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Oncotarget. 2018 Jun 8;9(44):27547-27563. doi: 10.18632/oncotarget.25547. eCollection 2018 Jun 8.

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

Author information

1
Pediatric Hemato-Oncology, Edmond and Lilly Safra Children's Hospital and Cancer Research Center, Sheba Medical Center, Ramat Gan 52621, Israel.
2
Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
3
The Talpiot Medical Leadership Program, Chaim Sheba Medical Center, Ramat Gan 52621, Israel.
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Contributed equally

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 anti-neoplastic 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.

KEYWORDS:

MutT homolog 1; Nudix hydrolase; PARP-1 inhibitors; adult and pediatric glioblastoma; histone deacetyase inhibitors

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare that they have no competing interest.

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