Targeting glioma stem cells in vivo by a G-quadruplex-stabilizing synthetic macrocyclic hexaoxazole

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 demon...

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Autores principales:	Takahiro Nakamura, Sachiko Okabe, Haruka Yoshida, Keisuke Iida, Yue Ma, Shogo Sasaki, Takao Yamori, Kazuo Shin-ya, Ichiro Nakano, Kazuo Nagasawa, Hiroyuki Seimiya
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3aa433890e6a4fbf9414876c5f696dba
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spelling	oai:doaj.org-article:3aa433890e6a4fbf9414876c5f696dba2021-12-02T15:06:24ZTargeting glioma stem cells in vivo by a G-quadruplex-stabilizing synthetic macrocyclic hexaoxazole10.1038/s41598-017-03785-82045-2322https://doaj.org/article/3aa433890e6a4fbf9414876c5f696dba2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03785-8https://doaj.org/toc/2045-2322Abstract 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.Takahiro NakamuraSachiko OkabeHaruka YoshidaKeisuke IidaYue MaShogo SasakiTakao YamoriKazuo Shin-yaIchiro NakanoKazuo NagasawaHiroyuki SeimiyaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Takahiro Nakamura Sachiko Okabe Haruka Yoshida Keisuke Iida Yue Ma Shogo Sasaki Takao Yamori Kazuo Shin-ya Ichiro Nakano Kazuo Nagasawa Hiroyuki Seimiya Targeting glioma stem cells in vivo by a G-quadruplex-stabilizing synthetic macrocyclic hexaoxazole
description	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.
format	article
author	Takahiro Nakamura Sachiko Okabe Haruka Yoshida Keisuke Iida Yue Ma Shogo Sasaki Takao Yamori Kazuo Shin-ya Ichiro Nakano Kazuo Nagasawa Hiroyuki Seimiya
author_facet	Takahiro Nakamura Sachiko Okabe Haruka Yoshida Keisuke Iida Yue Ma Shogo Sasaki Takao Yamori Kazuo Shin-ya Ichiro Nakano Kazuo Nagasawa Hiroyuki Seimiya
author_sort	Takahiro Nakamura
title	Targeting glioma stem cells in vivo by a G-quadruplex-stabilizing synthetic macrocyclic hexaoxazole
title_short	Targeting glioma stem cells in vivo by a G-quadruplex-stabilizing synthetic macrocyclic hexaoxazole
title_full	Targeting glioma stem cells in vivo by a G-quadruplex-stabilizing synthetic macrocyclic hexaoxazole
title_fullStr	Targeting glioma stem cells in vivo by a G-quadruplex-stabilizing synthetic macrocyclic hexaoxazole
title_full_unstemmed	Targeting glioma stem cells in vivo by a G-quadruplex-stabilizing synthetic macrocyclic hexaoxazole
title_sort	targeting glioma stem cells in vivo by a g-quadruplex-stabilizing synthetic macrocyclic hexaoxazole
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/3aa433890e6a4fbf9414876c5f696dba
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Targeting glioma stem cells in vivo by a G-quadruplex-stabilizing synthetic macrocyclic hexaoxazole

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