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Published ahead of print on January 16, 2009, doi:10.1164/rccm.200806-908OC
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American Journal of Respiratory and Critical Care Medicine Vol 179. pp. 1141-1150, (2009)
© 2009 American Thoracic Society
doi: 10.1164/rccm.200806-908OC

Original Article

Inhibition of Nonneuronal {alpha}7-Nicotinic Receptor for Lung Cancer Treatment

Laura Paleari1, Eva Negri2, Alessia Catassi1,3, Michele Cilli4, Denis Servent5, Rolando D'Angelillo6, Alfredo Cesario7,8, Patrizia Russo1 and Massimo Fini8

1 Lung Cancer Unit, National Cancer Research Institute, Genoa; 2 Istituto di Ricerche Farmacologiche Mario Negri, Clinical Epidemiology, Milan; 3 Thoracic Surgery Unit, University of Insubria, Varese; and 4 Animal Facility Unit, National Cancer Research Institute, Genoa, Italy; 5 Commissariat à l'Energie Atomique, Institut de Biologie et Technologies de Saclay, Service d'Ingénierie Moleculaire des Protéines, Gif sur Yvette, France; 6 Radiotherapy and Oncology Unit, Campus Bio-Medico University; 7 Thoracic Surgery Unit, Catholic University; and 8 Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, Rome, Italy

Correspondence and requests for reprints should be addressed to Patrizia Russo, Ph.D., Lung Cancer Unit, Department of Advanced Technology, Diagnostic National Cancer Research Institute, Largo Rosanna Benzi 10, I-16132 Genoa, Italy. E-mail: patrizia.russo{at}istge.it

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 {alpha}7 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 {alpha}7-nAChR antagonists.

Methods: (1) To check the correlation between {alpha}7-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-XL 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 {alpha}7-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.

Key Words: {alpha}7-nicotinic receptor • non–small cell lung cancer • apoptosis • caspase-9 • antitumor activity


AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject
The {alpha}7-nicotinic subunit has been found to be pivotal in the control of nicotine-induced lung cancer development and in growth signal transduction induced by nicotine.

What This Study Adds to the Field
We report the prolonged survival of {alpha}-CbT–treated animals in our mouse model of non–small cell lung cancer, which is most likely the result of multiple mechanisms, including various antiproliferative and antiangiogenic effects.

 

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