Inhibitory targeting of checkpoint kinase signaling overrides radiation-induced cell cycle gene regulation: a therapeutic strategy in tumor cell radiosensitization?

Radiother Oncol. 2004 Sep;72(3):305-10. doi: 10.1016/j.radonc.2004.07.002.


Background and purpose: The tumor cell defense response to ionizing radiation involves a temporary arrest at the cell cycle G(2) checkpoint, which is activated by a signaling cascade initiated by the ATM kinase response to DNA damage, ultimately leading to the outcome of further cell survival if the DNA is properly repaired. The inhibitory targeting of the checkpoint kinase signaling elicited by ATM may define a biologically based strategy to override the G(2) phase delay that prevents mitotic entry after DNA damage, thereby increasing the probability of mitotic cell death following exposure to ionizing radiation.

Materials and methods: Breast carcinoma cell lines with intact or defective function of the tumor-suppressor protein BRCA1 were exposed to ionizing radiation in the absence or presence of a specific inhibitor (UCN-01) of the checkpoint kinase CHK1, and the response profiles of cell cycle distribution and G(2) phase regulatory factors, as well as the efficiency of clonogenic regrowth, were analyzed.

Results: The radiation-induced G(2) phase accumulation was preceded by a transient down-regulation of the G(2) phase-specific polo-like kinase-1 and cyclin B1, which required intact function of both BRCA1 and CHK1. The concomitant treatment with UCN-01 seemed to amplify the cytotoxic effect of ionizing radiation on clonogenic regrowth.

Conclusion: The effector mechanism of DNA damage on cell cycle gene regulation signals through the checkpoint kinase network. Among molecular cell cycle-targeted drugs currently in pipeline for testing in early phase clinical trials, CHK1 inhibitors may have therapeutic potential as radiosensitizers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / physiology
  • Cell Line, Tumor
  • Checkpoint Kinase 1
  • Cyclin B / physiology
  • Cyclin B1
  • G2 Phase / physiology
  • G2 Phase / radiation effects*
  • Genes, BRCA1 / physiology
  • Genes, cdc / physiology
  • Genes, cdc / radiation effects*
  • Protein Kinases / physiology*
  • Radiation Tolerance / physiology*
  • Signal Transduction


  • Cyclin B
  • Cyclin B1
  • Protein Kinases
  • Checkpoint Kinase 1