Yonggang Ren1, Jia Tao2, Zhen Jiang1, Dongmei Guo3, Jiancai Tang4. 1. Department of Biochemistry, Nanchong Key Laboratory of Metabolic Drugs and Biological Products, North Sichuan Medical College, Nanchong 637000, China. 2. Department of Pathology, North Sichuan Medical College, Nanchong 637000, China. 3. Department of Biochemistry, North Sichuan Medical College, Nanchong 637000, China. Electronic address: dongmeiguo@nsmc.edu.cn. 4. Department of Biochemistry, Nanchong Key Laboratory of Metabolic Drugs and Biological Products, North Sichuan Medical College, Nanchong 637000, China. Electronic address: tangjiancai@nsmc.edu.cn.
Abstract
OBJECTIVE: Wnt/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 RESULTS: Pimozide 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. CONCLUSION: Pimozide exerts anticancer effect in CRC via inhibition of wnt/β‑catenin signaling pathway, suggesting it as a potential therapeutic drug for CRC.
OBJECTIVE: Wnt/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 RESULTS:Pimozide 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. CONCLUSION:Pimozide exerts anticancer effect in CRC via inhibition of wnt/β‑catenin signaling pathway, suggesting it as a potential therapeutic drug for CRC.