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

Pompsch, Mosche; Vogel, James A.; Classen, Fabian; Kranz, Philip; Iliakis, George; Riffkin, Helena; Brockmeier, Ulf; Metzen, Eric

doi:10.1186/s12885-018-5095-x

Cited by 12 publications

(6 citation statements)

References 30 publications

(38 reference statements)

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“…Several studies reported that specific MTH1 inhibition does not affect tumour cell viability and/ or apoptosis such as reported in non-small cell lung cancer [25,26,28,40]. While the cytotoxic effects of MTH1 inhibition in cancer are controversial in literature, TH588 has been shown to be cytotoxic in several studies [41,42]. We also found that TH588 and TH1579 induce apoptosis by increasing DNA damage as shown by comet assay and induction of H2AX phosphorylation in OS cells.…”

Section: Discussionsupporting

confidence: 57%

TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases development in osteosarcoma model

et al. 2020

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Background: Osteosarcoma (OS) is the most common primary malignant bone tumour. Unfortunately, no new treatments are approved and over the last 30 years the survival rate remains only 30% at 5 years for poor responders justifying an urgent need of new therapies. The Mutt homolog 1 (MTH1) enzyme prevents incorporation of oxidized nucleotides into DNA and recently developed MTH1 inhibitors may offer therapeutic potential as MTH1 is overexpressed in various cancers. Methods: The aim of this study was to evaluate the therapeutic benefits of targeting MTH1 with two chemical inhibitors, TH588 and TH1579 on human osteosarcoma cells. Preclinical efficacy of TH1579 was assessed in human osteosarcoma xenograft model on tumour growth and development of pulmonary metastases. Findings: MTH1 is overexpressed in OS patients and tumour cell lines, compared to mesenchymal stem cells. In vitro, chemical inhibition of MTH1 by TH588 and TH1579 decreases OS cells viability, impairs their cell cycle and increases apoptosis in OS cells. TH1579 was confirmed to bind MTH1 by CETSA in OS model. Moreover, 90 mg/kg of TH1579 reduces in vivo tumour growth by 80.5% compared to non-treated group at day 48. This result was associated with the increase in 8-oxo-dG integration into tumour cells DNA and the increase of apoptosis. Additionally, TH1579 also reduces the number of pulmonary metastases. Interpretation: All these results strongly provide a pre-clinical proof-of-principle that TH1579 could be a therapeutic option for patients with osteosarcoma. Funding: This study was supported by La Ligue Contre le Cancer, la SFCE and Enfants Cancers Sant e.

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Section: Discussionsupporting

confidence: 57%

TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases development in osteosarcoma model

et al. 2020

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“…NUDT1 sanitizes oxidized dNTP pools and prevents incorporation of damaged oxidized bases during DNA replication [8,18,19]. NUDT1 overexpression has been documented in several cancers [20][21][22][23], including renal-cell carcinomas [24], brain tumors [25,26], lung cancer [20,27], gastric cancer [28], and esophageal squamous cell carcinomas [29]. A previous study shows that NUDT1 influences growth and survival of HCC cell lines [14].…”

Section: Discussionmentioning

confidence: 99%

Nudix hydrolase 1 is a prognostic biomarker in hepatocellular carcinoma

et al. 2020

Aging

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We investigated the prognostic significance of Nudix hydrolase 1 (NUDT1) in hepatocellular carcinoma (HCC). NUDT1 mRNA and protein levels were significantly higher in HCC tissues than normal liver tissues. The level of NUDT1 expression correlated with tumor grade, stage, size, differentiation, degree of vascular invasion, overall survival (OS), and disease-free survival (DFS) in HCC patients. Multivariate analysis showed that NUDT1 expression was an independent prognostic factor for OS and DFS in HCC patients. We constructed a prognostic nomogram with NUDT1 expression, AFP levels, vascular invasion, Child-Pugh classification, age, sex, AJCC staging, and tumor differentiation as variables. This nomogram was highly accurate in predicting the 5-year OS of HCC patients (c-index= 0.709; AUC= 0.740). NUDT1 silencing in HCC cells significantly reduced their survival, colony formation, migration, and invasiveness. Gene set enrichment analysis showed that biological pathways related to cell cycle, fatty acid metabolism, bile acid and bile salt metabolism, and PLK1 signaling were associated with NUDT1, as were the gene ontology terms "DNA binding transcription activator activity," "RNA polymerase II," "nuclear division," and "transmembrane transporter activity." Our study thus demonstrates that NUDT1 is a prognostic biomarker with therapeutic potential in HCC patients.

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“…For example, MTH1 inhibition has been shown to alleviate immune suppression in experimental mesothelioma [28] and improve the efficacy of anti-PD-L1 immunotherapy, as well as enhance tumor sensitivity to radiotherapy. [29] Combination therapy with MTH1 inhibitors and reactive oxygen species enhancers can intensify oxidative damage, leading to increased cellular toxicity and inhibition of tumor growth. [30] Additionally, TH287 has been shown to enhance tumor sensitivity to the anti-cancer drug NaAsO2.…”

Section: Discussionmentioning

confidence: 99%

Targeting MutT homolog 1 (MTH1) for breast cancer suppression by a novel MTH1 inhibitor MA-24 with tumor-selective toxicity

Kang,

Ma,

et al. 2023

Preprint

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Background: Breast cancer is a commonly diagnosed cancer worldwide. Human MutT homolog 1 (MTH1) is found to be elevated in breast tumors and cancer cells are addicted to MTH1 for sur-vival. Pharmacological inhibition of MTH1 may be potentially beneficial in the treatment of breast cancer. Methods: MA-24 was screened by malachite green colorimetric assay from MTH1 inhibitors and the kinetic characteristics of MA-24 was assessed. Binding features of MA-24 with MTH1 was as-certained through molecular docking, and cytotoxic activity of MA-24 was validated in vitro and in vivo. Target engagement assays, comet assay and western blot confirmed that the intracellular target and mechanism of MA-24. Results: MA-24 with potent antitumor bioactivity both in vitro and in vivo. MA-24 competitively inhibited the MTH1 and further induce DNA strand breaks, leading to increased apoptosis of cancer cells depending on upregulation of cleaved-caspase 3 – cleaved-PARP axis. Especially, MA-24 exhibited a powerful efficacy and safety in vivo (tumor growth inhibition rate: 61.8%). Conclusions: MA-24 possesses a broad spectrum of breast cancer cytotoxicity and offered valuable insights for overcoming the challenges of chemotherapy-related toxicity, which holds great po-tential for further development MA-24 as an anti-cancer drug.

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

Cited by 12 publications

References 30 publications

TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases development in osteosarcoma model

TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases development in osteosarcoma model

Nudix hydrolase 1 is a prognostic biomarker in hepatocellular carcinoma

Targeting MutT homolog 1 (MTH1) for breast cancer suppression by a novel MTH1 inhibitor MA-24 with tumor-selective toxicity

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