Potent and Selective Inhibitors of MTH1 Probe Its Role in Cancer Cell Survival

Kettle, Jason G.; Alwan, Husam; Bista, Michal; Breed, J.; Davies, Nichola L.; Eckersley, Kay; Fillery, Shaun; Foote, Kevin M.; Goodwin, Louise; Jones, DM; Käck, Helena; Lau, Alan; Nissink, J. Willem M.; Read, Jonathan; Scott, James S.; Taylor, Benjamin; Walker, Graeme E.; Wissler, Lisa; Wylot, Marta

doi:10.1021/acs.jmedchem.5b01760

Cited by 125 publications

(183 citation statements)

References 22 publications

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“…1A), suggesting that the growth inhibition induced by TH588 is independent of oxidized stress. These results are consistent with reports that growth inhibition by TH588 may be due to off-target cytotoxic effects (17,18). However, it is possible that TH588 may act as an MTH1 inhibitor under oxidized stress conditions for cytotoxic effects.…”

Section: Combined Effects Of Th588 and Ros-inducers On The Growth Of supporting

confidence: 92%

“…One of the mechanisms that protects cancer cells from the cytotoxic effect of high levels of ROS is the expression of MTH1, which sanitizes oxidized dNTP pools by converting them to the corresponding monophosphates (10,11). TH588 is a potent and selective inhibitor of human MTH1, although the growth-inhibiting effect of TH588 is not associated with the inhibition of MTH1 (17,18). While MTH1 function may be critical to survival in cells with elevated levels of ROS, MTH1 is dispensable in cancer cells under normal culture conditions.…”

Section: Discussionmentioning

confidence: 99%

“…By aiming at a redox-adaptation mechanism, MTH1 inhibition represents a new approach for a therapeutic strategy against cancer (15,16). However, recent reports have indicated that growth inhibition by MTH1 inhibitors may be due to off-target cytotoxic effects (17,18 (17). These results suggest that low concentrations of MTH1 inhibitors may suppress the enzyme activity without anti-proliferative activity.…”

Section: Introductionmentioning

confidence: 99%

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TH588, an MTH1 inhibitor, enhances phenethyl isothiocyanate‑induced growth inhibition in pancreatic cancer cells

et al. 2017

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Abstract. Chemotherapy and radiotherapy are the most common approaches in cancer therapy. They may kill cancer cells through the generation of high levels of reactive oxygen species (ROS), which leads to oxidative DNA damage. However, tumor resistance to ROS is a problem in cancer therapy. MTH1 sanitizes oxidized dNTP pools to prevent the incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, cancer cells require MTH1 activity to avoid the incorporation of oxidized dNTPs, which would result in DNA damage and cell death. By targeting a redox-adaptation mechanism, MTH1 inhibition represents a novel therapeutic strategy against cancer. However, recent reports have indicated that growth inhibition by MTH1 inhibitors may be due to off-target cytotoxic effects. TH588, one of the first-in-class MTH1 inhibitors, kills cancer cells by an off-target effect. However, a low concentration of TH588 may effectively inhibit MTH1 activity without inhibiting cell proliferation. Phenethyl isothiocyanate (PEITC) is a dietary anticarcinogenic compound and an inducer of ROS. In the present study, it has been demonstrated that combined treatment with PEITC and TH588 effectively inhibited the growth of pancreatic cancer MIAPaCa-2 and Panc-1 cells. The antioxidant N-acetylcysteine negated this synergistic growth inhibition. PEITC and TH588 cooperatively induced the formation of 8-oxo-deoxyguanine in nuclei and pH2AX foci, a marker of DNA damage. However, the combined effects are not associated with MTH1 mRNA expression in several cancer cell lines, suggesting that the possibility of an off-target effect of TH588 cannot be eliminated. These results suggest that the combination of PEITC and TH588 has potential as a novel therapeutic strategy against pancreatic cancer. IntroductionPancreatic cancer remains a highly lethal neoplasm. Even with multimodality therapy for localized disease, patient survival is measured in months. Although the FOLFIRINOX regimen has produced substantial benefits in the treatment of metastatic pancreatic cancer, it is associated with severe adverse effects (1). The further development of better therapeutic regimens for pancreatic cancer requires new and potent anticancer agents.Ras transformation renders cells sensitive to reactive oxygen species (ROS)-induced cell death (2,3), and pancreatic cancers exhibit an extremely high mutation rate of K-ras (>90%) (4). Therefore, we investigated the anti-proliferative effects of ROS generators on pancreatic cancer cells. Phenethyl isothiocyanate (PEITC) is a potent ROS generator (5-8). PEITC belongs to the family of natural isothiocyanates, which are found in a variety of cruciferous vegetables and released when the vegetables are cut or masticated (5). PEITC has an inhibitory effect on the growth of several types of cancer cells, and is now being studied in phase 2 clinical trials for the prevention of lung and oral cancer (3,(5)(6)(7)(8). ROS results in the oxidation of cell constituents such as DNA, lipids and proteins, a...

