Natural agents targeting the alpha7-nicotinic-receptor in NSCLC: a promising prospective in anti-cancer drug development.
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 alpha7-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-kappaB activity was done using the Trans-AM NF-kappaB 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-kappaB. 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 alpha7-nAChR antagonists namely alpha-CbT may be useful adjuvant for treatment of NSCLC and potentially other cancers.
Grozio
Alessia
A
Lung Cancer Unit, National Cancer Research Institute, Genoa, Italy.
Paleari
Laura
L
Catassi
Alessia
A
Servent
Denis
D
Cilli
Michele
M
Piccardi
Federica
F
Paganuzzi
Michela
M
Cesario
Alfredo
A
Granone
Pierluigi
P
Mourier
Gilles
G
Russo
Patrizia
P
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D003039:Cobra Neurotoxin Proteins / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004546:Elapid Venoms / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D064569:alpha7 Nicotinic Acetylcholine Receptor
D000970:Antineoplastic Agents; C579166:Chrna7 protein, mouse; D003039:Cobra Neurotoxin Proteins; D004546:Elapid Venoms; D016328:NF-kappa B; C521753:Naja kaouthia venom; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C025154:alpha-cobratoxin; D020169:Caspases