Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 122, Issue 8, Pages 1911-1915Publisher
WILEY
DOI: 10.1002/ijc.23298
Keywords
alpha 7-nAChR; alpha-cobratoxin; apoptosis-induction; mouse models; NSCLC; tumor growth-inhibition
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Nicotinic acetylcholine receptors (nAChR) are expressed on normal bronchial epithelial and nonsmall cell lung cancer (NSCLC) cells and are involved in cell growth regulation. Nicotine induced cell proliferation. The purpose of this study was to determine if interruption of autocrine nicotinic cholinergic signaling might inhibit A549 NSCLC cell growth. For this purpose alpha-Cobratoxin (alpha-CbT), a high affinity alpha 7-nAChR antagonist was studied. Cell growth decrease was evaluated by Clonogenic and MTT assays. Evidence of apoptosis was identified staining cell with Annexin-V/PI. Characterization of the basal NF-kappa B activity was done using the Trans-AM NF-kappa B assay colorimetric kit. In vivo antitumour activity was evaluated in orthotopically transplanted nude mice monitored by In vivo Imaging System technology. alpha-CbT caused concentration-dependent cell growth decrease, mitochondrial apoptosis caspases-9 and 3-dependent, but caspase-2 and p53-independent and down-regulation of basal high levels of activated NF-kappa B. alpha-CbT treatment determines a significant reduction of tumor growth in nude mice orthotopically engrafted with A549-luciferase cells (4.6% of living cells vs. 31% in untreated mice). No sign of toxicity was reported related to treatment. These findings suggest that alpha 7-nAChR antagonists namely a-CbT may be useful adjuvant for treatment of NSCLC and potentially other cancers. (c) 2007 Wiley-Liss, Inc.
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