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.
Highlights
Glioblastoma is the most severe type of human brain tumor in both adults and children, with a median survival of 14.6 months for adults [1] and 13–18 months for pediatric patients [2, 3]
Genome analysis of tumors from primarily pediatric glioblastomas [6,7,8] as well as adult glioblastomas [9] revealed the existence of somatic heterozygous histone mutations that are mutually exclusive
We show that the combined treatment of vorinostat and ABT-888 leads to increased clonogenic death of both pediatric and adult glioblastoma cell lines
Summary
Glioblastoma is the most severe type of human brain tumor in both adults and children, with a median survival of 14.6 months for adults [1] and 13–18 months for pediatric patients [2, 3]. A significant percentage of pediatric patients’ glioblastoma are located in the midline region of the brain and either, like diffuse intrinsic pontine glioma (DIPG), are completely inaccessible for surgical resection or, like the diffuse thalamic midline gliomas, are not favorably recommended for it. The K27M mutation leads to increased activity of both chromatin domains that suppress differentiation and of those that support proliferation. Both types are essential for tumor survival [13,14,15]
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