Genomes and Genes
Can nicotinic antagonists prevent tobacco smoke-induced*
Principal Investigator: SERGEI GRANDO
Abstract: 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.
Funding Period: 2005-08-01 - 2007-06-30
more information: NIH RePORT
- Nicotinic receptors mediate tumorigenic action of tobacco-derived nitrosamines on immortalized oral epithelial cellsJuan Arredondo
Department of Dermatology, University of California at Davis, Davis, California, USA
Cancer Biol Ther 5:511-7. 2006..The obtained results establish the role of specific nAChR subtypes in tobacco-related carcinogenesis and open a novel avenue for oral cancer chemoprevention...
- The nicotinic receptor antagonists abolish pathobiologic effects of tobacco-derived nitrosamines on BEP2D cellsJuan Arredondo
Department of Dermatology, University of California, Davis, 3301 C Street, Suite 1400, Sacramento, CA 95816, USA
J Cancer Res Clin Oncol 132:653-63. 2006..The obtained results support the novel concept of receptor-mediated action of NNK and NNN placing cellular nAChRs in the center of the pathophysiologic loop, and suggest that an nAChR antagonist may serve as a chemopreventive agent...
- 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 keratinocytesJuan Arredondo
Department of Dermatology, University of California Davis, Sacramento, CA, USA
FASEB J 20:2093-101. 2006....
- SLURP-1 and -2 in normal, immortalized and malignant oral keratinocytesJuan Arredondo
Department of Dermatology, University of California, Davis, CA 95816, USA
Life Sci 80:2243-7. 2007..These "proof-of-concept" preliminary results have salient clinical implications...
- Receptor-mediated tobacco toxicity: alterations of the NF-kappaB expression and activity downstream of alpha7 nicotinic receptor in oral keratinocytesJuan Arredondo
Department of Dermatology, University of California, Davis, USA
Life Sci 80:2191-4. 2007....
- Overexpression of SLURP-1 and -2 alleviates the tumorigenic action of tobacco-derived nitrosamine on immortalized oral epithelial cellsJuan Arredondo
Department of Dermatology, University of California at Irvine, Irvine, CA 92697, USA
Biochem Pharmacol 74:1315-9. 2007..Thus, the anti-tumorigenic activities of SLURP-1 and -2 were demonstrated both in vitro and in vivo. The obtained results suggest that SLURP-like proteins may become useful for developing novel anti-cancer therapies...
- Basic and clinical aspects of non-neuronal acetylcholine: biological and clinical significance of non-canonical ligands of epithelial nicotinic acetylcholine receptorsSergei A Grando
Department of Dermatology, University of California Irvine 92697, USA
J Pharmacol Sci 106:174-9. 2008....
- Receptor-mediated tobacco toxicity: acceleration of sequential expression of alpha5 and alpha7 nicotinic receptor subunits in oral keratinocytes exposed to cigarette smokeJuan Arredondo
Department of Dermatology, University of California, Irvine, C340 Medical Sciences I, Irvine, CA 92697, USA
FASEB J 22:1356-68. 2008....