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Blood, 1 January 2008, Vol. 111, No. 1, pp. 369-375. Prepublished online as a Blood First Edition Paper on October 4, 2007; DOI 10.1182/blood-2007-04-085480. This Article Full Text (PDF) All Versions of this Article: blood-2007-04-085480v1 111/1/369    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 Cillessen, S. A. Articles by Oudejans, J. J Search for Related Content PubMed PubMed Citation Articles by Cillessen, S. A. Articles by Oudejans, J. J Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 13, 2007 Accepted September 19, 2007 Small-molecule XIAP antagonist restores caspase-9-mediated apoptosis in XIAP-positive diffuse large B-cell lymphoma cells Saskia AGM Cillessen, John C Reed, Kate Welsh, Clemencia Pinilla, Richard Houghten, Erik Hooijberg, Jose Deurhof, Kitty CM Castricum, Pim Kortman, Corine J Hess, Gert J Ossenkoppele, Chris JLM Meijer, and Joost J Oudejans* Department of Clinical Pathology, VU University Medical Center, Amsterdam, Netherlands Burnham Institute for Medical Research, La Jolla, CA, United States Torrey Pines Institute for Molecular Studies, San Diego, CA, United States Department of Hematology, VU University Medical Center, Amsterdam, Netherlands * Corresponding author; email: jj.oudejans{at}vumc.nl. Clinical outcome in patients with primary nodal diffuse large B-cell lymphomas (DLBCL) is correlated with expression of inhibitors of the intrinsic apoptosis pathway, including XIAP. XIAP suppresses apoptosis through inhibiting active caspases-3, -7 and -9. In this study we investigated if the small-molecule XIAP antagonist 1396-12 induces cell death in cultured lymphoma cells of DLBCL patients. Treatment with this XIAP antagonist resulted in relief of caspase 3 inhibition and in induction of apoptosis in 16 of 20 tested DLBCL samples. Sensitivity to the XIAP antagonist was observed in both chemotherapy refractory and responsive DLBCL, but did not affect peripheral blood mononuclear cells and tonsil germinal center B-cells from healthy donors. XIAP antagonist-sensitive cases were characterized by high expression levels of XIAP, relatively low expression levels of Bcl-2, and by constitutive caspase-9 activation. These data indicate that the small-molecule XIAP antagonist can induce apoptosis in cultured DLBCL cells and therefore should be considered for possible development as a therapy for these patients. In vitro sensitivity to the XIAP antagonist can be predicted based on biological markers suggesting the possibility of pre-defining patients most likely to benefit from XIAP antagonist therapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Fakler, S. Loeder, M. Vogler, K. Schneider, I. Jeremias, K.-M. Debatin, and S. Fulda Small molecule XIAP inhibitors cooperate with TRAIL to induce apoptosis in childhood acute leukemia cells and overcome Bcl-2-mediated resistance Blood, February 19, 2009; 113(8): 1710 - 1722. [Abstract] [Full Text] [PDF] J. J. Oudejans, J. J.F. Muris, S. A.G.M. Cillessen, and C. J.L.M. Meijer T-Cell Response in B-Cell Lymphomas: Favorable or Unfavorable? Clin. Cancer Res., April 15, 2008; 14(8): 2514 - 2514. [Full Text] [PDF]

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