Pimozide suppresses colorectal cancer via inhibition of Wnt/β-catenin signaling pathway

摘要

ObjectiveWnt/β?catenin signaling pathway plays important role in colorectal cancer (CRC) and acts as a potential therapeutic target. Pimozide is a FDA-approved clinical drug used to treat psychotic diseases and it has shown anticancer effect in some tumors partially via inhibition of Wnt/β?catenin signaling pathway. This study aimed to investigate whether pimozide exerts anticancer effect on CRC and explore underlying mechanism. Methods and resultsPimozide was administrated to treat HCT116 and SW480 cells. Quantitative real-time polymerase chain reaction and western blot were used to detect the expression of epithelial-to-mesenchymal transition markers and Wnt/β?catenin signaling pathway-related proteins. Cell proliferation and migration were measured by Cell Counting Kit-8 and Transwell assays respectively. HCT116 and SW480 cells were subcutaneously injected into nude mice and when the volume of tumor grown measureable (approximately 100?mm3) animals were treated with vehicle saline or pimozide at a dose of 25?mg/kg·d by oral gavage and then tumor size was measured at 7, 14, 21 and 28?days post treatment. Pimozide dose-dependently inhibited cell proliferation and migration in both HCT116 and SW480 cells, increased expression of E-cadherin and decreased expression of N?cadherin, vimentin and Snail. In addition, tumor growth was inhibited by pimozide in both HCT116 and SW480 xenografts in vivo. Expression of β?catenin and Wnt target genes c-Myc, cyclin D1, Axin 2 and survivin was reduced by pimozide treatment in both HCT 116 and SW480 cells. ConclusionPimozide exerts anticancer effect in CRC via inhibition of wnt/β?catenin signaling pathway, suggesting it as a potential therapeutic drug for CRC.