Article: article from journal or magazin.
Radiosensitization by Chir-124, a selective CHK1 inhibitor: effects of p53 and cell cycle checkpoints.
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
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.
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
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