Proteomic profiling of small-molecule inhibitors reveals dispensability of MTH1 for cancer cell survival

Kawamura, Tatsuro; Kawatani, Masahito; Muroi, Makoto; Kondoh, Yasumitsu; Futamura, Yushi; Aono, Harumi; Tanaka, Miho; Honda, Kaori; Osada, Hiroyuki

doi:10.1038/srep26521

Cited by 89 publications

(121 citation statements)

References 44 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: 82%

“…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: 39%

“…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%

“…These results suggest that low concentrations of MTH1 inhibitors may suppress the enzyme activity without anti-proliferative activity. TH588 has good metabolic stability and is available in vivo (17). In the present study, we examined the combined effects of TH588 and PEITC on the growth of human pancreatic cancer cells.…”

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: 82%

Section: Introductionmentioning

confidence: 39%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2017

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“…For example, MTH1 can hydrolyze 8-oxo-rATP, 8-oxo-dATP, 8-oxo-rGTP, 8-oxo-dGTP, 2-OH-dATP and 2-OH-rATP67891011. Therefore, MTH1 can prevent the incorporation of these oxidized nucleoside triphosphates into DNA, and thus effectively reduce the mutation and cell death.…”

mentioning

confidence: 99%

Understanding the molecular mechanism for the differential inhibitory activities of compounds against MTH1

Wang

Zhou

Chen

et al. 2017

Sci Rep

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MTH1 can hydrolyze oxidized nucleotides and is required for cancer survival. The IC50 values were 0.8 nM for TH287 with a methyl substitution, 5.0 nM for TH588 with a cyclopropyl substitution, and 2.1 μM for TH650 with an oxetanyl substitution. Thus, it is very significant to understand inhibitory mechanisms of these structurally similar compounds against MTH1 and influences of the substituent on the bioactivities. Our MD researches indicate that TH287 maintains significant hydrogen bonds with Asn33 and Asp119, stabilizes the binding site, and induces MTH1 adopt a closed motion, leading to a high inhibitory activity. When bound with TH588, the binding site can be partially stabilized and take a semi-closed state, which is because the cyclopropyl group in TH588 has larger steric hindrance than a methyl group in TH287. So TH588 has a slightly reduced inhibitory activity compared to TH287. TH650 induces greater conformation fluctuations than TH588 and the binding site adopts an opening state, which is caused by the large bulk of oxetanyl group and the interference of solvent on the oxetanyl substituent, leading to the lowest inhibitory activity. Thus, the inhibitory activity follows a TH287 > TH588 > TH650 trend, which well matches with the experimental finding.

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Targeting the DNA damage response and repair in cancer through nucleotide metabolism

Helleday

Rudd

2022

Molecular Oncology

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The exploitation of the DNA damage response and DNA repair proficiency of cancer cells is an important anticancer strategy. The replication and repair of DNA are dependent upon the supply of deoxynucleoside triphosphate (dNTP) building blocks, which are produced and maintained by nucleotide metabolic pathways. Enzymes within these pathways can be promising targets to selectively induce toxic DNA lesions in cancer cells. These same pathways also activate antimetabolites, an important group of chemotherapies that disrupt both nucleotide and DNA metabolism to induce DNA damage in cancer cells. Thus, dNTP metabolic enzymes can also be targeted to refine the use of these chemotherapeutics, many of which remain standard of care in common cancers. In this review article, we will discuss both these approaches exemplified by the enzymes MTH1, MTHFD2 and SAMHD1.

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Proteomic profiling of small-molecule inhibitors reveals dispensability of MTH1 for cancer cell survival

Cited by 89 publications

References 44 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

Understanding the molecular mechanism for the differential inhibitory activities of compounds against MTH1

Targeting the DNA damage response and repair in cancer through nucleotide metabolism

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