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.
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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)
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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
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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)
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