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
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Antineoplastic Agents / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Benzamides / pharmacology
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Benzimidazoles / pharmacology
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Checkpoint Kinase 1
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Glioblastoma / drug therapy*
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Glioblastoma / pathology
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Humans
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MAP Kinase Kinase 1 / antagonists & inhibitors
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MAP Kinase Kinase 2 / antagonists & inhibitors
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MAP Kinase Kinase 4 / metabolism
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Medulloblastoma / drug therapy
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Medulloblastoma / pathology
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Phosphorylation
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases / metabolism
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinases / metabolism*
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Radiation-Sensitizing Agents / pharmacology
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Staurosporine / analogs & derivatives
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Staurosporine / pharmacology
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Tumor Cells, Cultured
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bcl-2 Homologous Antagonist-Killer Protein / metabolism
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bcl-2-Associated X Protein / metabolism
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bcl-X Protein / metabolism
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src-Family Kinases / antagonists & inhibitors
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src-Family Kinases / metabolism
Substances
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2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
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AZD 6244
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Antineoplastic Agents
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BAK1 protein, human
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BAX protein, human
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BCL2L1 protein, human
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Benzamides
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Benzimidazoles
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Protein Kinase Inhibitors
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Radiation-Sensitizing Agents
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bcl-2 Homologous Antagonist-Killer Protein
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bcl-2-Associated X Protein
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bcl-X Protein
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7-hydroxystaurosporine
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PARP1 protein, human
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases
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Protein Kinases
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MAP2K2 protein, human
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src-Family Kinases
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CHEK1 protein, human
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Checkpoint Kinase 1
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2
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MAP Kinase Kinase 4
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MAP2K1 protein, human
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Staurosporine