Vesamicol, an inhibitor of vesicular acetylcholine transporter, causes apoptosis in human lung adenocarcinomas (151.3)

Abstract

Clinical studies show that the development of lung adenocarcinomas (LACs) is correlated with smoking habits. Nicotine, the addictive component of cigarettes, accelerates human LAC proliferation through nicotinic acetylcholine receptors (nAChRs). Human LACs contain all of the cholinergic system proteins, including acetylcholinesterase (AChE), choline acetyltransferase (ChAT), choline transporter 1 (CHT1), vesicular acetylcholine transporter (VAChT) and nAChRs. In the present study we show that nicotine upregulates VAChT and ChAT. Therefore, we hypothesized that VAChT antagonists, such as vesamicol, may abrogate the growth of human LACs. Vesamicol induced potent apoptosis of nicotine‐treated human LACs in cell culture and nude mice models. Vesamicol did not have any effect on EGF or IGF‐II‐induced growth of human LAC’s. The ablation of VAChT levels by siRNA methodology reversed the apoptotic activity of vesamicol. We also observed that vesamicol caused cell death by inhibiting Akt phosphorylation. Taken together, our data shows that inhibition of nicotine‐induced cholinergic pathway by agents such as vesamicol may be useful for the treatment of human LACs.Grant Funding Source: Supported by an NIH R15‐Area Grant, a FAMRI YCSA Grant, and WV INBRE