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Blood, 1 September 2005, Vol. 106, No. 5, pp. 1742-1748. Prepublished online as a Blood First Edition Paper on May 24, 2005; DOI 10.1182/blood-2005-02-0695. This Article Full Text (PDF) All Versions of this Article: 2005-02-0695v1 106/5/1742    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kater, A. P Articles by Kipps, T. J Search for Related Content PubMed PubMed Citation Articles by Kater, A. P Articles by Kipps, T. J Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 18, 2005 Accepted May 9, 2005 Inhibitors of XIAP sensitize CD40-activated chronic lymphocytic leukemia cells to CD95-mediated apoptosis Arnon P Kater, Frank Dicker, Massimo Mangiola, Kate Welsh, Richard Houghten, John Ostresh, Adel Nefzi, John C Reed, Clemencia Pinilla, and Thomas J Kipps* Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA; Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Chronic Lymphocytic Leukemia Research Consortium, La Jolla, CA, USA Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA; Chronic Lymphocytic Leukemia Research Consortium, La Jolla, CA, USA Burnham Institute, La Jolla, CA, USA; Chronic Lymphocytic Leukemia Research Consortium, La Jolla, CA, USA Burnham Institute, La Jolla, CA, USA Torrey Pines Institute for Molecular Sciences, San Diego, CA, USA * Corresponding author; email: tkipps{at}ucsd.edu. Chronic lymphocytic leukemia (CLL) patients treated with adenovirus (Ad)-CD154 (CD40L) gene therapy experienced rapid reductions in leukemia-cell counts and lymph-node size associated with the induced expression Fas (CD95). However, CLL cells initially resist CD95-mediated apoptosis within the first 3 days after CD40-ligation in vitro. Thereafter, they become sensitive, which is associated with the CD40-induced expression of the pro-apoptotic protein BH3 interacting domain death agonist (Bid). We hypothesized the initial resistance to CD95-mediated apoptosis may be due to the high-level expression of X-linked inhibitor of apoptosis protein (XIAP) by CLL cells. Consistent with this, CLL cells from patients one day after treatment with autologous Ad-CD154-transduced CLL cells became sensitive to CD95-mediated apoptosis following treatment with a novel XIAP inhibitor, 1540-14. Similarly, 1540-14 specifically enhanced CD95-mediated apoptosis of CLL cells following CD40-ligation in vitro. Immunoblot analyses demonstrated that treatment with 1540-14 allowed CD40-stimulated CLL cells to experience high-level activation of caspases 8 and 3 and cleavage of poly(ADP-ribose) polymerase following CD95-ligation. This study demonstrates that distal apoptosis regulators contribute to the initial resistance of CD40-activated CLL cells to CD95-mediated apoptosis and suggests that XIAP inhibitors might enhance the effectiveness of immune-based treatment strategies that target CD40, such as CD154 gene therapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Old and new drugs join forces against hematologic malignancies Fabio Malavasi Blood 2005 106: 1513-1514. [Full Text] [PDF] This article has been cited by other articles: S. Loeder, T. Zenz, A. Schnaiter, D. Mertens, D. Winkler, H. Dohner, K.-M. Debatin, S. Stilgenbauer, and S. 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Feldmann, C. Pinilla, K. Welsh, J. C. Reed, E. P. Armour, J. Wong, J. Herman, et al. Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein Mol. Cancer Ther., March 1, 2007; 6(3): 957 - 966. [Abstract] [Full Text] [PDF] F. Dicker, A. P. Kater, C. E. Prada, T. Fukuda, J. E. Castro, G. Sun, J. Y. Wang, and T. J. Kipps CD154 induces p73 to overcome the resistance to apoptosis of chronic lymphocytic leukemia cells lacking functional p53 Blood, November 15, 2006; 108(10): 3450 - 3457. [Abstract] [Full Text] [PDF] H. Kashkar, J.-M. Seeger, A. Hombach, A. Deggerich, B. Yazdanpanah, O. Utermohlen, G. Heimlich, H. Abken, and M. Kronke XIAP targeting sensitizes Hodgkin lymphoma cells for cytolytic T-cell attack Blood, November 15, 2006; 108(10): 3434 - 3440. [Abstract] [Full Text] [PDF] H. H. Cheung, E. C. LaCasse, and R. G. Korneluk X-linked inhibitor of apoptosis antagonism: strategies in cancer treatment. Clin. 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