title: Co-administration of ABT-737 and SAHA induces apoptosis, mediated by Noxa upregulation, Bax activation and mitochondrial dysfunction in PTEN-intact malignant human glioma cell lines.
abstract: We previously observed that glioma cells are differentially sensitive to ABT-737 and, when used as a single-agent, this drug failed to induce apoptosis. Identification of therapeutic strategies to enhance the efficacy of the Bcl-2 inhibitor ABT-737 in human glioma is of interest. Histone deacetylation inhibitors (HDACI) are currently being assessed clinically in patients with glioma, as regulation of epigenetic abnormalities is expected to produce pro-apoptotic effects. We hypothesized that co-treatment of glioma with a BH3-mimetic and HDACI may induce cellular death. We assessed the combination of ABT-737 and HDACI SAHA in established and primary cultured glioma cells. We found combination treatment led to significant cellular death when compared to either drug as single agent and demonstrated activation of the caspase cascade. This enhanced apoptosis also appears dependent upon the loss of mitochondrial membrane potential and the release of cytochrome c and AIF into the cytosol. The upregulation of Noxa, truncation of Bid, and activation of Bax caused by this combination were important factors for cell death and the increased levels of Noxa functioned to sequester Mcl-1. This combination was less effective in PTEN-deficient glioma cells. Both genetic and pharmacologic inactivation of the PI3K/Akt signaling pathway sensitized PTEN-deleted glioma cells to the combination. This study demonstrates that antagonizing apoptosis-resistance pathways, such as targeting the Bcl-2 family in combination with epigenetic modifiers, may induce cell death. These findings extend our previous observations that targeting the PI3K/Akt pathway may be additionally necessary to promote apoptosis in cancers lacking PTEN functionality.
authors.affiliation: Department of Neurosurgery, Children's Hospital of Pittsburgh, 4401 Penn Ave., Pittsburgh, PA, 15224, USA, fosterka@upmc.edu.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Foster
authors.forename: Esther P
authors.initials: EP
authors.lastname: Jane
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Premkumar
authors.forename: Alejandro
authors.initials: A
authors.lastname: Morales
authors.forename: Ian F
authors.initials: IF
authors.lastname: Pollack
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004359:Drug Therapy, Combination; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009596:Nitrophenols / Q000494:pharmacology*; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; D051023:BH3 Interacting Domain Death Agonist Protein; D001713:Biphenyl Compounds; D056572:Histone Deacetylase Inhibitors; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D051059:PTEN Phosphohydrolase