Inhibition of nonneuronal alpha7-nicotinic receptor for lung cancer treatment.
BACKGROUND
Studies strongly suggest that the nicotinic acetylcholine receptors for nicotine (nAChRs) play a significant role in lung cancer predisposition and natural history. The nAChR alpha7 subunit has been found to be pivotal in the control of nicotine-induced lung cancer development and in growth signal transduction induced by nicotine binding to nAChRs.


OBJECTIVE
To investigate the anticancer effects of alpha7-nAChR antagonists.


METHODS
(1) To check the correlation between alpha7-nAChR presence and alpha-cobratoxin (alpha-CbT) sensitivity, binding experiments were performed in various normal human cells, lung cancer cell lines, and primary tumoral cells; (2) to demonstrate that alpha-CbT might be an efficient adjuvant therapy for non-small cell lung cancer (NSCLC) we expanded our previous observations to a panel of NSCLCs of various subtypes orthotopically grafted on nonobese diabetic/severe combined immunodeficient mice; (3) to gain insight into the mechanism of alpha-CbT-induced tumor reduction, the cells obtained after enzymatic digestion of tumors were analyzed for procaspase-9, Bax, Bad, and Bcl-X(L) protein; and (4) Snail/E-cadherin expression was evaluated to acquire information about the chemoresistance of cancer cells to alpha-CbT.


RESULTS
We report herein the results of an experimental strategy aimed at investigating the antitumor effects of a powerful alpha7-nAChR antagonist, alpha-CbT, in an in vivo setting set to mimic the clinical setting of lung cancer; in addition, a possible explanation for alpha-CbT selectivity toward cancer cells is presented.


CONCLUSIONS
We report the prolonged survival of alpha-CbT-treated animals in our mouse model of NSCLC, which is most likely the result of multiple mechanisms, including various antiproliferative and antiangiogenic effects.
Paleari
Laura
L
Lung Cancer Unit, Department of Advanced Technology, Diagnostic National Cancer Research Institute, Largo Rosanna Benzi 10, Genoa, Italy.
Negri
Eva
E
Catassi
Alessia
A
Cilli
Michele
M
Servent
Denis
D
D'Angelillo
Rolando
R
Cesario
Alfredo
A
Russo
Patrizia
P
Fini
Massimo
M
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002038:Bungarotoxins; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003039:Cobra Neurotoxin Proteins / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D018733:Nicotinic Antagonists / Q000627:therapeutic use*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
D002038:Bungarotoxins; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D003039:Cobra Neurotoxin Proteins; D019394:Ki-67 Antigen; D018733:Nicotinic Antagonists; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C025154:alpha-cobratoxin