Enhancing CHK1 inhibitor lethality in glioblastoma

Cancer Biol Ther. 2012 Apr;13(6):379-88. doi: 10.4161/cbt.19240. Epub 2012 Apr 1.

Abstract

The present studies were initiated to determine whether inhibitors of MEK1/2 or SRC signaling, respectively, enhance CHK1 inhibitor lethality in primary human glioblastoma cells. Multiple MEK1/2 inhibitors (CI-1040 (PD184352); AZD6244 (ARRY-142886)) interacted with multiple CHK1 inhibitors (UCN-01, AZD7762) to kill multiple primary human glioma cell isolates that have a diverse set of genetic alterations typically found in the disease. Inhibition of SRC family proteins also enhanced CHK1 inhibitor lethality. Combined treatment of glioma cells with (MEK1/2 + CHK1) inhibitors enhanced radiosensitivity. Combined (MEK1/2 + CHK1) inhibitor treatment led to dephosphorylation of ERK1/2 and S6 ribosomal protein, whereas the phosphorylation of JNK and p38 was increased. MEK1/2 + CHK1 inhibitor-stimulated cell death was associated with the cleavage of pro-caspases 3 and 7 as well as the caspase substrate (PARP). We also observed activation of pro-apoptotic BCL-2 effector proteins BAK and BAX and reduced levels of pro-survival BCL-2 family protein BCL-XL. Overexpression of BCL-XL alleviated but did not completely abolish MEK1/2 + CHK1 inhibitor cytotoxicity in GBM cells. These findings argue that multiple inhibitors of the SRC-MEK pathway have the potential to interact with multiple CHK1 inhibitors to kill glioma cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Benzamides / pharmacology
  • Benzimidazoles / pharmacology
  • Checkpoint Kinase 1
  • Glioblastoma / drug therapy*
  • Glioblastoma / pathology
  • Humans
  • MAP Kinase Kinase 1 / antagonists & inhibitors
  • MAP Kinase Kinase 2 / antagonists & inhibitors
  • MAP Kinase Kinase 4 / metabolism
  • Medulloblastoma / drug therapy
  • Medulloblastoma / pathology
  • Phosphorylation
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / metabolism*
  • Radiation-Sensitizing Agents / pharmacology
  • Staurosporine / analogs & derivatives
  • Staurosporine / pharmacology
  • Tumor Cells, Cultured
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism
  • bcl-2-Associated X Protein / metabolism
  • bcl-X Protein / metabolism
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / metabolism

Substances

  • 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
  • AZD 6244
  • Antineoplastic Agents
  • BAK1 protein, human
  • BAX protein, human
  • BCL2L1 protein, human
  • Benzamides
  • Benzimidazoles
  • Protein Kinase Inhibitors
  • Radiation-Sensitizing Agents
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • 7-hydroxystaurosporine
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • Protein Kinases
  • MAP2K2 protein, human
  • src-Family Kinases
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • MAP Kinase Kinase 4
  • MAP2K1 protein, human
  • Staurosporine