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

Echizenya, Smile; Ishii, Yukiko; Kitazawa, Satoshi et al.

Neuro-Oncology, 2020, 22(2), 229-239

Permalink : https://hdl.handle.net/2115/80325

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論文情報

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アクセス権
open access
URI
https://hdl.handle.net/2115/80325
タイトル
Discovery of a new pyrimidine synthesis inhibitor eradicating glioblastoma-initiating cells
著者
Echizenya, Smile ; Ishii, Yukiko ; Kitazawa, Satoshi ; Tanaka, Tadashi ; Matsuda, Shun ; Watanabe, Eriko ; Umekawa, Masao ; Terasaka, Shunsuke ; Houkin, Kiyohiro ; Hatta, Tomohisa ; Natsume, Tohru ; Maeda, Yoshimasa ; Watanabe, Shin-ichi ; Hagiwara, Shinji ; Kondo, Toru
著者名
Echizenya, Smile
著者名
Ishii, Yukiko
著者名
Kitazawa, Satoshi
著者名
Tanaka, Tadashi
著者名
Matsuda, Shun
著者名
Watanabe, Eriko
著者名
Umekawa, Masao
e-Rad_Researcher
10447055
著者名
Terasaka, Shunsuke
e-Rad_Researcher
90229146
著者名
Houkin, Kiyohiro
著者名
Hatta, Tomohisa
e-Rad_Researcher
00357683
著者名
Natsume, Tohru
著者名
Maeda, Yoshimasa
著者名
Watanabe, Shin-ichi
著者名
Hagiwara, Shinji
e-Rad_Researcher
30270573
著者名
Kondo, Toru
言語
英語
キーワード
chemical screening
DHODH
glioblastoma-initiating cells, GICs
Sox2
O-GlcNAc
発行日
2020-02
出版者
Oxford University Press
収録物名
Neuro-Oncology
巻(号)
22(2)
ページ
229-239
抄録
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.
資源タイプ
学術雑誌論文
出版タイプ
Accepted Manuscript
権利情報
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: https://doi.org/10.1093/neuonc/noz170
PISSN
1522-8517
関連情報 (isVersionOf)
出版社版DOI
https://doi.org/10.1093/neuonc/noz170