Enhancing CHK1 inhibitor lethality in glioblastoma.
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.
Department of Neurosurgery, School of Medicine, Virginia Commonwealth University; Richmond, VA, USA.
Yong
Y
Tang
Yun
Y
Dai
Steven
S
Grant
Paul
P
Dent
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D000071877:Checkpoint Kinase 1; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008527:Medulloblastoma / Q000188:drug therapy / Q000473:pathology; D010766:Phosphorylation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; C517975:AZD 6244; D000970:Antineoplastic Agents; C494772:BAK1 protein, human; C494826:BAX protein, human; C494811:BCL2L1 protein, human; D001549:Benzamides; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C054852:7-hydroxystaurosporine; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D011494:Protein Kinases; C482128:MAP2K2 protein, human; D019061:src-Family Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D048670:MAP Kinase Kinase 4; C482125:MAP2K1 protein, human; D019311:Staurosporine