Department of Biochemistry, Nanchong Key Laboratory of Metabolic Drugs and Biological Products, North Sichuan Medical College, Nanchong 637000, China.
Department of Pathology, North Sichuan Medical College, Nanchong 637000, China.
Life Sci. 2018 Sep 15;209:267-273. doi: 10.1016/j.lfs.2018.08.027. Epub 2018 Aug 11.
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.
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 mm) 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.
Pimozide exerts anticancer effect in CRC via inhibition of wnt/β‑catenin signaling pathway, suggesting it as a potential therapeutic drug for CRC.
Wnt/β-连环蛋白信号通路在结直肠癌（CRC）中发挥重要作用，可作为潜在的治疗靶点。匹莫齐特是一种经美国食品和药物管理局批准的用于治疗精神疾病的临床药物，它在部分肿瘤中通过抑制 Wnt/β-连环蛋白信号通路显示出抗癌作用。本研究旨在探讨匹莫齐特是否对 CRC 具有抗癌作用，并探讨其潜在机制。
匹莫齐特用于治疗 HCT116 和 SW480 细胞。采用定量实时聚合酶链反应和蛋白质印迹法检测上皮-间充质转化标志物和 Wnt/β-连环蛋白信号通路相关蛋白的表达。分别通过细胞计数试剂盒-8 和 Transwell 测定细胞增殖和迁移。将 HCT116 和 SW480 细胞皮下注射到裸鼠体内，当肿瘤生长体积可测量（约 100mm）时，动物用载体生理盐水或匹莫齐特（剂量为 25mg/kg·d）灌胃治疗，然后在治疗后 7、14、21 和 28 天测量肿瘤大小。匹莫齐特剂量依赖性地抑制了 HCT116 和 SW480 细胞的增殖和迁移，增加了 E-钙粘蛋白的表达，降低了 N-钙粘蛋白、波形蛋白和 Snail 的表达。此外，匹莫齐特在 HCT116 和 SW480 异种移植瘤体内也抑制了肿瘤生长。匹莫齐特处理降低了 HCT116 和 SW480 细胞中β-连环蛋白和 Wnt 靶基因 c-Myc、cyclin D1、Axin 2 和 survivin 的表达。
匹莫齐特通过抑制 wnt/β-连环蛋白信号通路在 CRC 中发挥抗癌作用，表明其可作为 CRC 的潜在治疗药物。
