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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.

Original publication

DOI

10.1182/blood-2008-11-190587

Type

Journal article

Journal

Blood

Publication Date

06/08/2009

Volume

114

Pages

1217 - 1225

Keywords

Aged, Aged, 80 and over, Annexin A5, Antineoplastic Agents, Apoptosis, Caspase 3, Cytochromes c, Cytosol, Dose-Response Relationship, Drug, Drug Resistance, Drug Screening Assays, Antitumor, Female, Gene Expression Regulation, Leukemic, Hematopoietic Stem Cells, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Mitochondria, Poly(ADP-ribose) Polymerases, Protein Transport, Proto-Oncogene Proteins c-bcl-2, Sulfonamides, T-Lymphocytes, Time Factors, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Up-Regulation, bcl-2-Associated X Protein