Reactive Oxygen Species Dictate the Apoptotic Response of Melanoma Cells to TH588

Wang, Jia Yu; Jin, Lei; Yan, Xu Guang; Sherwin, Simonne; Farrelly, Margaret; Zhang, Xu Dong; Liu, Fen; Wang, Chun Yan; Guo, Su; Yari, Hamed; La, Ting; McFarlane, Jennifer; Lei, Fu Xi; Tabatabaee, Hessam; Chen, Jie Zhong; Croft, Amanda; Jiang, Chen Chen

doi:10.1016/j.jid.2016.06.625

Cited by 37 publications

(45 citation statements)

References 39 publications

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“…We thus suggest that the improved survival in response to TH588 and TH1579 treatment in cells, where the spindle assembly checkpoint is disturbed, can be explained by less time spent in mitosis, ultimately resulting in lower levels of ROS generation and reduced accumulation of toxic 8-oxodG in DNA. Previously, both we and others have demonstrated that cell death caused by TH588 treatment is associated with ROS formation, supporting this hypothesis[25,26]. Hence, MTH1i of 8-oxodGTPase only becomes relevant in presence of ROS in mitotically arrested cells.…”

supporting

confidence: 76%

MTH1 promotes mitotic progression to avoid oxidative DNA damage in cancer cells

Mortusewicz

Rudd

et al. 2019

Preprint

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BACKGROUND: We developed MTH1 inhibitors (MTH1i) TH588 and TH1579 showing broad anti-cancer activity, while structurally distinct MTH1i fail to kill cancer cells. Here, we describe a new role of MTH1 in mitosis and the detailed mechanism of action of TH1579 (karonudib) and other structurally distinct MTH1i. MATERIALS AND METHODS: Cancer cell lines or zebrafish embryos were treated with MTH1i or siRNA targeting MTH1 and analysed primarily by live cell and immunofluorescence microscopy, survival assays, DNA fibre or COMET assays. MTH1 and tubulin interactions were analysed in vitro using co-immunoprecipitation and tubulin polymerisation assays. RESULTS: Here, we describe a mitotic role for the MTH1 protein, which binds to tubulin, is required for microtubule polymerisation, correct spindle assembly, mitosis progression and suppression reactive oxygen species (ROS) generation in mitosis. Potent MTH1i display differential abilities to break the MTH1-tubulin interaction and cause mitotic arrest, demonstrating 8-oxodGTPase and mitotic function of MTH1 are mechanistically distinct. TH588 and TH1579 have more profound effect on mitotic arrest than other MTH1i explained by additional direct inhibition of tubulin polymerisation. MTH1i only inhibiting 8-oxodGTPase activity synergize with mitotic poisons. CONCLUSIONS: Efficient MTH1 have a dual mechanism of action: inhibiting mitosis (to generate ROS) and promoting 8-oxodGTP incorporation into DNA during mitotic replication, dependent on ROS generation. Direct inhibition of tubulin polymerisation of TH588 and TH1579 increase their ability to arrest cells and generate ROS in mitosis. Furthermore, non-cytotoxic MTH1 can become effective and increase incorporation of oxidised nucleotides into DNA when combined with sub-therapeutic concentrations of mitotic inhibitors or challenged directly by 8-oxodGTP.

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supporting

confidence: 76%

MTH1 promotes mitotic progression to avoid oxidative DNA damage in cancer cells

Mortusewicz

Rudd

et al. 2019

Preprint

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“…Similar effects of TH588 regarding cellular survival were shown recently [15, 25, 28]. Our results show a potent induction of apoptotic cell death mechanisms upon TH588 treatment (Fig 2).…”

Section: Discussionsupporting

confidence: 91%

“…Our results show a potent induction of apoptotic cell death mechanisms upon TH588 treatment (Fig 2). An increase of apoptosis due to TH588 treatment has also been described lately [15, 25]. The PI3K-Akt-mTOR pathway is one of the principal proliferative pathways and often up-regulated in human cancer [30].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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Modulation of the redox system in cancer cells has been considered a promising target for anti-cancer therapy. The novel MTH1 inhibitor TH588 proved tremendous potential in terms of cancer cell eradication, yet its specificity has been questioned by recent reports, indicating that TH588 may also induce cancer cell death by alternative mechanisms than MTH1 inhibition. Here we used a panel of heterogeneous neuroendocrine tumor cells in order to assess cellular mechanisms and molecular signaling pathways implicated in the effects of TH588 alone as well as dual-targeting approaches combining TH588 with everolimus, cytotoxic 5-fluorouracil or γ-irradiation. Our results reflect that TH588 alone efficiently decreased the survival of neuroendocrine cancer cells by PI3K-Akt-mTOR axis downregulation, increased apoptosis and oxidative stress. However, in the dual-targeting approaches cell survival was further decreased due to an even stronger downregulation of the PI3K-Akt-mTOR axis and augmentation of apoptosis but not oxidative stress. Furthermore, we could attribute TH588 chemo- and radio-sensitizing properties. Collectively our data not only provide insights into how TH588 exactly kills cancer cells but also depict novel perspectives for combinatorial treatment approaches encompassing TH588.

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“…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. Wang et al (26) reported that the sensitivity of melanoma cells to TH588 is correlated with the level of endogenous ROS, although the cytotoxicity of TH588 is not associated with its inhibitory effect on MTH1. In the present study, TH588 enhanced the formation of 8-oxo-dG induced by PEITC (Fig.…”

Section: Discussionmentioning

confidence: 99%

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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Reactive Oxygen Species Dictate the Apoptotic Response of Melanoma Cells to TH588

Cited by 37 publications

References 39 publications

MTH1 promotes mitotic progression to avoid oxidative DNA damage in cancer cells

MTH1 promotes mitotic progression to avoid oxidative DNA damage in cancer cells

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

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

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