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Nitrosamine-induced lung carcinogenesis and Ca2+/calmodulin antagonists
1Department of Pathobiology, University of Tennessee, Knoxville 37901.
Abstract:
This review summarizes recent data which implicate cell membrane receptors and their associated signal transduction pathways as molecular targets of tobacco-related lung carcinogenesis as well as therapy of such cancers. It is shown that the two nitrosamines N-nitrosodiethylamine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone bind to nicotinic cholinergic receptors in hamster lung. Binding of the nitrosamines as well as nicotine to this receptor stimulates proliferation of human lung carcinoid cells in vitro. These data suggest chronic stimulation of nicotinic receptors by nicotine and nitrosamines in smokers as one of the molecular events responsible for stimulation of neuroendocrine cell proliferation and ultimately the development of lung tumors with neuroendocrine differentiation. On the other hand, a selective antiproliferative effect of the dihydropyridine derivative B859-35 on neuroendocrine lung tumor cells in vivo and in vitro suggests the potential use of such agents as cancer therapeutics. The demonstrated inhibition of Ca2+/calmodulin and protein kinase C by B859-35 as reported in other in vitro systems suggests interference with such elements of signal transduction pathways as the molecular mechanism of the observed antiproliferative effects.
Insights
Tobacco carcinogens like nitrosamines activate nicotinic receptors, promoting lung cancer cell growth. A novel compound, B859-35, shows promise in inhibiting neuroendocrine lung tumor proliferation.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Cell membrane receptors and signal transduction pathways are implicated in tobacco-related lung carcinogenesis.
- Nicotine and tobacco-specific nitrosamines are potential molecular targets for lung cancer therapy.
Purpose of the Study:
- To review recent data on molecular targets in tobacco-related lung carcinogenesis.
- To explore the therapeutic potential of novel compounds against neuroendocrine lung tumors.
Main Methods:
- Review of existing literature on nitrosamine binding to nicotinic cholinergic receptors.
- In vitro and in vivo studies on the antiproliferative effects of dihydropyridine derivative B859-35 on lung tumor cells.
- Investigation of B859-35's mechanism of action, including inhibition of Ca2+/calmodulin and protein kinase C.
Main Results:
- N-nitrosodiethylamine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone bind to nicotinic cholinergic receptors in hamster lung.
- Nitrosamine and nicotine binding stimulates proliferation of human lung carcinoid cells in vitro.
- B859-35 exhibits selective antiproliferative effects on neuroendocrine lung tumor cells.
Conclusions:
- Chronic stimulation of nicotinic receptors by nicotine and nitrosamines may drive neuroendocrine lung tumor development in smokers.
- B859-35's inhibition of key signal transduction pathways suggests its potential as a therapeutic agent for neuroendocrine lung cancers.