Inhibition of nonneuronal alpha7-nicotinic receptor for lung cancer treatment.

Abstract

RATIONALE:

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.

OBJECTIVES:

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.

MEASUREMENTS AND MAIN 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.

• Authors: Laura Paleari, Eva Negri, Alessia Catassi, Michele Cilli, Denis Servent, Rolando D'Angelillo, Alfredo Cesario, Patrizia Russo, Massimo Fini
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 179 Issue 12 Pg. 1141-50 (Jun 15 2009) ISSN: 1535-4970 [Electronic] United States
• PMID: 19151195 (Publication Type: Comparative Study, Journal Article, Retracted Publication)

Chemical References

• Bungarotoxins
• Chrna7 protein, human
• Chrna7 protein, mouse
• Cobra Neurotoxin Proteins
• Ki-67 Antigen
• Nicotinic Antagonists
• Platelet Endothelial Cell Adhesion Molecule-1
• Receptors, Nicotinic
• alpha7 Nicotinic Acetylcholine Receptor
• alpha-cobratoxin

Topics

• Animals
• Apoptosis
• Blotting, Western
• Bungarotoxins
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cobra Neurotoxin Proteins (therapeutic use)
• Humans
• Immunohistochemistry
• Ki-67 Antigen (metabolism)
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred NOD
• Neoplasm Transplantation
• Neoplasms, Experimental (metabolism, pathology, therapy)
• Nicotinic Antagonists (therapeutic use)
• Platelet Endothelial Cell Adhesion Molecule-1 (metabolism)
• Receptors, Nicotinic (drug effects, metabolism)
• alpha7 Nicotinic Acetylcholine Receptor