|
|
Hokkaido University Collection of Scholarly and Academic Papers >
Institute for Genetic Medicine >
Peer-reviewed Journal Articles, etc >
Discovery of a new pyrimidine synthesis inhibitor eradicating glioblastoma-initiating cells
Files in This Item:
| Echizenya, Ishii, et al-revised Supplementary Table 1.docx | | 12.94 kB | Microsoft Word XML | View/Open | | Echizenya, Ishii, et al-revised Supplementary Table 2.docx | | 13.86 kB | Microsoft Word XML | View/Open | | Echizenya, Ishii, et al-revised Supplementary figures.pdf | | 956.14 kB | PDF | View/Open | | Echizenya, Ishii, et al-revised Supplementary information.docx | | 28.07 kB | Microsoft Word XML | View/Open | | Echizenya, Ishii, et al-revised manuscript-final.pdf | | 858.57 kB | PDF | View/Open |
|
|
|
| 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 | | DHODH | | glioblastoma-initiating cells, GICs | | Sox2 | | O-GlcNAc |
| 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: https://doi.org/10.1093/neuonc/noz170 |
| Type: | article (author version) |
| URI: | http://hdl.handle.net/2115/80325 |
| 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
|
