A gene signature-based approach identifies thioridazine as an inhibitor of phosphatidylinositol-3′-kinase (PI3K)/AKT pathway in ovarian cancer cells

ObjectiveThioridazine, a derivative of phenothiazine, has been reported to have antiproliferative activity on tumor cells. However, the mechanism has not been well defined.MethodsUsing 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.ResultsThe 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 G0/G1 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.ConclusionsThe 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.

Research Highlights
► The gene signature based query could identify unveiled function of a drug.
► Thioridazine has a role in the inhibition of PI3K/Akt pathway in ovarian cancer cell.
► Thioridazine exerts cytotoxicity on ovarian cancer cell by inducing cell-growth arrest.