title: Fluvoxamine, an anti-depressant, inhibits human glioblastoma invasion by disrupting actin polymerization.
abstract: Glioblastoma multiforme (GBM) is the most common malignant brain tumor with a median survival time about one year. Invasion of GBM cells into normal brain is the major cause of poor prognosis and requires dynamic reorganization of the actin cytoskeleton, which includes lamellipodial protrusions, focal adhesions, and stress fibers at the leading edge of GBM. Therefore, we hypothesized that inhibitors of actin polymerization can suppress GBM migration and invasion. First, we adopted a drug repositioning system for screening with a pyrene-actin-based actin polymerization assay and identified fluvoxamine, a clinically used antidepressant. Fluvoxamine, selective serotonin reuptake inhibitor, was a potent inhibitor of actin polymerization and confirmed as drug penetration through the blood-brain barrier (BBB) and accumulation of whole brain including brain tumor with no drug toxicity. Fluvoxamine inhibited serum-induced ruffle formation, cell migration, and invasion of human GBM and glioma stem cells in vitro by suppressing both FAK and Akt/mammalian target of rapamycin signaling. Daily treatment of athymic mice bearing human glioma-initiating cells with fluvoxamine blocked tumor cell invasion and prolonged the survival with almost same dose of anti-depressant effect. In conclusion, fluvoxamine is a promising anti-invasive treatment against GBM with reliable approach.
authors.affiliation: Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.|Department of Pharmacy, Okayama University Hospital, Okayama, Japan.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Michiue
authors.affiliation: Department of Neuroscience, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Takata
authors.affiliation: Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nakayama
authors.affiliation: Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Fan-Yan
authors.initials: FY
authors.lastname: Wei
authors.affiliation: Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Fujimura
authors.affiliation: Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan.|Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tazawa
authors.affiliation: Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Asai
authors.affiliation: Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Naohisa
authors.initials: N
authors.lastname: Ogo
authors.affiliation: Division of Pharmaceutical Sciences, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyachi
authors.affiliation: Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Tei-ichi
authors.initials: T
authors.lastname: Nishiki
authors.affiliation: Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Tomizawa
authors.affiliation: Department of Neuroscience, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Takei
authors.affiliation: Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Matsui
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D058492:Drug Repositioning; D016666:Fluvoxamine / Q000008:administration & dosage* / Q000494:pharmacology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D016666:Fluvoxamine