Anti‐tumor and Anti‐Angiogenic activity of the Choline Acetyltransferase Inhibitor BW813U, in Human Lung Adenocarcinoma

Abstract

Lung adenocarcinoma (LACs) accounts for about 60% of all lung cancer cases in the United States. Epidemiological studies show that the development of lung adenocarcinoma is strongly correlated to smoking habits. Although, cigarette smoke is a complex mixture of over 4000 chemicals, nicotine is the active and addictive component of cigarette smoke. Our previous data show that nicotine accelerates the growth of human lung cancers by promoting angiogenesis. The endogenous ligand for nicotine in lung cancer cells is the neurotransmitter ACh. The enzyme choline acetyltransferase (ChAT) synthesizes ACh in mammalian cells. The present study aims to determine the anti-tumor and anti-angiogenic activity of BW813U in human LACs. Human microvascular endothelial cells from the lung (HMEC-L) robustly express enzymatically active ChAT. BW813U robustly blocked the proliferation and angiogenic tubule formation of HMEC-Ls. These experiments were repeated in lung adenocarcinoma-associated endothelial cells (LAAECs) and similar results were obtained. The anti-angiogenic activity of BW813 was confirmed in rat retinal explants assay and chicken chorioallantoic membrane (CAM) assays. Finally, the administration of BW813U potently suppressed the growth of human LAC tumors xenotransplanted in athymic mice. Immunoshistochemical experiments revealed that BW813U-treated human LAC tumors (isolated from athymic mice) contained fewer number of blood vessels than vehicle-treated mice. The anti-angiogenic activity of BW813U was mediated by nicotinic acetylcholine receptors on HMEC-Ls and required the Akt pathway. The administration of BW813U did not cause any discomfort or toxicity in mice. Therefore ChAT blockers (like BW813U) may be useful in suppressing angiogenesis and growth of human LACs.