Metabolic-Pathway-Oriented Screening Targeting <i>S</i>-Adenosyl-<scp>l</scp>-methionine Reveals the Epigenetic Remodeling Activities of Naturally Occurring Catechols

Ogihara, Shinji; Komatsu, Toshimitsu; Itoh, Yukihiro; Miyake, Yuka; Suzuki, Takayoshi; Yanagi, Kouichi; Kimura, Yusuke; Ueno, Takahiro; Hanaoka, Kenjiro; Kojima, Hirotatsu; Okabe, Takayoshi; Nagano, Tetsuo; Urano, Yasuteru

doi:10.1021/jacs.9b08698

Cited by 6 publications

(3 citation statements)

References 25 publications

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“…Regorafenib is a multikinase inhibitor of angiogenic, stromal, and oncogenic-receptor tyrosine kinases. In an in vitro study using the human colorectal cancer cell line HT-29, regorafenib increased the intra-cellular S-adenosyl-Lmethionine (SAM) level by 34.5% compared to the control (19). SAM is the only provider of methyl groups to DNA, RNA, histones and other proteins.…”

Section: Discussionmentioning

confidence: 99%

Recombinant Methioninase Lowers the Effective Dose of Regorafenib Against Colon-Cancer Cells: A Strategy for Widespread Clinical Use of a Toxic Drug

CHOOBIN,

KUBOTA,

HAN

et al. 2023

CDP

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Background/Aim: Regorafenib is a multi-kinase inhibitor, targeting vascular endothelial growth factor receptor 2, fibroblast growth factor receptor 1 and other oncogenic kinases. Regorafenib has efficacy in metastatic colon cancer, but has severe dose-limiting toxicities which cause patients to stop taking the drug. The aim of the present study was to determine if recombinant methioninase (rMETase) could lower the effective concentration of regorafenib in vitro against a colorectal-cancer cell line. Materials and Methods: Firstly, we examined the half-maximal inhibitory concentration (IC50) of regorafenib alone and rMETase alone for the HCT-116 human colorectal-cancer cell line. After that, using the IC50 concentration of each drug, we investigated the efficacy of the combination of regorafenib and rMETase. Results: While both methioninase alone (IC50=0.61 U/ml) and regorafenib alone (IC50=2.26 U/ml) inhibited the viability of HCT-116 cells, the combination of the two agents was more than twice as effective as either alone. Addition of rMETase at 0.61 U/ml lowered the IC50 of regorafenib from 2.26 μM to 1.46 μM. Conclusion: rMETase and regorafenib are synergistic, giving rise to the possibility of lowering the effective dose of regorafenib in patients, thereby reducing its severe toxicity, allowing more cancer patients to be treated with regorafenib.

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Section: Discussionmentioning

confidence: 99%

Recombinant Methioninase Lowers the Effective Dose of Regorafenib Against Colon-Cancer Cells: A Strategy for Widespread Clinical Use of a Toxic Drug

CHOOBIN,

KUBOTA,

HAN

et al. 2023

CDP

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“…We recently established the concept of live cell-based coupled assays for monitoring targeted metabolic pathways for live cellbased HTS 20,21 . In this metabolic pathway-oriented screening methodology, we specify the input and output metabolites, and the in situ detection of the extracellular metabolite (output) that is generated and released from cells can be used as a readout of the activity of the targeted metabolic pathways.…”

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confidence: 99%

Development of pathway-oriented screening to identify compounds to control 2-methylglyoxal metabolism in tumor cells

Yanagi

Komatsu²,

Fujikawa³

et al. 2023

Commun Chem

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Controlling tumor-specific alterations in metabolic pathways is a useful strategy for treating tumors. The glyoxalase pathway, which metabolizes the toxic electrophile 2-methylglyoxal (MG), is thought to contribute to tumor pathology. We developed a live cell-based high-throughput screening system that monitors the metabolism of MG to generate d-lactate by glyoxalase I and II (GLO1 and GLO2). It utilizes an extracellular coupled assay that uses d-lactate to generate NAD(P)H, which is detected by a selective fluorogenic probe designed to respond exclusively to extracellular NAD(P)H. This metabolic pathway-oriented screening is able to identify compounds that control MG metabolism in live cells, and we have discovered compounds that can directly or indirectly inhibit glyoxalase activities in small cell lung carcinoma cells.

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“…8,9 Recently, MOCbased porous salts composed of cationic and anionic MOCs synthesized by metathesis reactions have emerged as a promising new type of permanently microporous solid. [10][11][12] Such solids are ultratunable because cavities with different compositions, shapes, sizes and charges can be incorporated into a unique framework, which is difficult to achieve in metalorganic frameworks (MOFs). In addition, the combination of cationic and anionic MOCs also helps to exclude small inorganic ions and anions, 10 thus releasing more cavities for related applications, especially for adsorption.…”

mentioning

confidence: 99%

Encapsulation of a metal–organic cage-based porous salt in silica nanopores

Liu

Zhou

et al. 2023

Chem. Commun.

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Metabolic-Pathway-Oriented Screening Targeting S-Adenosyl-l-methionine Reveals the Epigenetic Remodeling Activities of Naturally Occurring Catechols

Cited by 6 publications

References 25 publications

Recombinant Methioninase Lowers the Effective Dose of Regorafenib Against Colon-Cancer Cells: A Strategy for Widespread Clinical Use of a Toxic Drug

Recombinant Methioninase Lowers the Effective Dose of Regorafenib Against Colon-Cancer Cells: A Strategy for Widespread Clinical Use of a Toxic Drug

Development of pathway-oriented screening to identify compounds to control 2-methylglyoxal metabolism in tumor cells

Encapsulation of a metal–organic cage-based porous salt in silica nanopores

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