title: ABT-737 synergizes with bortezomib to induce apoptosis, mediated by Bid cleavage, Bax activation, and mitochondrial dysfunction in an Akt-dependent context in malignant human glioma cell lines.
abstract: We observed that glioma cells are differentially sensitive to N-{4-[4-(4'-chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzoyl}-4-(3-dimethylamino-1-phenylsulfanylmethyl-propylamino)-3-nitro-benzenesulfonamide (ABT-737) and administration of ABT-737 at clinically achievable doses failed to induce apoptosis. Although elevated Bcl-2 levels directly correlated with sensitivity to ABT-737, overexpression of Bcl-2 did not influence sensitivity to ABT-737. To understand the molecular basis for variable and relatively modest sensitivity to the Bcl-2 homology domain 3 mimetic drug ABT-737, the abundance of Bcl-2 family members was assayed in a panel of glioma cell lines. Bcl-2 family member proteins, Bcl-xL, Bcl-w, Mcl-1, Bax, Bak, Bid, and Noxa, were found to be expressed ubiquitously at similar levels in all cell lines tested. We then examined the contribution of other apoptosis-resistance pathways to ABT-737 resistance. Bortezomib, an inhibitor of nuclear factor-kappaB (NF-κB), was found to enhance sensitivity of ABT-737 in phosphatase and tensin homolog on chromosome 10 (PTEN)-wild type, but not PTEN-mutated glioma cell lines. We therefore investigated the association between phosphatidylinositol 3-kinase (PI3K)/Akt activation and resistance to the combination of ABT-737 and bortezomib in PTEN-deficient glioma cells. Genetic and pharmacological inhibition of PI3K inhibition sensitized PTEN-deficient glioma cells to bortezomib- and ABT-737-induced apoptosis by increasing cleavage of Bid protein, activation and oligomerization of Bax, and loss of mitochondrial membrane potential. Our data further suggested that PI3K/Akt-dependent protection may occur upstream of the mitochondria. This study demonstrates that interference with multiple apoptosis-resistance signaling nodes, including NF-κB, Akt, and Bcl-2, may be required to induce apoptosis in highly resistant glioma cells, and therapeutic strategies that target the PI3K/Akt pathway may have a selective role for cancers lacking PTEN function.
authors.affiliation: Department of Neurosurgery, Children's Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA 15224, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Premkumar
authors.forename: Esther P
authors.initials: EP
authors.lastname: Jane
authors.forename: Joseph D
authors.initials: JD
authors.lastname: DiDomenico
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Vukmer
authors.forename: Naomi R
authors.initials: NR
authors.lastname: Agostino
authors.forename: Ian F
authors.initials: IF
authors.lastname: Pollack
mesh_terms: D017302:Annexins / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor / Q000378:metabolism; D049109:Cell Proliferation; D004357:Drug Synergism; D005910:Glioma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D028361:Mitochondrial Diseases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: C501332:ABT-737; D017302:Annexins; D000970:Antineoplastic Agents; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D001713:Biphenyl Compounds; D001897:Boronic Acids; D016328:NF-kappa B; D009596:Nitrophenols; D010879:Piperazines; D011719:Pyrazines; D013449:Sulfonamides; D051028:bcl-2-Associated X Protein; D000069286:Bortezomib; D051057:Proto-Oncogene Proteins c-akt