Increased MTH1-specific 8-oxodGTPase activity is a hallmark of cancer in colon, lung and pancreatic tissue

McPherson, Lisa; Troccoli, Clara I.; Ji, Debin; Bowles, Annie E.; Gardiner, Makelle L.; Mohsen, Michael G.; Nagathihalli, Nagaraj S.; Nguyen, Dao M.; Robbins, David J.; Merchant, Nipun B.; Kool, Eric T.; Rai, Priyamvada; Ford, James M.

doi:10.1016/j.dnarep.2019.102644

Cited by 23 publications

(23 citation statements)

References 35 publications

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“…The overexpression and crucial role of MTH1 have been verified for a broad spectrum of tumors, such as renal-cell carcinoma, brain tumors, primary non-small cell lung tumors, colorectal cancer, non-small cell lung cancer, gliomas, breast cancer, myeloma, squamous cell carcinoma, etc. 28 , 50 . It was also proposed that MTH1 might be a therapeutic target for metastasis of cancer, as MTH1 was observed to stimulate migration and invasion potential of thyroid cancer cells 51 .…”

Section: Discussionmentioning

confidence: 99%

Targeting human MutT homolog 1 (MTH1) for cancer eradication: current progress and perspectives

Yin

Chen

2020

Acta Pharmaceutica Sinica B

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Since accelerated metabolism produces much higher levels of reactive oxygen species (ROS) in cancer cells compared to ROS levels found in normal cells, human MutT homolog 1 (MTH1), which sanitizes oxidized nucleotide pools, was recently demonstrated to be crucial for the survival of cancer cells, but not required for the proliferation of normal cells. Therefore, dozens of MTH1 inhibitors have been developed with the aim of suppressing cancer growth by accumulating oxidative damage in cancer cells. While several inhibitors were indeed confirmed to be effective, some inhibitors failed to kill cancer cells, complicating MTH1 as a viable target for cancer eradication. In this review, we summarize the current status of developing MTH1 inhibitors as drug candidates, classify the MTH1 inhibitors based on their structures, and offer our perspectives toward the therapeutic potential against cancer through the targeting of MTH1.

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Section: Discussionmentioning

confidence: 99%

Targeting human MutT homolog 1 (MTH1) for cancer eradication: current progress and perspectives

Yin

Chen

2020

Acta Pharmaceutica Sinica B

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“…To the best of our knowledge, this is the first time that the Cdc25 inhibition activity of the tested compounds has been assayed. On the other hand, among the tested compounds, phosphatase inhibition activity is documented only for the clinically approved anticancer agent PZ0240 ((S)-crizotinib), which, in addition to its effect as a kinase inhibitor, is a stereospecific inhibitor of 2-hydroxy-dATP diphosphatase1 or MutT homolog 1 (MHT1) phosphatase [ 60 ], an enzyme required for the survival of cancer cells and involved in DNA repair processes to maintain genome stability under oxidative stress [ 61 , 62 ].…”

Section: Resultsmentioning

confidence: 99%

In Silico Identification of Small Molecules as New Cdc25 Inhibitors through the Correlation between Chemosensitivity and Protein Expression Pattern

Lauria

Martorana

Monica

et al. 2021

IJMS

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The cell division cycle 25 (Cdc25) protein family plays a crucial role in controlling cell proliferation, making it an excellent target for cancer therapy. In this work, a set of small molecules were identified as Cdc25 modulators by applying a mixed ligand-structure-based approach and taking advantage of the correlation between the chemosensitivity of selected structures and the protein expression pattern of the proposed target. In the first step of the in silico protocol, a set of molecules acting as Cdc25 inhibitors were identified through a new ligand-based protocol and the evaluation of a large database of molecular structures. Subsequently, induced-fit docking (IFD) studies allowed us to further reduce the number of compounds biologically screened. In vitro antiproliferative and enzymatic inhibition assays on the selected compounds led to the identification of new structurally heterogeneous inhibitors of Cdc25 proteins. Among them, J3955, the most active inhibitor, showed concentration-dependent antiproliferative activity against HepG2 cells, with GI50 in the low micromolar range. When J3955 was tested in cell-cycle perturbation experiments, it caused mitotic failure by G2/M-phase cell-cycle arrest. Finally, Western blotting analysis showed an increment of phosphorylated Cdk1 levels in cells exposed to J3955, indicating its specific influence in cellular pathways involving Cdc25 proteins.

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“…We have previously shown that MTH1 expression and 8-oxo-dGTPase activity are elevated in human lung adenocarcinomas relative to counterpart normal tissues [ 4 , 19 , 37 , 38 ]. To assess whether OGG1/MTH1 co-inhibition is likely to enhance anti-tumor outcomes, we evaluated whether OGG1 levels were elevated globally in human lung adenocarcinoma specimens or in tumor subsets without enhanced MTH1 expression.…”

Section: Resultsmentioning

confidence: 99%

OGG1 co-inhibition antagonizes the tumor-inhibitory effects of targeting MTH1

et al. 2021

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Increased MTH1-specific 8-oxodGTPase activity is a hallmark of cancer in colon, lung and pancreatic tissue

Cited by 23 publications

References 35 publications

Targeting human MutT homolog 1 (MTH1) for cancer eradication: current progress and perspectives

Targeting human MutT homolog 1 (MTH1) for cancer eradication: current progress and perspectives

In Silico Identification of Small Molecules as New Cdc25 Inhibitors through the Correlation between Chemosensitivity and Protein Expression Pattern

OGG1 co-inhibition antagonizes the tumor-inhibitory effects of targeting MTH1

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