Targeting radiation-induced G(2) checkpoint activation with the Wee-1 inhibitor MK-1775 in glioblastoma cell lines

Mol Cancer Ther. 2011 Dec;10(12):2405-14. doi: 10.1158/1535-7163.MCT-11-0469. Epub 2011 Oct 12.


The purpose of this study was to determine the capacity of MK-1775, a potent Wee-1 inhibitor, to abrogate the radiation-induced G(2) checkpoint arrest and modulate radiosensitivity in glioblastoma cell models and normal human astrocytes. The radiation-induced checkpoint response of established glioblastoma cell lines, glioblastoma neural stem (GNS) cells, and astrocytes were determined in vitro by flow cytometry and in vivo by mitosis-specific staining using immunohistochemistry. Mechanisms underlying MK-1775 radiosensitization were determined by mitotic catastrophe and γH2AX expression. Radiosensitivity was determined in vitro by the clonogenic assay and in vivo by tumor growth delay. MK-1775 abrogated the radiation-induced G(2) checkpoint and enhanced radiosensitivity in established glioblastoma cell lines in vitro and in vivo, without modulating radiation response in normal human astrocytes. MK-1775 appeared to attenuate the early-phase of the G(2) checkpoint arrest in GNS cell lines, although the arrest was not sustained and did not lead to increased radiosensitivity. These results show that MK-1775 can selectively enhance radiosensitivity in established glioblastoma cell lines. Further work is required to determine the role Wee-1 plays in checkpoint activation of GNS cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Line, Tumor
  • G2 Phase Cell Cycle Checkpoints / drug effects*
  • G2 Phase Cell Cycle Checkpoints / radiation effects*
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • Mice
  • Mice, Nude
  • Molecular Targeted Therapy
  • Nuclear Proteins / antagonists & inhibitors
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use*
  • Pyrimidinones
  • Radiation Tolerance / drug effects
  • Radiation-Sensitizing Agents / pharmacokinetics
  • Radiation-Sensitizing Agents / pharmacology
  • Up-Regulation / drug effects
  • Up-Regulation / radiation effects
  • Xenograft Model Antitumor Assays


  • Cell Cycle Proteins
  • Nuclear Proteins
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Pyrimidinones
  • Radiation-Sensitizing Agents
  • Protein-Tyrosine Kinases
  • WEE1 protein, human
  • adavosertib