AG490 influences UCN-01-induced cytotoxicity in glioma cells in a p53-dependent fashion, correlating with effects on BAX cleavage and BAD phosphorylation.
We determined the cytotoxicity of AG490 as a single agent and in combination with 7-hydroxystaurosporine (UCN-01) in a panel of malignant human glioma cell lines. Because p53 has important roles in cell cycle checkpoints, it has been anticipated that modulation of checkpoint pathways should sensitize p53 defective cells while sparing the normal cells. Cell proliferation was determined from dose-response curves. AG490 was effective as a cytotoxic agent alone regardless of p53 status. Combining the Chk1 inhibitor UCN-01 dramatically enhanced the response to AG490 in p53-mutated or deleted glioma cells. An opposite effect was noted in p53-wild type cells, in which UCN-01 and AG490 had antagonistic effects on cell proliferation and viability. We found that AG490 enhanced BAD phosphorylation in p53 wild type glioma cells, which appeared to protect against UCN-01-induced cytotoxicity, whereas AG490 enhanced UCN-01-induced cytotoxicity in p53 defective cell lines by suppression of BAD phosphorylation and induction of BAX and PARP cleavage. These observations highlight the potential for genotype-dependent factors to strongly influence response to signaling-targeted therapies in malignant gliomas and the importance of considering such factors in correlative response analyses for these agents.
Jane
Esther P
EP
Department of Neurosurgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Premkumar
Daniel R
DR
Pollack
Ian F
IF
D017304:Annexin A5 / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D016158:Genes, p53; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015398:Signal Transduction; D019311:Staurosporine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D020032:Tyrphostins / Q000008:administration & dosage*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D051025:bcl-Associated Death Protein / Q000378:metabolism*
D017304:Annexin A5; D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; C054852:7-hydroxystaurosporine; D011065:Poly(ADP-ribose) Polymerases; D019311:Staurosporine