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

Neuro-oncology
Jian TengBakhos A Tannous

Abstract

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. 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. 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 simi...Continue Reading

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Citations

Jun 29, 2018·Expert Opinion on Therapeutic Patents·Matthew HarrisDavid Bailey
Apr 17, 2019·Bioscience Reports·Songsong TengChengqing Yi
Oct 3, 2019·Cells·Cintia Carla da HoraBakhos A Tannous
Nov 24, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Yaqiong ZhanYunqing Qiu
Jan 5, 2021·Neuro-oncology Advances·Cyrillo G BrahmRudolf S N Fehrmann
Mar 9, 2021·Frontiers in Oncology·Monserrat Llaguno-MunivePatricia Garcia-Lopez
Oct 16, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hyeon Ji Kim, Do-Yeon Kim

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