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Section: Combined Effects Of Th588 and Ros-inducers On The Growth Of supporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TH588, an MTH1 inhibitor, enhances phenethyl isothiocyanate‑induced growth inhibition in pancreatic cancer cells

et al. 2017

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“…Tumors frequently have shortened telomeres despite the presence of telomerase 52 . Whether the telomerase negative U2OS cancer cell line, which maintains telomeres by ALT (alternative lengthening of telomeres), is sensitive to MTH1 inhibitors is controversial 14,53 . Collectively, these studies indicate that dependence on robust telomerase activity, may partly explain why cancer cells are more sensitive to oxidized dNTPs than normal cells.…”

Section: Discussionmentioning

confidence: 99%

Oxidative guanine base damage regulates human telomerase activity

Fouquerel

Lormand

Bose

et al. 2016

Nat Struct Mol Biol

151

168

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Changes in telomere length are associated with degenerative diseases and cancer. Oxidative stress and DNA damage have been linked to both positive and negative alterations in telomere length and integrity. Here we examined how the common oxidative lesion 8-oxo-7,8-dihydro-2′-deoxyguanine (8-oxoG) regulates telomere elongation by telomerase. When present in the deoxynucleoside triphosphate pool as 8-oxodGTP, telomerase utilization of the oxidized nucleotide during telomere extension is mutagenic and terminates further elongation. Depletion of the enzyme that removes oxidized dNTPs, MTH1, increases telomere dysfunction and cell death in telomerase positive cancer cells harboring shortened telomeres. In contrast, a pre-existing 8-oxoG within the telomeric DNA sequence promotes telomerase activity by destabilizing G-quadruplex structure in the DNA. We show that the mechanism by which 8-oxoG arises in the telomere, either by insertion of oxidized nucleotides or by direct reaction with free radicals, dictates whether telomerase is inhibited or stimulated and thereby, mediates the biological outcome.

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“…Therefore, MTH1 has been explored as a potential cancer therapeutic target, and indeed inhibition of MTH1 by small molecules TH588 and TH287, the first-in-class nudix hydrolase family inhibitors, Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry causes incorporation of oxidized dNTPs in cancer cells leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse on xenografts [54,55]. Unfortunately, this finding has been seriously challenged by recent studies demonstrating that MTH1 is dispensable for cancer cell survival [56,57]. Thus, it remains to be established how much cancer cells really rely on MTH1 activity.…”

Section: Mth1 Mth2mentioning

confidence: 99%

Hepatitis B Virus X Protein Increases 8-Oxo-7,8-Dihydro-2ʹ-Deoxyguanosine (8-Oxodg) Level via Repressing MTH1/ MTH2 Expression in Hepatocytes

Lin

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Chronic hepatitis B virus (HBV) infection markedly increases the risk of development of hepatocellular carcinoma (HCC). Among the seven viral proteins that HBV encodes, HBV X protein (HBx) appears to have the most oncogenic potential. The mitochondria-associated HBx can induce oxidative stress in hepatocytes, leading to the production of abundant reactive oxygen species (ROS). High levels of ROS usually induce oxidative DNA damage and 8-hydroxy-2-deoxyguanosine (8-OHdG), also known as 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG), which is one of the major products of DNA oxidation and an important biomarker for oxidative stress and carcinogenesis. Cells have evolved a mechanism to prevent oxidized nucleotides from their incorporation into DNA through nucleotide pool sanitization enzymes of MTH1 (NUDT1), MTH2 (NUDT15), MTH3 (NUDT18) and NUDT5. However, little is known as to whether HBx can regulate the expression of those enzymes and modulate the formation and accumulation of 8-oxodG in hepatocytes. Methods: The level of 8-oxodG was assessed by ELISA in stable HBV-producing hepatoma cell lines, an HBV infectious mouse model, HBV and HBx transgenic mice and HBV-infected patients versus their respective controls. Expression of MTH1, MTH2, MTH3 and NUDT5 was determined by a real-time quantitative PCR and western blot analysis. Transcriptional regulation of MTH1 and MTH2 expression by HBx and the effect of HBx on MTH1 and MTH2 promoter hypermethylation were examined using a luciferase reporter assay and bisulfite sequencing analysis. Results: In comparison with controls, significantly higher levels of 8-oxodG were detected in the genome and culture supernatant of stable HBV-producing HepG2.2.15 cells, in the sera and liver tissues of HBV infectious mice and HBV or HBx transgenic mice, and in the sera of HBV-infected patients. Expression of HBx in hepatocytes significantly increased 8-oxodG level and reduced the expression of MTH1 and MTH2 at both mRNA and protein levels. It was also demonstrated that HBx markedly attenuated the MTH1 or MTH2 promoter activities through hypermethylation. Furthermore, enhancement of 8-oxodG production by HBx was reversible by overexpression of MTH1 and MTH2. Conclusion: Our data show that HBx expression results in the accumulation of 8-oxodG in hepatocytes through inhibiting the expression of MTH1 and MTH2. This may implicate that HBx may act as a tumor promoter through facilitating the mutational potential of 8-oxodG thus connecting a possible link between HBV infection and liver carcinogenesis.

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Potent and Selective Inhibitors of MTH1 Probe Its Role in Cancer Cell Survival

Cited by 125 publications

References 22 publications

TH588, an MTH1 inhibitor, enhances phenethyl isothiocyanate‑induced growth inhibition in pancreatic cancer cells

TH588, an MTH1 inhibitor, enhances phenethyl isothiocyanate‑induced growth inhibition in pancreatic cancer cells

Oxidative guanine base damage regulates human telomerase activity

Hepatitis B Virus X Protein Increases 8-Oxo-7,8-Dihydro-2ʹ-Deoxyguanosine (8-Oxodg) Level via Repressing MTH1/ MTH2 Expression in Hepatocytes

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