title: Use of an anti-viral drug, Ribavirin, as an anti-glioblastoma therapeutic.
abstract: The median survival for glioblastoma patients is ~15 months despite aggressive surgery and radio-chemotherapy approaches. Thus, developing new therapeutics is necessary to improve the treatment of these invasive brain tumors, which are known to show high levels of the eukaryotic initiation factor, eIF4E, a potent oncogene. Ribavirin, the only clinically approved drug known to target eIF4E, is an anti-viral molecule currently used in hepatitis C treatment. Here, we report the effect of ribavirin on proliferation, cell cycle, cell death and migration of several human and murine glioma cell lines, as well as human glioblastoma stem-like cells, in vitro. In addition, we tested ribavirin efficacy in vivo, alone and in combination with temozolomide and radiation. Our work showed that ribavirin inhibits glioma cell growth and migration, and increases cell cycle arrest and cell death, potentially through modulation of the eIF4E, EZH2 and ERK pathways. We also demonstrate that ribavirin treatment in combination with temozolomide or irradiation increases cell death in glioma cells. Finally and most importantly, ribavirin treatment in vivo significantly enhances chemo-radiotherapy efficacy and improves survival of rats and mice orthotopically implanted with gliosarcoma tumors or glioma stem-like cells, respectively. On the basis of these results, we propose that ribavirin represents a new therapeutic option for glioblastoma patients as an enhancer of the cytotoxic effects of temozolomide and radiotherapy.
authors.affiliation: Department of Neurosurgery, Hunterian Neurosurgical Research Laboratory, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: F
authors.initials: F
authors.lastname: Volpin
authors.affiliation: Department of Neurosurgery, Hunterian Neurosurgical Research Laboratory, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Casaos
authors.affiliation: Department of Neurosurgery, Hunterian Neurosurgical Research Laboratory, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, USA.|INSERM U1037, Centre de Recherche en Cancérologie de Toulouse, CRCT, Toulouse, France.
authors.forename: J
authors.initials: J
authors.lastname: Sesen
authors.affiliation: Department of Neurosurgery, Hunterian Neurosurgical Research Laboratory, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Mangraviti
authors.affiliation: Department of Neurosurgery, Hunterian Neurosurgical Research Laboratory, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Neurosurgery, Hunterian Neurosurgical Research Laboratory, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: N
authors.initials: N
authors.lastname: Gorelick
authors.affiliation: Department of Neurosurgery, Hunterian Neurosurgical Research Laboratory, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Frikeche
authors.affiliation: Department of Neurosurgery, Hunterian Neurosurgical Research Laboratory, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: T
authors.initials: T
authors.lastname: Lott
authors.affiliation: Department of Neurosurgery, Hunterian Neurosurgical Research Laboratory, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: R
authors.initials: R
authors.lastname: Felder
authors.affiliation: Department of Neurosurgery, Hunterian Neurosurgical Research Laboratory, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Scotland
authors.affiliation: Department of Pathology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: T S K
authors.initials: TSK
authors.lastname: Eisinger-Mathason
authors.affiliation: Department of Neurosurgery, Hunterian Neurosurgical Research Laboratory, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: H
authors.initials: H
authors.lastname: Brem
authors.affiliation: Department of Neurosurgery, Hunterian Neurosurgical Research Laboratory, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: B
authors.initials: B
authors.lastname: Tyler
authors.affiliation: Department of Neurosurgery, Hunterian Neurosurgical Research Laboratory, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, USA.|INSERM U1037, Centre de Recherche en Cancérologie de Toulouse, CRCT, Toulouse, France.
authors.forename: N
authors.initials: N
authors.lastname: Skuli
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000998:Antiviral Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D058492:Drug Repositioning; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D051381:Rats; D011916:Rats, Inbred F344; D012254:Ribavirin / Q000627:therapeutic use*; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D000998:Antiviral Agents; D012254:Ribavirin; D003606:Dacarbazine; D000077204:Temozolomide