Inhibition of nonneuronal α7-nicotinic receptor for lung cancer treatment

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

Research output: Contribution to journalArticle

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 α7 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 α7-nAChR antagonists. Methods: (1) To check the correlation between α7-nAChR presence and α-cobratoxin (α-CbT) sensitivity, binding experiments were performed in various normal human cells, lung cancer cell lines, and primary tumoral cells; (2) to demonstrate that α-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 α-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 α-CbT. Measurements and Main Results: We report herein the results of an experimental strategy aimed at investigating the antitumor effects of a powerful α7-nAChR antagonist, α-CbT, in an in vivo setting set to mimic the clinical setting of lung cancer; in addition, a possible explanation for α-CbT selectivity toward cancer cells is presented. Conclusions: We report the prolonged survival of α-CbT-treated animals in our mouse model of NSCLC, which is most likely the result of multiple mechanisms, including various antiproliferative and antiangiogenic effects.

Original languageEnglish
Pages (from-to)1141-1150
Number of pages10
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume179
Issue number12
DOIs
Publication statusPublished - Jun 15 2009

Keywords

  • α7-nicotinic receptor
  • Antitumor activity
  • Apoptosis
  • Caspase-9
  • Non-small cell lung cancer

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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