Radiosensitization by Chir-124, a selective CHK1 inhibitor: effects of p53 and cell cycle checkpoints.

Details

Serval ID
serval:BIB_6D8E573DA590
Type
Article: article from journal or magazin.
Collection
Publications
Title
Radiosensitization by Chir-124, a selective CHK1 inhibitor: effects of p53 and cell cycle checkpoints.
Journal
Cell Cycle
Author(s)
Tao Y., Leteur C., Yang C., Zhang P., Castedo M., Pierré A., Golsteyn R.M., Bourhis J., Kroemer G., Deutsch E.
ISSN
1551-4005 (Electronic)
ISSN-L
1551-4005
Publication state
Published
Issued date
2009
Peer-reviewed
Oui
Volume
8
Number
8
Pages
1196-1205
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Abstract
Checkpoint kinase-1 (CHK1) is a key regulator of the DNA damage-elicited G(2)-M checkpoints. The aim of the present study was to investigate the effects of a selective CHK1 inhibitor, Chir124, on cell survival and cell cycle progression following ionizing radiation (IR). Treatment with Chir-124 resulted in reduced clonogenic survival and abrogated the IR-induced G(2)-M arrest in a panel of isogenic HCT116 cell lines after IR. This radiosensitizing effect was relatively similar between p53(-/-) and p53-sufficient wild type (WT) HCT116 cells. However, the number of mitotic cells (as measured by assessing the phosphorylation of mitotic proteins) increased dramatically in p53(-/-) HCT116 cells after concomitant Chir-124 exposure, compared to IR alone, while no such effect was observed in p53-sufficient WT HCT116 cells. In p53(-/-) cells, Chir-124 treatment induced a marked accumulation of polyploid cells that were characterized by micronucleation or multinucleation. p21(-/-) HCT116 cells displayed a similar pattern of response as p53(-/-) cells. Chir-124 was able to radiosensitize HCT116 cells that lack checkpoint kinase-2 (CHK2) or that were deficient for the spindle checkpoint protein Mad2. Finally, Chir-124 could radiosensitize tetraploid cell lines, which were relatively resistant against DNA damaging agents. Altogether these results suggest that Chir-124-mediated radiosensitization is profoundly influenced by the p53 and cell cycle checkpoint system.
Keywords
14-3-3 Proteins/metabolism, Animals, Calcium-Binding Proteins/metabolism, Cell Cycle/drug effects, Cell Cycle/radiation effects, Cell Cycle Proteins/metabolism, Cell Survival/drug effects, Cell Survival/radiation effects, DNA Damage, Enzyme Activation/drug effects, Enzyme Activation/radiation effects, Flow Cytometry, G2 Phase/drug effects, G2 Phase/radiation effects, HCT116 Cells, Humans, Immunohistochemistry, Mad2 Proteins, Mice, Mitotic Index, Polyploidy, Protein Kinases/metabolism, Quinolines/pharmacology, Quinuclidines/pharmacology, Radiation, Ionizing, Radiation-Sensitizing Agents/pharmacology, Repressor Proteins/metabolism, Spindle Apparatus/drug effects, Spindle Apparatus/radiation effects, Tumor Stem Cell Assay, Tumor Suppressor Protein p53/metabolism
Pubmed
Web of science
Create date
01/12/2014 17:20
Last modification date
20/08/2019 14:27
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