Division of Gynecologic Cancer Research, Research Institute and Hospital, National Cancer Center, Goyang 410-769, Republic of Korea.
Gynecol Oncol. 2011 Jan;120(1):121-7. doi: 10.1016/j.ygyno.2010.10.003. Epub 2010 Oct 29.
Thioridazine, a derivative of phenothiazine, has been reported to have antiproliferative activity on tumor cells. However, the mechanism has not been well defined.
Using in-silico gene signature based approach, we have demonstrated that thioridazine could inhibit phosphatidylinositol-3'-kinase (PI3K)/Akt pathway, and thus exert cytotoxicity in ovarian cancer cells.
The Connectivity Map indicated that thioridazine induces gene signature similar to that of Akt inhibition. Moreover, preexisting inhibitors of PI3K/Akt pathway were also found to reveal similar signature. In SKOV-3 cells, immunoblot using p85 antibody showed that thioridazine could inhibit PI3K signal. In addition, thioridazine was found to inhibit p-Akt (Ser 473) in a dose-dependent manner. Furthermore, thioridazine was found to decrease cell viability and induce apoptosis. Exposure to thioridazine induced G(0)/G(1) arrest and down-regulated the cell cycle regulator, Cyclin D1 and CDK4, and up-regulated p21, p16, and p-CDC25A. Finally, additive cytotoxicity was observed when cisplatin and thioridazine were treated simultaneously.
The current study indicated that in-silico approach, such as Connectivity Map, is a potentially useful method to identify the unknown cellular function among the drugs already in use in clinic. Owing to the property of Akt inhibition and additive cytotoxicity observed with the platinum compound, further research should be focused on this drug.
噻吨嗪是吩噻嗪的衍生物，据报道对肿瘤细胞具有抗增殖活性。然而，其机制尚未得到很好的定义。
我们使用基于基因表达谱的计算方法，证明噻吨嗪可以抑制磷脂酰肌醇-3'-激酶（PI3K）/Akt 通路，从而在卵巢癌细胞中发挥细胞毒性。
连接图谱表明，噻吨嗪诱导的基因特征类似于 Akt 抑制。此外，还发现现有的 PI3K/Akt 通路抑制剂也具有相似的特征。在 SKOV-3 细胞中，使用 p85 抗体的免疫印迹显示噻吨嗪可以抑制 PI3K 信号。此外，噻吨嗪被发现以剂量依赖性方式抑制 p-Akt（Ser 473）。此外，噻吨嗪被发现降低细胞活力并诱导细胞凋亡。暴露于噻吨嗪诱导 G0/G1 期停滞，并下调细胞周期调节剂 Cyclin D1 和 CDK4，上调 p21、p16 和 p-CDC25A。最后，当顺铂和噻吨嗪同时处理时，观察到相加的细胞毒性。
本研究表明，基于 Connectivity Map 的计算方法是一种潜在有用的方法，可以识别临床中已使用的药物的未知细胞功能。鉴于观察到 Akt 抑制和与铂化合物的相加细胞毒性的特性，应进一步集中研究这种药物。
