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

Cell Cycle. 2009 Apr 15;8(8):1196-205. doi: 10.4161/cc.8.8.8203. Epub 2009 Apr 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Checkpoint Kinase 1
  • 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*


  • 14-3-3 Proteins
  • CHIR-124
  • Calcium-Binding Proteins
  • Cell Cycle Proteins
  • MAD2L1 protein, human
  • Mad2 Proteins
  • Quinolines
  • Quinuclidines
  • Radiation-Sensitizing Agents
  • Repressor Proteins
  • Tumor Suppressor Protein p53
  • Protein Kinases
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Chek1 protein, mouse