Discovery of a new pyrimidine synthesis inhibitor eradicating glioblastoma-initiating cells
Discovery of a new pyrimidine synthesis inhibitor eradicating glioblastoma-initiating cells
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DOI：
10.1093/neuonc/noz170
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发表时间：
2020-02-01
期刊：
影响因子：
15.9
通讯作者：
Kondo, Toru
中科院分区：
文献类型：
--
作者：
Echizenya, Smile;Ishii, Yukiko;Kondo, Toru
背景。胶质母细胞瘤起始细胞（GICs）由一种致瘤性细胞亚群组成，这些细胞对放疗和化疗具有耐药性，并与癌症复发有关。本研究的目的是利用高通量药物筛选方法鉴定特异性根除GICs的新化合物。我们使用10560个独立的化合物进行了基于细胞增殖/死亡的药物筛选。通过配体钓鱼和质谱分析，鉴定了hit化合物10580的靶蛋白为二氢酸脱氢酶（DHODH）。通过体外细胞增殖/死亡和分化及体内致瘤性实验考察了10580的药效。在有效的化合物中，我们发现10580可以诱导细胞周期阻滞，降低GICs中干细胞因子的表达，并在口服后防止肿瘤发生，没有任何明显的副作用。机制研究表明，10580通过拮抗DHODH酶活性，降低嘧啶核苷酸水平，增强性别决定区Y-box 2核输出。DHODH是一种新的嘧啶合成酶。在本研究中，我们发现10580是一种很有前景的抗GICs新药。考虑到正常组织细胞，特别是脑细胞，倾向于使用嘧啶合成的替代补救途径，我们的研究结果表明，10580可用于胶质母细胞瘤治疗而无副作用。
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.