Targeting radiation-induced G2/M checkpoint activation with the Wee-1 inhibitor MK-1775 in glioblastoma cell lines
Menée in vitro sur des cellules de glioblastome et des astrocytes humains, cette étude évalue la capacité du MK-1775, un inhibiteur potentiel de la protéine kinase Wee-1, à renforcer la sensibilité des cellules de glioblastome aux rayonnements ionisants
Define the capacity of MK-1775, a potent Wee-1 inhibitor, to abrogate the radiation induced G2 checkpoint arrest and modulate radiation sensitivity in glioblastoma cell models and normal human astrocytes. The radiation-induced checkpoint response of established glioblastoma cell lines, glioblastoma neural stem (GNS) cells, and normal human 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 target modulation was assessed by western blot. Radiation sensitivity was determined in vitro by the clonogenic assay and in vivo by tumor growth delay. MK-1775 abrogated the radiation-induced G2 checkpoint and enhanced radiation sensitivity 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 G2 checkpoint arrest in GNS cell lines, although the arrest was not sustained and did not lead to increased radiation sensitivity. These results demonstrate that MK-1775 can selectively enhance radiation sensitivity in established glioblastoma cell lines. Further work is required to determine the role Wee1 plays in checkpoint activation of GNS cells.
http://mct.aacrjournals.org/content/early/2011/10/07/1535-7163.MCT-11-0469.abstract