title: In vitro screening of clinical drugs identifies sensitizers of oncolytic viral therapy in glioblastoma stem-like cells.
abstract: Oncolytic viruses (OV) have broad potential as an adjuvant for the treatment of solid tumors. The present study addresses the feasibility of clinically applicable drugs to enhance the oncolytic potential of the OV Delta24-RGD in glioblastoma. In total, 446 drugs were screened for their viral sensitizing properties in glioblastoma stem-like cells (GSCs) in vitro. Validation was done for 10 drugs to determine synergy based on the Chou Talalay assay. Mechanistic studies were undertaken to assess viability, replication efficacy, viral infection enhancement and cell death pathway induction in a selected panel of drugs. Four viral sensitizers (fluphenazine, indirubin, lofepramine and ranolazine) were demonstrated to reproducibly synergize with Delta24-RGD in multiple assays. After validation, we underscored general applicability by testing candidate drugs in a broader context of a panel of different GSCs, various solid tumor models and multiple OVs. Overall, this study identified four viral sensitizers, which synergize with Delta24-RGD and two other strains of OVs. The viral sensitizers interact with infection, replication and cell death pathways to enhance efficacy of the OV.
authors.affiliation: Department of Neurosurgery, Brain Tumor Center Erasmus MC, Rotterdam, The Netherlands.
authors.forename: L M E
authors.initials: LM
authors.lastname: Berghauser Pont
authors.affiliation: Department of Neurosurgery, Brain Tumor Center Erasmus MC, Rotterdam, The Netherlands.
authors.forename: R K
authors.initials: RK
authors.lastname: Balvers
authors.affiliation: Department of Neurosurgery, Brain Tumor Center Erasmus MC, Rotterdam, The Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Kloezeman
authors.affiliation: Harvey Cushing Neuro-oncology Laboratories, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: M O
authors.initials: MO
authors.lastname: Nowicki
authors.affiliation: Department of Neurosurgery, Brain Tumor Center Erasmus MC, Rotterdam, The Netherlands.|Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: van den Bossche
authors.affiliation: Department of Bioinformatics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Kremer
authors.affiliation: Department of Neurosurgery, Massachussets General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Wakimoto
authors.affiliation: Department of Viroscience Erasmus MC, Rotterdam, The Netherlands.
authors.forename: B G
authors.initials: BG
authors.lastname: van den Hoogen
authors.affiliation: Department of Neurosurgery, Brain Tumor Center Erasmus MC, Rotterdam, The Netherlands.|Department of Neurosurgery, Elisabeth Hospital, Tilburg, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Leenstra
authors.affiliation: Department of Neurosurgery, Brain Tumor Center Erasmus MC, Rotterdam, The Netherlands.
authors.forename: C M F
authors.initials: CM
authors.lastname: Dirven
authors.affiliation: Harvey Cushing Neuro-oncology Laboratories, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Chiocca
authors.affiliation: Harvey Cushing Neuro-oncology Laboratories, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Lawler
authors.affiliation: Department of Neurosurgery, Brain Tumor Center Erasmus MC, Rotterdam, The Netherlands.
authors.forename: M L M
authors.initials: ML
authors.lastname: Lamfers
mesh_terms: D001932:Brain Neoplasms / Q000188:drug therapy / Q000628:therapy / Q000821:virology; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D005476:Fluphenazine / Q000494:pharmacology; D005909:Glioblastoma / Q000188:drug therapy / Q000628:therapy* / Q000821:virology; D045325:HCT116 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000821:virology*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000187:drug effects* / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D007211:Indoles; D005476:Fluphenazine; C027185:indirubin