Title:Targeting Neuronal Nicotinic Receptors in Cancer: New Ligands and Potential Side-Effects
VOLUME: 8 ISSUE: 1
Author(s):Paola Ambrosi and Andrea Becchetti
Affiliation:Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy.
Keywords:Allosteric, CHRNA, CHRNB, GABA, nitrosamine, NSCLC, partial agonist, SCLC
Abstract:In the nervous system, the neuronal nicotinic acetylcholine receptors (nAChRs) mediate fast excitatory postsynaptic
potentials as well as slower paracrine actions of ACh. They are also widely expressed in non-nervous tissue, including
the neoplastic, which is intriguing as smoking is an established risk factor for cancer. Moreover, recent evidence
attributes to the gene cluster coding for the 3/5/4 nAChR subunits a role in both development of lung cancer and nicotine
addiction. Many cellular effects of nicotine and the tobacco-derived carcinogenic N-nitrosamines are probably caused
by nAChR activation, which regulates cell proliferation, migration, apoptosis and neoangiogenesis. Nonetheless, the precise
nAChR roles in tumors are difficult to determine because cancer cells express a wide variety of nicotinic subunits,
whose function is unclear. Patented compounds which selectively target nAChRs subtypes are increasingly available and
will hopefully allow better understanding of the physiology of these channels in specific cell types, as well as suggest
novel diagnostic and therapeutic approaches. At the present state, however, thorough functional studies of these compounds
are still limited and whether they act as agonists, antagonists or partial agonists is often unclear. Such a blurred
distinction between activators and inhibitors makes detailed studies in expression systems sorely needed for both physiological
understanding and outlining the possible side-effects.
