title: Chemical Screening Identifies EUrd as a Novel Inhibitor Against Temozolomide-Resistant Glioblastoma-Initiating Cells.
abstract: Glioblastoma (GBM), one of the most malignant human cancers, frequently recurs despite multimodal treatment with surgery and chemo/radiotherapies. GBM-initiating cells (GICs) are the likely cell-of-origin in recurrences, as they proliferate indefinitely, form tumors in vivo, and are resistant to chemo/radiotherapies. It is therefore crucial to find chemicals that specifically kill GICs. We established temozolomide (the standard medicine for GBM)-resistant GICs (GICRs) and used the cells for chemical screening. Here, we identified 1-(3-C-ethynyl-β-d-ribopentofuranosyl) uracil (EUrd) as a selective drug for targeting GICRs. EUrd induced the death in GICRs more effectively than their parental GICs, while it was less toxic to normal neural stem cells. We demonstrate that the cytotoxic effect of EUrd on GICRs partly depended on the increased expression of uridine-cytidine kinase-like 1 (UCKL1) and the decreased one of 5'-nucleotidase cytosolic III (NT5C3), which regulate uridine-monophosphate synthesis positively and negatively respectively. Together, these findings suggest that EUrd can be used as a new therapeutic drug for GBM with the expression of surrogate markers UCKL1 and NT5C3. Stem Cells 2016;34:2016-2025.
authors.affiliation: Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.|Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tsukamoto
authors.affiliation: Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ohtsu
authors.affiliation: Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.|Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Smile
authors.initials: S
authors.lastname: Echizenya
authors.affiliation: Center for Research and Education on Drug Discovery, Hokkaido University, Sapporo, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Otsuguro
authors.affiliation: Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Ogura
authors.affiliation: Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Natsumeda
authors.affiliation: Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Isogawa
authors.affiliation: Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Aoki
authors.affiliation: Center for Research and Education on Drug Discovery, Hokkaido University, Sapporo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ichikawa
authors.affiliation: Center for Research and Education on Drug Discovery, Hokkaido University, Sapporo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sakaitani
authors.affiliation: Center for Research and Education on Drug Discovery, Hokkaido University, Sapporo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuda
authors.affiliation: Center for Research and Education on Drug Discovery, Hokkaido University, Sapporo, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Maenaka
authors.affiliation: Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Fujii
authors.affiliation: Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kondo
mesh_terms: D015720:5'-Nucleotidase / Q000378:metabolism; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D016513:Mice, SCID; D000077204:Temozolomide; D014498:Uracil / Q000494:pharmacology / Q000627:therapeutic use*; D014529:Uridine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C103085:1-(3-C-ethynylribopentofuranosyl)uracil; D006023:Glycoproteins; D014498:Uracil; D003606:Dacarbazine; D015720:5'-Nucleotidase; C412794:NT5C3A protein, human; D014529:Uridine; D000077204:Temozolomide
keywords: 1-(3-C-ethynyl-β-d-ribopentofuranosyl) uracil; 5′-Nucleotidase cytosolic III; Glioblastoma-initiating cells; Temozolomide; Uridine-cytidine kinase-like 1