G2 checkpoint kinase inhibitors exert their radiosensitizing effects prior to the G2/M transition.
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 h 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 h 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 antitumour effects in vivo.
Sturgeon
Christopher M
CM
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.
Roberge
Michel
M
D002455:Cell Division / Q000187:drug effects* / Q000502:physiology; D000071877:Checkpoint Kinase 1; D016195:G2 Phase / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D047428:Protein Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1