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Blood, 19 February 2009, Vol. 113, No. 8, pp. 1710-1722. Prepublished online as a Blood First Edition Paper on November 25, 2008; DOI 10.1182/blood-2007-09-114314. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-09-114314v1 113/8/1710    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 Fakler, M. Articles by Fulda, S. Search for Related Content PubMed PubMed Citation Articles by Fakler, M. Articles by Fulda, S. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 21, 2007 Accepted November 15, 2008 Small molecule XIAP inhibitors cooperate with TRAIL to induce apoptosis in childhood acute leukemia cells and overcome Bcl-2-mediated resistance Melanie Fakler, Sandra Loder, Meike Vogler, Katja Schneider, Irmela Jeremias, Klaus-Michael Debatin, and Simone Fulda* University Children's Hospital, Ulm, Germany GSF - Research Center for Environment and Health, Munich, Germany * Corresponding author; email: simone.fulda{at}uniklinik-ulm.de. Defects in apoptosis signaling contribute to poor outcome in pediatric acute lymphoblastic leukemia (ALL) calling for novel strategies that counter apoptosis resistance. Here, we demonstrate for the first time that small molecule inhibitors of the antiapoptotic protein XIAP cooperate with TRAIL to induce apoptosis in childhood acute leukemia cells. XIAP inhibitors at subtoxic concentrations, but not a structurally related control compound, synergize with TRAIL to trigger apoptosis and to inhibit clonogenic survival of acute leukemia cells, whereas they do not affect viability of normal peripheral blood mononuclear cells, suggesting some tumor selectivity. Analysis of signaling pathways reveals that XIAP inhibitors enhance TRAIL-induced activation of caspases, loss of mitochondrial membrane potential and cytochrome c release in a caspase-dependent manner, indicating that they promote a caspase-dependent feedback mitochondrial amplification loop. Of note, XIAP inhibitors even overcome Bcl-2-mediated resistance to TRAIL by enhancing Bcl-2 cleavage and Bak conformational change. Importantly, XIAP inhibitors kill leukemic blasts from children with ALL ex vivo and cooperate with TRAIL to induce apoptosis. In vivo, they significantly reduce leukemic burden in a mouse model of pediatric ALL engrafted in NOD/SCID mice. Thus, small molecule XIAP inhibitors present a promising novel approach for apoptosis-based therapy of childhood acute leukemia. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? 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. Fulda A Novel Paradigm to Trigger Apoptosis in Chronic Lymphocytic Leukemia Cancer Res., December 1, 2009; 69(23): 8977 - 8986. [Abstract] [Full Text] [PDF] M. E. Shawgo, S. N. Shelton, and J. D. Robertson Caspase-9 Activation by the Apoptosome Is Not Required for Fas-mediated Apoptosis in Type II Jurkat Cells J. Biol. Chem., November 27, 2009; 284(48): 33447 - 33455. [Abstract] [Full Text] [PDF]

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