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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Caspase 3 / metabolism
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Cell Cycle Proteins
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Cell Division / drug effects
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Cell Line, Tumor
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Cell Survival
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Cyclin A / biosynthesis
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Cyclin D1 / biosynthesis
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Cyclin-Dependent Kinase 4 / biosynthesis
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Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
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Cyclin-Dependent Kinase Inhibitor p27 / biosynthesis
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Down-Regulation
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Endometrial Neoplasms / metabolism*
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Female
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HeLa Cells
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Humans
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoproteins / metabolism
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Phosphorylation / drug effects
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Proto-Oncogene Proteins c-akt / metabolism
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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Signal Transduction / drug effects
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TOR Serine-Threonine Kinases / metabolism
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Thioridazine / pharmacology*
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Uterine Cervical Neoplasms / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents
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CDKN1A protein, human
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Cell Cycle Proteins
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Cyclin A
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Cyclin-Dependent Kinase Inhibitor p21
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EIF4EBP1 protein, human
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Phosphoproteins
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Cyclin D1
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Cyclin-Dependent Kinase Inhibitor p27
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MTOR protein, human
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Proto-Oncogene Proteins c-akt
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Ribosomal Protein S6 Kinases, 70-kDa
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TOR Serine-Threonine Kinases
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CDK4 protein, human
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Cyclin-Dependent Kinase 4
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Caspase 3
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Thioridazine