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Neuro Oncol. 2018 Apr 9;20(5):642-654. doi: 10.1093/neuonc/nox198.

Recycling drug screen repurposes hydroxyurea as a sensitizer of glioblastomas to temozolomide targeting de novo DNA synthesis, irrespective of molecular subtype.

Author information

1
Department of Neurology, Neuro-Oncology Division, Massachusetts General Hospital, Boston, Massachusetts, USA.
2
NeuroDiscovery Center, Harvard Medical School, Boston, Massachusetts, USA.
3
Department of Neurosurgery, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
4
Department of Pediatric Oncology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
5
Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
6
Faculty of Natural and Applied Sciences, Notre Dame University-Louaize, Zouk Mosbeh, Lebanon.
7
Division of Neuro-Oncology, Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York, USA.
8
Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
9
Department of Pathology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
10
Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
11
Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Abstract

Background:

Glioblastoma (GBM) is the most common and most aggressive primary malignant brain tumor. Standard-of-care treatment involves maximal surgical resection of the tumor followed by radiation and chemotherapy (temozolomide [TMZ]). The 5-year survival rate of patients with GBM is <10%, a colossal failure that has been partially attributed to intrinsic and/or acquired resistance to TMZ through O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status in the tumor.

Methods:

A drug screening aimed at evaluating the potential recycling and repurposing of known drugs was conducted in TMZ-resistant GBM cell lines and primary cultures of newly diagnosed GBM with different MGMT promoter methylation status, phenotypic/genotypic background and subtype, and validated with sphere formation, cell migration assays, and quantitative invasive orthotopic in vivo models.

Results:

We identified hydroxyurea (HU) to synergize with TMZ in GBM cells in culture and in vivo, irrespective of MGMT promoter methylation status, subtype, and/or stemness. HU acts specifically on the S-phase of the cell cycle by inhibiting the M2 unit of enzyme ribonucleotide reductase. Knockdown of this enzyme using RNA interference and other known chemical inhibitors exerted a similar effect to HU in combination with TMZ both in culture and in vivo.

Conclusions:

We demonstrate preclinical efficacy of repurposing hydroxyurea in combination with TMZ for adjuvant GBM therapy. This combination benefit is of direct clinical interest given the extensive use of TMZ and the associated problems with TMZ-related resistance and treatment failure.

PMID:
29099956
PMCID:
PMC5892145
DOI:
10.1093/neuonc/nox198
[Indexed for MEDLINE]
Free PMC Article

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