Targeting Neuronal Nicotinic Receptors in Cancer: New Ligands and Potential Side-Effects

Paola      Ambrosi; Andrea      Becchetti

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.

Keywords: Allosteric, CHRNA, CHRNB, GABA, nitrosamine, NSCLC, partial agonist, SCLC