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01-11-2013 | Laboratory Investigation

The Cdk inhibitor flavopiridol enhances temozolomide-induced cytotoxicity in human glioma cells

Authors: Takuro Hayashi, Kazuhide Adachi, Shigeo Ohba, Yuichi Hirose

Published in: Journal of Neuro-Oncology | Issue 2/2013

Abstract

The recent progress in chemotherapy for malignant gliomas is attributable to the introduction of the DNA-methylating agent temozolomide (TMZ); however, drug resistance remains a major issue. Previous studies have shown that TMZ induces prolonged arrest of human glioma cells in the G2/M phase of the cell cycle followed by a senescence-like phenomenon or mitotic catastrophe. These findings suggest that the G2 checkpoint is linked to DNA repair mechanisms. We investigated the effect of a cyclin-dependent kinase (Cdk) inhibitor flavopiridol (FP) that inhibits the action of Cdc2, a key protein in the G2 checkpoint pathway, on TMZ-treated glioma cells. Colony formation efficiency revealed that FP potentiated the cytotoxicity of TMZ in glioma cells in a p53-independent manner. This effect was clearly associated with the suppression of key proteins at the G2-M transition, accumulation of the cells exclusively at the G2 phase, and increase in a double-stranded DNA break marker (seen on performing immunoblotting). TMZ-resistant clones showed activation of the G2 checkpoint in response to TMZ, while FP treatment resensitized these clones to TMZ. FP also enhanced the cytotoxicity of TMZ in U87MG-AktER cells. Moreover, administration of TMZ and/or FP to nude mice with xenografted U87MG cells revealed that FP sensitized xenografted U87MG cells to TMZ in these mice. Our findings suggest that TMZ resistance could be promoted by enhanced DNA repair activity in the G2-M transition and that a Cdk inhibitor could suppress this activity, leading to potentiation of TMZ action on glioma cells.

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Title: The Cdk inhibitor flavopiridol enhances temozolomide-induced cytotoxicity in human glioma cells
Authors: Takuro Hayashi
Kazuhide Adachi
Shigeo Ohba
Yuichi Hirose
Publication date: 01-11-2013
Publisher: Springer US
Published in: Journal of Neuro-Oncology / Issue 2/2013
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-013-1220-5

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The Cdk inhibitor flavopiridol enhances temozolomide-induced cytotoxicity in human glioma cells

Abstract

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Abstract

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