title: A chemical screen for medulloblastoma identifies quercetin as a putative radiosensitizer.
abstract: Treatment of medulloblastoma in children fails in approximately 30% of patients, and is often accompanied by severe late sequelae. Therefore, more effective drugs are needed that spare normal tissue and diminish long-term side effects. Since radiotherapy plays a pivotal role in the treatment of medulloblastoma, we set out to identify novel drugs that could potentiate the effect of ionizing radiation.Thereto, a small molecule library, consisting of 960 chemical compounds, was screened for its ability to sensitize towards irradiation. This small molecule screen identified the flavonoid quercetin as a novel radiosensitizer for the medulloblastoma cell lines DAOY, D283-med, and, to a lesser extent, D458-med at low micromolar concentrations and irradiation doses used in fractionated radiation schemes. Quercetin did not affect the proliferation of neural precursor cells or normal human fibroblasts. Importantly, in vivo experiments confirmed the radiosensitizing properties of quercetin. Administration of this flavonoid at the time of irradiation significantly prolonged survival in orthotopically xenografted mice. Together, these findings indicate that quercetin is a potent radiosensitizer for medulloblastoma cells that may be a promising lead for the treatment of medulloblastoma in patients.
authors.affiliation: Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.|Department of Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Tonny
authors.initials: T
authors.lastname: Lagerweij
authors.affiliation: Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.|Department of Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Lotte
authors.initials: L
authors.lastname: Hiddingh
authors.affiliation: Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Dennis
authors.initials: D
authors.lastname: Biesmans
authors.affiliation: Department of Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Matheus H W
authors.initials: MH
authors.lastname: Crommentuijn
authors.affiliation: Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Cloos
authors.affiliation: Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Li
authors.affiliation: Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Mari
authors.initials: M
authors.lastname: Kogiso
authors.affiliation: Department of Neurology, Molecular Neurogenetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Bakhos A
authors.initials: BA
authors.lastname: Tannous
authors.affiliation: Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: W Peter
authors.initials: WP
authors.lastname: Vandertop
authors.affiliation: Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.|Department of Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: David P
authors.initials: DP
authors.lastname: Noske
authors.affiliation: Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Gertjan J L
authors.initials: GJ
authors.lastname: Kaspers
authors.affiliation: Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.|Department of Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.|Department of Neurology, Molecular Neurogenetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Würdinger
authors.affiliation: Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.|Department of Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Hulleman
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002478:Cells, Cultured; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D008527:Medulloblastoma / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy; D008819:Mice, Nude; D015394:Molecular Structure; D011794:Quercetin / Q000737:chemistry / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D011838:Radiation-Sensitizing Agents; D011794:Quercetin
keywords: medulloblastoma; quercetin; radiosensitizer; screen; small molecule