title: Thioridazine inhibits angiogenesis and tumor growth by targeting the VEGFR-2/PI3K/mTOR pathway in ovarian cancer xenografts.
abstract: Thioridazine, a member of the phenothiazine family, is a powerful anti-anxiety and anti-psychotic drug. It can also suppress the growth of several types of tumor in vitro. In the current study, we evaluated the direct anti-tumor and anti-angiogenic effects of thioridazine in vivo. The injection of thioridazine into human ovarian tumor xenografts in nude mice significantly inhibited tumor growth by ~fivefold, and also decreased tumor vascularity. In addition, thioridazine inhibited the phosphorylation of the signaling molecules downstream of phosphatidylinositol-3'-kinase (PI3K), including Akt, phosphoinositide-dependent protein kinase 1 (PDK1), and mammalian target of rapamycin (mTOR), during ovarian tumor progression via vascular endothelial growth factor receptor 2 (VEGFR-2). These results provide convincing evidence that thioridazine regulates endothelial cell function and subsequent angiogenesis by inhibiting VEGFR-2/PI3K/mTOR signal transduction. Collectively, these results strongly suggest that thioridazine might be a novel anti-tumor and anti-angiogenic agent for use in ovarian cancer.
authors: Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, Goyang-si Gyeonggi-do, Republic of Korea.
authors: Mi Sun
authors: MS
authors: Park
authors: Seung Myung
authors: SM
authors: Dong
authors: Boh-Ram
authors: BR
authors: Kim
authors: Seung Hee
authors: SH
authors: Seo
authors: Sokbom
authors: S
authors: Kang
authors: Eun-Ju
authors: EJ
authors: Lee
authors: Seung-Hoon
authors: SH
authors: Lee
authors: Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, Goyang-si Gyeonggi-do, Republic of Korea.
authors: Seung Bae
authors: SB
authors: Rho
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013881:Thioridazine / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D014150:Antipsychotic Agents; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; D013881:Thioridazine; D040301:Vascular Endothelial Growth Factor Receptor-2