2-Phenylacetylenesulfonamide (PAS) induces p53-independent apoptotic killing of B-chronic lymphocytic leukemia (CLL) cells
Authors: Elisabeth P Nacheva
Panagiotis Kottaridis
Anastasios Chanalaris
R Gitendra Wickremasinghe
A Victor Hoffbrand
Archibald G Prentice
Birunthini C Yogashangary
Andrew J Steele
Edward R Samuel
Janet M North
Kate Cwynarski
Stephen M Hart
Mark W Lowdell
Journal: Blood (2009)
Discipline: CLINICAL MEDICINE
Keywords: 2-phenylacetylenesulfonamide (PAS); B-chronic lymphocytic leukemia (CLL); apoptosis; Noxa; Bax
Affiliations: Department of Hematology, Cancer Institute, University College London Medical School, London, United Kingdom., Department of Hematology, Cancer Institute, University College London Medical School, London, United Kingdom

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. 

Retracted: No

PubPeer comments:
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 ---------- Forwarded message --------- From: McGhee, Nick n.mcghee@ucl.ac.uk Date: Wed, Jan 23, 2019 at 9:40 AM Subject: RE: Problematic data UCL publication Blood. 2009 Aug 6;114(6):1217-25. To: claire Francis claire.francis1492@gmail.com Cc: Appleby, Wendy w.appleby@ucl.ac.uk Dear Ms Francis I am writing on behalf of the Registrar in response to your email of 2 January, below. The lead author to this paper has responded as follows: I have been back and looked at the data and spoken with my former colleagues. All we can deduce is that it appears we have put two slightly different analysis of the same experiment into the figure by mistake ie same data analysed two ways by mistake caused by the slight moving of the SSC and FSC gate. The image has not been manipulated because itu2019s the same data. We are going to have to write to blood and let them know of the mistake and include the figure thatu2019s should have been in Figure 2 Basically the image is not manipulated just the wrong data has been added. Thanks for bringing this to our attention, let me know whether you need anything else from me UCLu2019s Procedure provides that u2018Straightforward allegations that are not considered to be serious in nature, where the Registrar determines that there is not an intent to deceive, might be resolved by the Registrar at the initial assessment stage.u2019 In this case, in view of the authoru2019s response and proposed course of action, and as there is no further detail in the allegation, the Registrar is satisfied that the matter is therefore resolved. Yours sincerely, Nick McGhee , 
 2019 erratum. http: www.bloodjournal.org content 134 8 719 In Figure 2A-B on page 1219, the same flow cytometry plots are inadvertently replicated. Due to the time between the publication and the detection of this error, the data for patient AS31 were reanalyzed with FlowJo 10.5.3 rather than with the BD software originally cited. Consequently, the data for patient AS32 were also reanalyzed, resulting in some very minor changes in the percentages of cells in each quadrant for this patient, as shown in the following table. The corrected Figure 2 is shown below. Figure 2A has been replaced, while Figure 2B is a reanalysis of the same data. The figure legend is unchanged. Figure 2A is a representative example of a patient with p53 wild-type status and no 17p deletion (17p del), while Figure 2B shows data for a patient with 97% p53 deletion (17p del). This required updating the data in Table 1 (page 1220) for patients AS31 and AS32. The corrected Table 1 is also shown below. These changes do not alter the biological outcome and meaning of the study. The authors apologize for the figure duplication. ,