Journal
STEM CELLS
Volume 34, Issue 8, Pages 2016-2025Publisher
WILEY
DOI: 10.1002/stem.2380
Keywords
Glioblastoma-initiating cells; Temozolomide; 1-(3-C-ethynyl-beta-D-ribopentofuranosyl) uracil; Uridine-cytidine kinase-like 1; 5 '-Nucleotidase cytosolic III
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Funding
- Ministry of Education, Culture, Sports, Science and Technology Japan
- Ministry of Education, Culture, Sports, Science (MEXT)
- Japan Agency for Medical Research and development (AMED)
- Grants-in-Aid for Scientific Research [16K18447] Funding Source: KAKEN
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Glioblastoma (GBM), one of the most malignant human cancers, frequently recurs despite multi-modal treatment with surgery and chemo/radiotherapies. GBM-initiating cells (GICs) are the likely cell-of-origin in recurrences, as they proliferate indefinitely, form tumors in vivo, and are resistant to chemo/radiotherapies. It is therefore crucial to find chemicals that specifically kill GICs. We established temozolomide (the standard medicine for GBM)-resistant GICs (GICRs) and used the cells for chemical screening. Here, we identified 1-(3-C-ethynyl-beta-D-ribopentofuranosyl) uracil (EUrd) as a selective drug for targeting GICRs. EUrd induced the death in GICRs more effectively than their parental GICs, while it was less toxic to normal neural stem cells. We demonstrate that the cytotoxic effect of EUrd on GICRs partly depended on the increased expression of uridine-cytidine kinase-like 1 (UCKL1) and the decreased one of 5'-nucleotidase cytosolic III (NT5C3), which regulate uridine-monophosphate synthesis positively and negatively respectively. Together, these findings suggest that EUrd can be used as a new therapeutic drug for GBM with the expression of surrogate markers UCKL1 and NT5C3.
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