The MTH1 inhibitor TH588 demonstrates anti-tumoral effects alone and in combination with everolimus, 5-FU and gamma-irradiation in neuroendocrine tumor cells

Prada, Elke Tatjana Aristizabal; Orth, Michael; Nölting, Svenja; Spöttl, Gerald; Maurer, Julian; Auernhammer, Christoph J.

doi:10.1371/journal.pone.0178375

Cited by 11 publications

(7 citation statements)

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“…As mentioned above, independent groups have confirmed cytotoxic effects of TH588 in several studies [ 7 , 13 ]. Some studies have also identified MTH1 inhibitors with similar or even lower IC50 [ 13 , 25 ] which either caused cytotoxic effects regarded as MTH1 independent or had no significant impact on cell viability thus challenging the concept of MTH1 inhibition as an anti-tumor strategy.…”

Section: Discussionmentioning

confidence: 74%

“…Consequently, targeting this enzymatic function has been proposed to induce single strand breaks and G:C to T:A transversion mutations during DNA replication [ 5 ]. The MTH1 inhibitor TH588 was identified by Gad and co-authors in 2014 [ 6 ] and has been used in several studies subsequently [ 7 – 9 ]. Other investigators have generated inhibitors independently as reviewed very recently [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…Secondly, our intention was to test TH588 in combination with ionizing radiation (IR) which is frequently used in colorectal carcinoma patients. Of particular importance, one very recent study has suggested “radiosensitizing” activity of TH588 in neuroendocrine tumor cells [ 7 ]. IR is known to cause single and double strand breaks of the DNA at least in part via generation of reactive oxygen species (ROS).…”

Section: Introductionmentioning

confidence: 99%

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The presumed MTH1-inhibitor TH588 sensitizes colorectal carcinoma cells to ionizing radiation in hypoxia

et al. 2018

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BackgroundThe nudix family member enzyme MutT homologue-1 (MTH1) hydrolyses the oxidized nucleotides 8-oxo-dGTP and 2-hydroxy-dATP and thus prevents the incorporation of damaged nucleotides into nuclear and mitochondrial DNA. Therefore MTH1 was proposed to protect cancer cells from oxidative DNA lesions and subsequent cell death. We investigated whether the bona fide MTH1 inhibitor TH588 affects responses of cultured colorectal tumor cells to ionizing radiation (IR) in normoxia and in moderate or severe hypoxia.MethodsTH588 was tested in cell viability and survival assays (tetrazolium dye (MTT), propidium iodide staining, caspase-3 activity, and colony formation assays (CFA)) in colorectal carcinoma cells (HCT116 and SW480) in combination with IR in normoxia and in hypoxia. Additionally, MTH1 was targeted by lentiviral shRNA expression. Human umbilical vein endothelial cells (HUVEC) were assessed in MTT assays.ResultsIn all cell lines tested, TH588 dose-dependently impaired cell survival. In CFAs, TH588 and IR effects on carcinoma cells were additive in normoxia and in hypoxia. Using 3 different shRNAs, the lentiviral approach was detrimental to SW480, but not to HCT116.ConclusionsTH588 has cytotoxic effects on transformed and untransformed cells and synergizes with IR in normoxia and in hypoxia. TH588 toxicity is not fully explained by MTH1 inhibition as HCT116 were unaffected by lentiviral suppression of MTH1 expression. TH588 should be explored further because it has radiosensitizing effects in hypoxia.

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Section: Discussionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The presumed MTH1-inhibitor TH588 sensitizes colorectal carcinoma cells to ionizing radiation in hypoxia

et al. 2018

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“…This result is of vital importance to pediatric glioblastoma patients, whose main treatment-option is ionizing radiation. An increased response to ionizing radiation in TH588-treated neuroendocrine tumor cell lines has recently been reported by Prada et al [ 50 ]. In contrast to the glioblastoma cell lines, the MTH1 inhibitor failed to affect the clonogenic survival of irradiated fibroblasts.…”

Section: Discussionmentioning

confidence: 76%

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

et al. 2018

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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.

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“…On top of the MTH1 inhibition, alternative mechanisms of TH588 have been reported as its anti-cancer effects including tubulin depolymerization and AKT signaling downregulation [ 32 , 33 ]. To confirm it, we investigated the spindle morphology of mitotic cells upon treatment of 5 and 10 µM of TH588.…”

Section: Resultsmentioning

confidence: 99%

A high-throughput drug combination screen identifies an anti-glioma synergism between TH588 and PI3K inhibitors

Chen

Zhou

et al. 2020

Cancer Cell Int

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Background: Glioblastoma multiforme (GBM) is the most common and lethal type of primary brain tumor. More than half of GBMs contain mutation(s) of PTEN/PI3K/AKT, making inhibitors targeting the PI3K pathway very attractive for clinical investigation. However, so far, PI3K/AKT/mTOR inhibitors have not achieved satisfactory therapeutic effects in clinical trials of GBM. In this study, we aimed to develop a high-throughput screening method for high-throughput identification of potential targeted agents that synergize with PI3K inhibitors in GBM. Methods: A Sensitivity Index (SI)-based drug combination screening method was established to evaluate the interactions between BKM120, a pan-PI3K inhibitor, and compounds from a library of 606 target-selective inhibitors. Proliferation, colony and 3D spheroid formation assays, western blotting, comet assay, γ-H2AX staining were used to evaluate the anti-glioma effects of the top-ranked candidates. The drug combination effects were analyzed by the Chou-Talalay method. Results: Six compounds were successfully identified from the drug screen, including three previously reported compounds that cause synergistic antitumor effects with PI3K/mTOR inhibitors. TH588, an putative MTH1 inhibitor exhibited significant synergy with BKM120 in suppressing the proliferation, colony formation and 3D spheroid formation of GBM cells. Further investigation revealed that both DNA damage and apoptosis were markedly enhanced upon combination treatment with TH588 and BKM120. Finally, activation of PI3K or overexpression of AKT compromised the anti-glioma efficacy of TH588. Conclusions: The screening method developed in this study demonstrated its usefulness in the rapid identification of synergistic drug combinations of PI3K inhibitors and targeted agents.

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The MTH1 inhibitor TH588 demonstrates anti-tumoral effects alone and in combination with everolimus, 5-FU and gamma-irradiation in neuroendocrine tumor cells

Cited by 11 publications

References 50 publications

The presumed MTH1-inhibitor TH588 sensitizes colorectal carcinoma cells to ionizing radiation in hypoxia

The presumed MTH1-inhibitor TH588 sensitizes colorectal carcinoma cells to ionizing radiation in hypoxia

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

A high-throughput drug combination screen identifies an anti-glioma synergism between TH588 and PI3K inhibitors

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