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: Andrew J Steele, Archibald G Prentice, A Victor Hoffbrand, Birunthini C Yogashangary, Stephen M Hart, Mark W Lowdell, Edward R Samuel, Janet M North, Elisabeth P Nacheva, Anastasios Chanalaris, Panagiotis Kottaridis, Kate Cwynarski, R Gitendra Wickremasinghe
• Journal: Blood (Blood) Vol. 114 Issue 6 Pg. 1217-25 (Aug 06 2009) ISSN: 1528-0020 [Electronic] United States
• PMID: 19515722 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Annexin A5
• Antineoplastic Agents
• BAX protein, human
• PMAIP1 protein, human
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• TP53 protein, human
• Tumor Suppressor Protein p53
• bcl-2-Associated X Protein
• Cytochromes c
• Poly(ADP-ribose) Polymerases
• CASP3 protein, human
• Caspase 3

Topics

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