Oncotarget

Research Papers:

A chemical screen for medulloblastoma identifies quercetin as a putative radiosensitizer

Tonny Lagerweij _, Lotte Hiddingh, Dennis Biesmans, Matheus H.W. Crommentuijn, Jacqueline Cloos, Xiao-Nan Li, Mari Kogiso, Bakhos A. Tannous, W. Peter Vandertop, David P. Noske, Gertjan J.L. Kaspers, Tom Würdinger and Esther Hulleman

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Oncotarget. 2016; 7:35776-35788. https://doi.org/10.18632/oncotarget.7980

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Abstract

Tonny Lagerweij1,2,3,*, Lotte Hiddingh1,2,3,*, Dennis Biesmans1,3, Matheus H.W. Crommentuijn3, Jacqueline Cloos1, Xiao-Nan Li4, Mari Kogiso4, Bakhos A. Tannous5, W. Peter Vandertop2, David P. Noske2,3, Gertjan J.L. Kaspers1, Tom Würdinger2,3,5, Esther Hulleman1,2,3

1Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands

2Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands

3Department of Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands

4Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA

5Department of Neurology, Molecular Neurogenetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

*These authors have contributed equally to this work

Correspondence to:

Esther Hulleman, email: [email protected]

Keywords: medulloblastoma, quercetin, radiosensitizer, small molecule, screen

Received: October 04, 2015     Accepted: February 20, 2016     Published: March 8, 2016

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.


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