G2 checkpoint kinase inhibitors exert their radiosensitizing effects prior to the G2/M transition

Christopher M. Sturgeon, Michel Roberge

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Chemical inhibitors of the G2 checkpoint can sensitize p53-defective cancer cells to DNA damage and several are in preclinical or clinical development. These compounds are commonly thought to increase killing at the G2/M transition by forcing cells to divide with unrepaired DNA. We examined the effects of the ATM/ATR inhibitor caffeine and the Chk1 inhibitor isogranulatimide on the clonogenic survival of two p53-defective cell lines, MCF7-mp53 and HCT-116 p53-/- cells, when added at different times after exposure to ionizing radiation. Exposure 16-24 hrs after irradiation, when G2 arrest is maximal, forced premature entry into mitosis but increased clonogenic survival. Radiosensitization occurred mostly upon exposure between 2 and 16 hrs after irradiation, correlating with S-phase traversal. These results suggest that inhibition of the S phase activities of ATM/ATR and Chk1 may be more relevant to radiosensitization of p53-defective cells than G2 checkpoint abrogation and that careful scheduling of combination treatments might be required for synergistic antitumor effects in vivo.

Original languageEnglish
Pages (from-to)572-575
Number of pages4
JournalCell Cycle
Volume6
Issue number5
DOIs
StatePublished - Mar 1 2007
Externally publishedYes

Keywords

  • Cell cycle
  • Checkpoint
  • Checkpoint kinase inhibitors
  • DNA damage
  • G arrest
  • G phase
  • Ionizing radiation
  • NHEJ
  • S-phase

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