title: 2-Phenylacetylenesulfonamide (PAS) induces p53-independent apoptotic killing of B-chronic lymphocytic leukemia (CLL) cells.
abstract: We studied the actions of 2-phenylacetylenesulfonamide (PAS) on B-chronic lymphocytic leukemia (CLL) cells. PAS (5-20 microM) initiated apoptosis within 24 hours, with maximal death at 48 hours asassessed by morphology, cleavage of poly(ADP-ribose) polymerase (PARP), caspase 3 activation, and annexin V staining. PAS treatment induced Bax proapoptotic conformational change, Bax movement from the cytosol to the mitochondria, and cytochrome c release, indicating that PAS induced apoptosis via the mitochondrial pathway. PAS induced approximately 3-fold up-regulation of proapoptotic Noxa protein and mRNA levels. In addition, Noxa was found unexpectedly to be bound to Bcl-2 in PAS-treated cells. PAS treatment of CLL cells failed to up-regulate p53, suggesting that PAS induced apoptosis independently of p53. Furthermore, PAS induced apoptosis in CLL isolates with p53 gene deletion in more than 97% of cells. Normal B lymphocytes were as sensitive to PAS-induced Noxa up-regulation and apoptosis as were CLL cells. However, both T lymphocytes and bone marrow hematopoietic progenitor cells were relatively resistant to PAS. Our data suggest that PAS may represent a novel class of drug that induces apoptosis in CLL cells independently of p53 status by a mechanism involving Noxa up-regulation.
authors.affiliation: Department of Hematology, Cancer Institute, University College London Medical School, London, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Steele
authors.forename: Archibald G
authors.initials: AG
authors.lastname: Prentice
authors.forename: A Victor
authors.initials: AV
authors.lastname: Hoffbrand
authors.forename: Birunthini C
authors.initials: BC
authors.lastname: Yogashangary
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hart
authors.forename: Mark W
authors.initials: MW
authors.lastname: Lowdell
authors.forename: Edward R
authors.initials: ER
authors.lastname: Samuel
authors.forename: Janet M
authors.initials: JM
authors.lastname: North
authors.forename: Elisabeth P
authors.initials: EP
authors.lastname: Nacheva
authors.forename: Anastasios
authors.initials: A
authors.lastname: Chanalaris
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Kottaridis
authors.forename: Kate
authors.initials: K
authors.lastname: Cwynarski
authors.forename: R Gitendra
authors.initials: RG
authors.lastname: Wickremasinghe
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017304:Annexin A5 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D013449:Sulfonamides / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D017304:Annexin A5; D000970:Antineoplastic Agents; C494826:BAX protein, human; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3