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 Blood, 6 August 2009, Vol. 114, No. 6, pp. 1217-1225.
Prepublished online as a Blood First Edition Paper on June 10, 2009; DOI 10.1182/blood-2008-11-190587.

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Submitted November 19, 2008
Accepted May 30, 2009

2-phenylacetylenesulfonamide (PAS) induces p53-independent apoptotic killing of B-chronic lymphocytic leukemia (CLL) cells

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, and R. Gitendra Wickremasinghe*

Department of Hematology, Cancer Institute, University College London Medical School, London, United Kingdom

* Corresponding author; email: r.wickremasinghe{at}medsch.ucl.ac.uk.

We studied the actions of 2-phenylacetylenesulfonamide (PAS) on CLL cells. PAS (5-20µM) initiated apoptosis within 24 hours, with maximal death at 48 hours as assessed by morphology, cleavage of poly(ADP ribose) polymerase (PARP), caspase 3 activation and annexin V staining. PAS treatment induced Bax pro-apoptotic 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 three-fold upregulation of pro-apoptotic 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 upregulate p53, suggesting that PAS induced apoptosis independently of p53. Furthermore, PAS induced apoptosis in CLL isolates with p53 gene deletion in >97% of cells. Normal B-lymphocytes were as sensitive to PAS-induced Noxa upregulation 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 which induces apoptosis in CLL cells independently of p53 status by a mechanism involving Noxa upregulation.


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