Targeting glioma stem cells in vivo by a G-quadruplex-stabilizing synthetic macrocyclic hexaoxazole
Type: article
Abstract: G-quadruplex (G4) is a higher-order nucleic acid structure that is formed by guanine-rich sequences. G4 stabilization by small-molecule compounds called G4 ligands often causes cytotoxicity, although the potential medicinal impact of this effect has not been fully established. Here we demonstrate that a synthetic G4 ligand, Y2H2-6M(4)-oxazole telomestatin derivative (6OTD), limits the growth of intractable glioblastoma (grade IV glioma) and glioma stem cells (GSCs). Experiments involving a human cancer cell line panel and mouse xenografts revealed that 6OTD exhibits antitumor activity against glioblastoma. 6OTD inhibited the growth of GSCs more potently than it did the growth of differentiated non-stem glioma cells (NSGCs). 6OTD caused DNA damage, G1 cell cycle arrest, and apoptosis in GSCs but not in NSGCs. These DNA damage foci tended to colocalize with telomeres, which contain repetitive G4-forming sequences. Compared with temozolomide, a clinical DNA-alkylating agent against glioma, 6OTD required lower concentrations to exert anti-cancer effects and preferentially affected GSCs and telomeres. 6OTD suppressed the intracranial growth of GSC-derived tumors in a mouse xenograft model. These observations indicate that 6OTD targets GSCs through G4 stabilization and promotion of DNA damage responses. Therefore, G4s are promising therapeutic targets for glioblastoma.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Development of G-quadruplex ligands that target cancer stem cells, Development of small molecules that stabilize i-motif DNA structures composed in the C-rich regions., Development of cancer molecular therapeutics that targets telomere-regulating factors, グアニン四重鎖リガンドのがん幹細胞に対する作用機序解明と抗がん剤への展開, G3111881881, Synthetic lethality-based identification of drug-sensitive genome profiles, Development of high throughput screening method of G-quadruplexes using small molecules, Selective detection and stabilization of G-quadruplexes in genome using G4 ligands, Development of G-quadruplex stabilizing agent for growth inhibition of cancer stem cells, G6158379319, Development of Light-up type G-quadruplex ligand for live cell imaging, 機能性グアニン四重鎖を選択的に安定化するリガンドの創製研究, Advanced Animal Model Support
OpenAlex ID: W7155116408