Referenced in: none

Automatically associated channels: ClC4

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

Authors: Laura Paleari, Eva Negri, Alessia Catassi, Michele Cilli, Denis Servent, Rolando D'Angelillo, Alfredo Cesario, Patrizia Russo, Massimo Fini

Journal, date & volume: Am. J. Respir. Crit. Care Med., 2009 Jun 15 , 179, 1141-50

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/19151195

Abstract
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.To investigate the anticancer effects of alpha7-nAChR antagonists.(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.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.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.