TY - JOUR
T1 - A chemical screen for medulloblastoma identifies quercetin as a putative radiosensitizer
AU - Lagerweij, Tonny
AU - Hiddingh, Lotte
AU - Biesmans, Dennis
AU - Crommentuijn, Matheus H.W.
AU - Cloos, Jacqueline
AU - Li, Xiao-Nan
AU - Kogiso, Mari
AU - Tannous, Bakhos A.
AU - Vandertop, William P.
AU - Noske, David P.
AU - Kaspers, Gertjan J.L.
AU - Wurdinger, Thomas
AU - Hulleman, Esther
PY - 2016/6/14
Y1 - 2016/6/14
N2 - 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
AB - 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
KW - quercetin
KW - medulloblastoma
KW - screen
KW - radiosensitizer
KW - small molecule
UR - http://www.scopus.com/inward/record.url?scp=84978079841&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.7980
DO - 10.18632/oncotarget.7980
M3 - Article
SN - 1949-2553
VL - 7
SP - 35776
EP - 35788
JO - Oncotarget
JF - Oncotarget
IS - 24
ER -