title: Indatraline inhibits Rho- and calcium-mediated glioblastoma cell motility and angiogenesis.
abstract: Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor of the central nervous system (CNS). As an attempt to identify drugs for GBM therapeutics, phenotypic assays were used to screen 1000 chemicals from a clinical compound library. GBM subtypes exhibited different capabilities to induce angiogenesis when cultured on Matrigel; proneural cells migrated and formed a tube-like structure without endothelial cells. Among the compounds screened, indatraline, a nonselective monoamine transporter inhibitor, suppressed these morphological changes; it dose dependently inhibited cell spreading, migration, and in vitro/in vivo tube formation. In addition to intracellular calcium concentration, indatraline increased the level of Rho GTPase and its activity. Moreover, indatraline downregulated angiogenesis-related genes such as IGFBP2, PTN, VEGFA, PDGFRA, and VEGFR as well as nestin, a stem cell marker. These findings collectively suggest that the activation of Rho GTPase and the suppression of angiogenesis-related factors mediate the antiangiogenic activity of indatraline in proneural GBM culture.
authors: Pharmacology Research Group, Drug Discovery Division, Korea Research Institute of Chemical Technology (KRICT), 141 Gajeong-ro, Yuseong, Daejeon 305-343, Republic of Korea.
authors: Jin-Chul
authors: JC
authors: Heo
authors: Pharmacology Research Group, Drug Discovery Division, Korea Research Institute of Chemical Technology (KRICT), 141 Gajeong-ro, Yuseong, Daejeon 305-343, Republic of Korea; Pharmacology Research Medicinal and Pharmaceutical Chemistry, University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon 305-343, Republic of Korea.
authors: Tae-Hoon
authors: TH
authors: Jung
authors: Pharmacology Research Group, Drug Discovery Division, Korea Research Institute of Chemical Technology (KRICT), 141 Gajeong-ro, Yuseong, Daejeon 305-343, Republic of Korea.
authors: Dae-Young
authors: DY
authors: Jung
authors: Pharmacology Research Group, Drug Discovery Division, Korea Research Institute of Chemical Technology (KRICT), 141 Gajeong-ro, Yuseong, Daejeon 305-343, Republic of Korea.
authors: Woo Kyu
authors: WK
authors: Park
authors: Pharmacology Research Group, Drug Discovery Division, Korea Research Institute of Chemical Technology (KRICT), 141 Gajeong-ro, Yuseong, Daejeon 305-343, Republic of Korea. Electronic address: hycho@krict.re.kr.
authors: Heeyeong
authors: H
authors: Cho
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005909:Glioblastoma / Q000150:complications / Q000378:metabolism*; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D008744:Methylamines / Q000494:pharmacology*; D009389:Neovascularization, Pathologic / Q000150:complications / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D042501:Angiogenic Proteins; D007189:Indans; D008744:Methylamines; C418119:indatraline; D020741:rho GTP-Binding Proteins; D002118:Calcium
keywords: GBM; Glioblastoma multiforme; IGFBP2; Indatraline; PDGFRA; PTN; Proneural; Rho-GTP; VEGFA; VEGFR; glioblastoma multiforme; insulin-like growth factor-binding protein 2; platelet-derived growth factor receptor alpha; pleiotropin; vascular endothelial growth factor A; vascular endothelial growth factor receptor