The choline acetyltransferase inhibitor BW813U inhibits angiogenesis and tumor growth in human lung adenocarcinoma

Abstract

Angiogenesis refers to the development of new blood vessels from preexisting blood vessels. The angiogenic pathway is essential for the growth and progression of almost every kind of human cancer. Nicotine, the addictive component of tobacco smoke is known to accelerate the growth of human lung tumors by stimulating tumor angiogenesis. The pro‐angiogenic effects of nicotine are mediated by nicotinic acetylcholine receptors (nAChRs). The endogenous ligand for nicotine is the neurotransmitter acetylcholine (ACh). Published reports show that ACh acts as growth factor for human lung cancers. Almost all lung tissues (including fetal lung) express signaling proteins involved in the synthesis, transport of the ACh‐signaling pathway. These include choline acetyl transferase enzyme (ChAT), vesicular acetylcholine transporter (VAChT), acetylcholine esterase (AChE) and choline transporter (ChT). The primary objective of our studies was to determine if disruption of ChAT could inhibit angiogenesis and suppress the growth of human LACs. We used a small molecule inhibitor of ChAT namely BW813U for our studies. BW813U robustly suppressed angiogenesis in Matrigel assays and chicken chorioallantoic membrane (CAM) assays. The administration of BW813U potenetly decreased the growth rate of H838 tumors xenotransplanted in SCID mice. Immunohistochemical staining experiments revealed that the anti‐tumor activity of BW813U was correlated with decrease of CD31 angiogenic biomarker in H813 tumor sections. The anti‐angiogenic activity of BW813U was mediated by the alpha7‐nAChR pathway and involved the nitric oxide pathway. Taken together, our studies show that ChAT antagonists like BW813U may have applications in the treatment of LAC.