MutT homolog 1 counteracts the effect of anti-neoplastic treatments in adult and pediatric glioblastoma cells

Ziv Versano, Eitan Shany, Shany Freedman, Liron Tuval-Kochen, Moshe Leitner, Shoshana Paglin, Amos Toren, Michal Yalon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Glioblastoma, a fatal disease in both adult and pediatric patients, currently has limited treatment options that offer no more than temporary relief. Our experiments with adult and pediatric glioblastoma cell lines showed that radiation induces a dose-dependent increase in the level of MutT homolog 1 (MTH1) - an enzyme that hydrolyzes oxidized purine nucleoside triphosphates. Similarly, the combination of vorinostat, which is a histone deacetylase inhibitor, and ABT-888, which is a PARP-1 inhibitor, enhanced clonogenic death and increased the MTH1 level, relative to each treatment alone. This result suggests that the MTH1 level is directly related to the damage that is inflicted upon the cells, and its activity protects them against antineoplastic therapy. Indeed, the MTH1 inhibitor TH588 and MTH1 siRNA increased glioblastoma's response to both radiation and the combination of vorinostat and ABT-888. TH588 also inhibited glioblastoma's capacity for migration and invasion. In normal fibroblasts, low radiation doses and the combination of vorinostat and ABT- 888 decreased the level of the enzyme. TH588 did not alter the fibroblasts' response to radiation and only mildly affected their response to the combination of vorinostat and ABT-888. In summary, the inhibition of MTH1 is required to better realize the therapeutic potential of anti-neoplastic treatments in glioblastoma.

Original languageEnglish
Pages (from-to)27547-27563
Number of pages17
JournalOncotarget
Volume9
Issue number44
DOIs
StatePublished - 1 Jun 2018

Keywords

  • Adult and pediatric glioblastoma
  • Histone deacetyase inhibitors
  • MutT homolog 1
  • Nudix hydrolase
  • PARP-1 inhibitors

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