title: Thioridazine induces apoptosis by targeting the PI3K/Akt/mTOR pathway in cervical and endometrial cancer cells.
abstract: Recently, thioridazine (10-[2-(1-methyl-2-piperidyl) ethyl]-2-methylthiophenothiazine), a well-known anti-psychotic agent was found to have anti-cancer activity in cancer cells. However, the molecular mechanism of the agent in cellular signal pathways has not been well defined. Thioridazine significantly increased early- and late-stage apoptotic fraction in cervical and endometrial cancer cells, suggesting that suppression of cell growth by thioridazine was due to the induction of apoptosis. Cell cycle analysis indicated thioridazine induced the down-regulation of cyclin D1, cyclin A and CDK4, and the induction of p21 and p27, a cyclin-dependent kinase inhibitor. Additionally, we compared the influence of thioridazine with cisplatin used as a control, and similar patterns between the two drugs were observed in cervical and endometrial cancer cell lines. Furthermore, as expected, thioridazine successfully inhibited phosphorylation of Akt, phosphorylation of 4E-BP1 and phosphorylation of p70S6K, which is one of the best characterized targets of the mTOR complex cascade. These results suggest that thioridazine effectively suppresses tumor growth activity by targeting the PI3K/Akt/mTOR/p70S6K signaling pathway.
authors.affiliation: Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769, Republic of Korea.
authors.forename: Sokbom
authors.initials: S
authors.lastname: Kang
authors.forename: Seung Myung
authors.initials: SM
authors.lastname: Dong
authors.forename: Boh-Ram
authors.initials: BR
authors.lastname: Kim
authors.forename: Mi Sun
authors.initials: MS
authors.lastname: Park
authors.forename: Barry
authors.initials: B
authors.lastname: Trink
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Byun
authors.forename: Seung Bae
authors.initials: SB
authors.lastname: Rho
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival; D019925:Cyclin A / Q000096:biosynthesis; D019938:Cyclin D1 / Q000096:biosynthesis; D051358:Cyclin-Dependent Kinase 4 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D015536:Down-Regulation; D016889:Endometrial Neoplasms / Q000378:metabolism*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013881:Thioridazine / Q000494:pharmacology*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D053148:Caspase 3; D018797:Cell Cycle Proteins; D019925:Cyclin A; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D013881:Thioridazine; C493956:CDKN1A protein, human; C087000:EIF4EBP1 protein, human; C546842:MTOR protein, human; C495900:CDK4 protein, human