title: Anti-angiogenic effects of thioridazine involving the FAK-mTOR pathway.
abstract: Thioridazine is a type of anti-psychotic drug that also includes anti-tumor activity. In this study, we assessed the effects of thioridazine, as a novel anti-angiogenic agent, on the suppression of angiogenesis-mediated cell proliferation. Thioridazine was found to inhibit growth in ovarian cancer cells (OVCAR-3 and 2774), but did not possess any inhibitory effects on normal cell types such as HOSE-E6E7, MCF-10A, MRC-5, and BEAS-2B. Thioridazine also suppressed vascular endothelial growth factor (VEGF)-stimulated HUVEC migration in a dose-time-dependent manner. We also showed that being treated with thioridazine inhibited VEGF-stimulated proliferation, invasion, and capillary-like structure tube formation in vitro. Thioridazine suppressed phosphorylation of the signaling regulators downstream of the focal adhesion kinase (FAK) through αvβ3 integrin, which also include Akt, phosphoinositide-dependent protein kinase 1 (PDK-1), mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase (p70S6K), but had no effect on VEGF-stimulated extracellular signal-regulated kinase (ERK) phosphorylation. We found the molecular mechanism of thioridazine to be a novel anti-angiogenic protein. These results provide evidence for the regulation of endothelial cell functions that are relevant to angiogenesis through the suppression of the αvβ3/FAK/mTOR signaling pathway.
authors.affiliation: Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, Goyang-si Gyevonggi-do 410-769, Republic of Korea.
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Byun
authors.forename: Jeong Heon
authors.initials: JH
authors.lastname: Lee
authors.forename: Boh-Ram
authors.initials: BR
authors.lastname: Kim
authors.forename: Sokbom
authors.initials: S
authors.lastname: Kang
authors.forename: Seung Myung
authors.initials: SM
authors.lastname: Dong
authors.forename: Mi Sun
authors.initials: MS
authors.lastname: Park
authors.forename: Seung-Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Park
authors.forename: Seung Bae
authors.initials: SB
authors.lastname: Rho
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013881:Thioridazine / Q000494:pharmacology*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D048049:Extracellular Signal-Regulated MAP Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D039302:Integrin alphaVbeta3; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; D013881:Thioridazine; C546842:MTOR protein, human