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Discovery of a new pyrimidine synthesis inhibitor eradicating glioblastoma-initiating cells

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Title: Discovery of a new pyrimidine synthesis inhibitor eradicating glioblastoma-initiating cells
Authors: Echizenya, Smile Browse this author
Ishii, Yukiko Browse this author
Kitazawa, Satoshi Browse this author
Tanaka, Tadashi Browse this author
Matsuda, Shun Browse this author
Watanabe, Eriko Browse this author
Umekawa, Masao Browse this author
Terasaka, Shunsuke Browse this author →KAKEN DB
Houkin, Kiyohiro Browse this author →KAKEN DB
Hatta, Tomohisa Browse this author
Natsume, Tohru Browse this author →KAKEN DB
Maeda, Yoshimasa Browse this author
Watanabe, Shin-ichi Browse this author
Hagiwara, Shinji Browse this author
Kondo, Toru Browse this author →KAKEN DB
Keywords: chemical screening
glioblastoma-initiating cells, GICs
Issue Date: Feb-2020
Publisher: Oxford University Press
Journal Title: Neuro-Oncology
Volume: 22
Issue: 2
Start Page: 229
End Page: 239
Publisher DOI: 10.1093/neuonc/noz170
Abstract: Background. Glioblastoma-initiating cells (GICs) comprise a tumorigenic subpopulation of cells that are resistant to radio- and chemotherapies and are responsible for cancer recurrence. The aim of this study was to identify novel compounds that specifically eradicate GICs using a high throughput drug screening approach. Methods. We performed a cell proliferation/death-based drug screening using 10560 independent compounds. We identified dihydroorotate dehydrogenase (DHODH) as a target protein of hit compound 10580 using ligand-fishing and mass spectrometry analysis. The medical efficacy of 10580 was investigated by in vitro cell proliferation/death and differentiation and in vivo tumorigenic assays. Results. Among the effective compounds, we identified 10580, which induced cell cycle arrest, decreased the expression of stem cell factors in GICs, and prevented tumorigenesis upon oral administration without any visible side effects. Mechanistic studies revealed that 10580 decreased pyrimidine nucleotide levels and enhanced sex determining region Y-box 2 nuclear export by antagonizing the enzyme activity of DHODH, an essential enzyme for the de novo pyrimidine synthesis. Conclusion. In this study, we identified 10580 as a promising new drug against GICs. Given that normal tissue cells, in particular brain cells, tend to use the alternative salvage pathway for pyrimidine synthesis, our findings suggest that 10580 can be used for glioblastoma therapy without side effects.
Rights: This is a pre-copyedited, author-produced version of an article accepted for publication in Neuro-Oncology following peer review. The version of record Smile Echizenya, Yukiko Ishii, Satoshi Kitazawa, Tadashi Tanaka, Shun Matsuda, Eriko Watanabe, Masao Umekawa, Shunsuke Terasaka, Kiyohiro Houkin, Tomohisa Hatta, Tohru Natsume, Yoshimasa Maeda, Shin-Ichi Watanabe, Shinji Hagiwara, Toru Kondo, Discovery of a new pyrimidine synthesis inhibitor eradicating glioblastoma-initiating cells, Neuro-Oncology, Volume 22, Issue 2, February 2020, Pages 229-239, is available online at:
Type: article (author version)
Appears in Collections:遺伝子病制御研究所 (Institute for Genetic Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 近藤 亨

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