A Novel Mechanism for Nicotinic Acetylcholine Receptor Antagonist-Induced Cancer Cell Cytotoxicity

Abstract

Nicotinic acetylcholine receptors (nAChRs) are common ligand-activated neurotransmitter receptors located throughout the body. The up-regulation of nAChRs subunits has been observed in a number of cancer types; while current literature has identified various nAChR pathways that contribute to the development of cancer. The present study identified a novel mechanism for the observed cytotoxicity of the highly potent nAChR antagonist, pinnatoxin (PnTX), on human epithelial carcinoma cell lines. Cell cycle and intracellular calcium studies suggest that PnTX exerts its cytotoxic effects by inducing changes in the cell cycle via antagonism of the highly calcium permeable α7-, and to a certain extent, the α4β2-nAChR receptors. This leads to an induction of cell apoptosis via calcium-independent pathways. The use of nAChRs in combination with other known cytotoxic agents, such as cyclosporin A, or apoptotic inducing chemotherapy agents, may provide a sensitising tool that can reduce the dose required to elicit a cytotoxic response on developing tumours.