title: Inhibition of phosphatidylinositol 3-kinase/AKT signaling by NVP-BKM120 promotes ABT-737-induced toxicity in a caspase-dependent manner through mitochondrial dysfunction and DNA damage response in established and primary cultured glioblastoma cells.
abstract: Identification of therapeutic strategies that might enhance the efficacy of B-cell lymphoma-2 (Bcl-2) inhibitor ABT-737 [N-{4-[4-(4-chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzoyl}-4-(3-dimethylamino-1-phenylsulfanylmethyl-propylamino)-3-nitro-benzenesulfonamide] is of great interest in many cancers, including glioma. Our recent study suggested that Akt is a crucial mediator of apoptosis sensitivity in response to ABT-737 in glioma cell lines. Inhibitors of phosphatidylinositol 3-kinase (PI3K)/Akt are currently being assessed clinically in patients with glioma. Because PI3K/Akt inhibition would be expected to have many proapoptotic effects, we hypothesized that there may be unique synergy between PI3K inhibitors and Bcl-2 homology 3 mimetics. Toward this end, we assessed the combination of the PI3K/Akt inhibitor NVP-BKM120 [5-(2,6-dimorpholinopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine] and the Bcl-2 family inhibitor ABT-737 in established and primary cultured glioma cells. We found that the combined treatment with these agents led to a significant activation of caspase-8 and -3, PARP, and cell death, irrespective of PTEN status. The enhanced lethality observed with this combination also appears dependent on the loss of mitochondrial membrane potential and release of cytochrome c, smac/DIABLO, and apoptosis-inducing factor to the cytosol. Further study revealed that the upregulation of Noxa, truncation of Bid, and activation of Bax and Bak caused by these inhibitors were the key factors for the synergy. In addition, we demonstrated the release of proapoptotic proteins Bim and Bak from Mcl-1. We found defects in chromosome segregation leading to multinuclear cells and loss of colony-forming ability, suggesting the potential use of NVP-BKM120 as a promising agent to improve the anticancer activities of ABT-737.
authors.affiliation: Department of Neurologic Surgery, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania (E.P.J., D.R.P., K.A.F., I.F.P.); University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (E.P.J., D.R.P., A.M., K.A.F., I.F.P.); and University of Pittsburgh Brain Tumor Center, Pittsburgh, Pennsylvania (K.A.F., I.F.P.).
authors.forename: Esther P
authors.initials: EP
authors.lastname: Jane
authors.affiliation: Department of Neurologic Surgery, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania (E.P.J., D.R.P., K.A.F., I.F.P.); University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (E.P.J., D.R.P., A.M., K.A.F., I.F.P.); and University of Pittsburgh Brain Tumor Center, Pittsburgh, Pennsylvania (K.A.F., I.F.P.).
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Premkumar
authors.affiliation: Department of Neurologic Surgery, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania (E.P.J., D.R.P., K.A.F., I.F.P.); University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (E.P.J., D.R.P., A.M., K.A.F., I.F.P.); and University of Pittsburgh Brain Tumor Center, Pittsburgh, Pennsylvania (K.A.F., I.F.P.).
authors.forename: Alejandro
authors.initials: A
authors.lastname: Morales
authors.affiliation: Department of Neurologic Surgery, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania (E.P.J., D.R.P., K.A.F., I.F.P.); University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (E.P.J., D.R.P., A.M., K.A.F., I.F.P.); and University of Pittsburgh Brain Tumor Center, Pittsburgh, Pennsylvania (K.A.F., I.F.P.).
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Foster
authors.affiliation: Department of Neurologic Surgery, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania (E.P.J., D.R.P., K.A.F., I.F.P.); University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (E.P.J., D.R.P., A.M., K.A.F., I.F.P.); and University of Pittsburgh Brain Tumor Center, Pittsburgh, Pennsylvania (K.A.F., I.F.P.) ian.pollack@chp.edu.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Pollack
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D001713:Biphenyl Compounds / Q000633:toxicity*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D020090:Chromosome Segregation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D004357:Drug Synergism; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology*; D009596:Nitrophenols / Q000633:toxicity*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000633:toxicity; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D061251:Primary Cell Culture; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000633:toxicity*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C501332:ABT-737; D000631:Aminopyridines; D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; C494772:BAK1 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D001713:Biphenyl Compounds; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009025:Morpholines; C571178:NVP-BKM120; D009596:Nitrophenols; C498702:PMAIP1 protein, human; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases
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