Long-term Objective: To develop pharmacological chemoprevention of lung cancer in former smokes, and in people exposed to secondhand smoke. Rationale: During the first few years after smoking cessation, former smokers have an increased risk for lung cancer, compared to current or never smokers. Background: Nicotine and carcinogenic nitrosamines have been shown to alter pulmonary cells via the nicotinic class of acetylcholine receptors (nAChRs) expressed on the plasma membrane of non-neuronal cells. Chronic exposure to environmental tobacco smoke (ETS) or pure nicotine in both cases alter cell growth regulation, and also changes repertoire of cellular nAChR subtypes. Working Hypotheses: Pharmacological antagonism at nAChRs should decrease the frequency of tobacco-induced lung tumors by blocking the signaling pathways used by nicotine and carcinogenic nitrosamines.
Specific Aims : To determine the ability of nAChR antagonists to prevent ETS- or 4(methylnitrosamino)-1- (3-pyridyl)-1-butanone (NNK)-induced increase of lung tumors in A/J mice. Methodology: This proposal will utilize an established animal model to study chemoprevention of tobacco smoke carcinogenesis in the lung. The strain A/J mice develop lung tumors after exposure to ETS for 5 months, followed by a 4-months recovery period in air. The mice will be treated with ETS, NNK or pure nicotine in the absence or presence of pharmacological antagonists of alpha7 or non-alpha7 nAChRs. Both tumor incidence and tumor multiplicity will be analyzed at the end of experiments. Significance. Results of this proposal will lay a groundwork for future studies in this novel direction for the development of efficacious methods of chemoprevention of tobacco-related cancers through pharmacological blockade of pulmonary nAChRs. DESCRIPTION. The proposed research stems from the well-substantiated hypothesis that an increased frequency of lung cancer in former smokers results from nicotine-induced alterations of binding to and signaling within the lung cells of the local hormone acetylcholine. The proposed studies will determine if specific drugs that can abolish an ability of nicotine and its carcinogenic derivatives to affect pulmonary cells through this pathway can decrease lung tumor development in the stain A/J mice, an established animal model for studying tumor-producing effects of cigarette smoke and chemical carcinogens.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
7R03CA117327-03
Application #
7522178
Study Section
Special Emphasis Panel (ZCA1-SRRB-U (M1))
Program Officer
Steele, Vernon E
Project Start
2005-08-01
Project End
2008-07-31
Budget Start
2007-12-01
Budget End
2008-07-31
Support Year
3
Fiscal Year
2006
Total Cost
$18,059
Indirect Cost
Name
University of California Irvine
Department
Dermatology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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Grando, Sergei A (2008) Basic and clinical aspects of non-neuronal acetylcholine: biological and clinical significance of non-canonical ligands of epithelial nicotinic acetylcholine receptors. J Pharmacol Sci 106:174-9
Arredondo, Juan; Chernyavsky, Alexander I; Jolkovsky, David L et al. (2007) Receptor-mediated tobacco toxicity: alterations of the NF-kappaB expression and activity downstream of alpha7 nicotinic receptor in oral keratinocytes. Life Sci 80:2191-4
Arredondo, Juan; Chernyavsky, Alex I; Grando, Sergei A (2007) Overexpression of SLURP-1 and -2 alleviates the tumorigenic action of tobacco-derived nitrosamine on immortalized oral epithelial cells. Biochem Pharmacol 74:1315-9
Arredondo, Juan; Chernyavsky, Alexander I; Grando, Sergei A (2007) SLURP-1 and -2 in normal, immortalized and malignant oral keratinocytes. Life Sci 80:2243-7
Arredondo, Juan; Chernyavsky, Alex I; Grando, Sergei A (2006) Nicotinic receptors mediate tumorigenic action of tobacco-derived nitrosamines on immortalized oral epithelial cells. Cancer Biol Ther 5:511-7
Arredondo, Juan; Chernyavsky, Alexander I; Jolkovsky, David L et al. (2006) Receptor-mediated tobacco toxicity: cooperation of the Ras/Raf-1/MEK1/ERK and JAK-2/STAT-3 pathways downstream of alpha7 nicotinic receptor in oral keratinocytes. FASEB J 20:2093-101
Arredondo, Juan; Chernyavsky, Alex I; Grando, Sergei A (2006) The nicotinic receptor antagonists abolish pathobiologic effects of tobacco-derived nitrosamines on BEP2D cells. J Cancer Res Clin Oncol 132:653-63