically as an nAChR antagonist may reduce the adverse cardiovascular changes associated with smoking and may also aid in smoking cessation.…”

Section: Introductionmentioning

confidence: 99%

Mecamylamine (Inversine®): an old antihypertensive with new research directions

et al. 2002

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Mecamylamine (Inversine  ), the first orally available antihypertensive agent, is now rarely used. Although celebrated in the 1950s, mecamylamine fell out of favour because of its widespread ganglionic side effects at antihypertensive doses (30-90 mg/day). However, recent studies suggest that mecamylamine is very effective at relatively low doses (2.5-5 mg b.i.d.) for blocking the physiological effects of nicotine and improving abstinence rates in smoking cessation studies, particularly for women. When these lower doses of mecamylamine are given, patients do not experience the severity of side effects that made the drug unpopular for the

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Interaction of tobacco-specific toxicants with the neuronal α7 nicotinic acetylcholine receptor and its associated mitogenic signal transduction pathway: potential role in lung carcinogenesis and pediatric lung disorders

Cited by 106 publications

References 48 publications

Gastrin-releasing peptide (GRP) induces angiogenesis and the specific GRP blocker 77427 inhibits tumor growth in vitro and in vivo

Gastrin-releasing peptide (GRP) induces angiogenesis and the specific GRP blocker 77427 inhibits tumor growth in vitro and in vivo

Receptor-mediated tobacco toxicity: Alterations of the NF-κB expression and activity downstream of α7 nicotinic receptor in oral keratinocytes

Mecamylamine (Inversine®): an old antihypertensive with new research directions

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