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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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LYMPHOID NEOPLASIA

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

Andrew J. Steele1, Archibald G. Prentice1, A. Victor Hoffbrand1, Birunthini C. Yogashangary1, Stephen M. Hart1, Mark W. Lowdell1, Edward R. Samuel1, Janet M. North1, Elisabeth P. Nacheva1, Anastasios Chanalaris1, Panagiotis Kottaridis1, Kate Cwynarski1, and R. Gitendra Wickremasinghe1

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

We studied the actions of 2-phenylacetylenesulfonamide (PAS) on B-chronic lymphocytic leukemia (CLL) cells. PAS (5-20 µM) 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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