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Blood First Edition Paper, prepublished online November 6, 2009; DOI 10.1182/blood-2009-03-212563. This Article Full Text (PDF) 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 CrossRef Google Scholar Articles by Carter, B. Z. Articles by Andreeff, M. PubMed PubMed Citation Articles by Carter, B. Z. Articles by Andreeff, M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 26, 2009; accepted October 4, 2009. Simultaneous activation of p53 and inhibition of XIAP enhance the activation of apoptosis signaling pathways in AML Bing Z. Carter1, Duncan H. Mak1, Wendy D. Schober1, Erich Koller2, Clemencia Pinilla3, Lyubomir T. Vassilev4, John C. Reed5 and Michael Andreeff6,6 1 Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, United States; 2 Isis Pharmaceuticals, Carlsbad, CA, United States; 3 Torrey Pines Institute for Molecular Studies, La Jolla, CA, United States; 4 Roche Pharmaceuticals, Nutley, NJ, United States; 5 Burnham Institute for Medical Research, La Jolla, CA, United States; 6 Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, United States * Corresponding author; email: mandreef{at}mdanderson.org Abstract Activation of p53 by MDM2 antagonist nutlin-3a or inhibition of XIAP induces apoptosis in AML cells. We demonstrate here that concomitant inhibition of MDM2 by nutlin-3a and of XIAP by small molecule antagonists synergistically induced apoptosis in p53 wild-type OCI-AML3 and Molm13 cells. Knockdown of p53 by shRNA blunted the synergy, and downregulation of XIAP by antisense oligonucleotide (ASO) enhanced nutlin-3a-induced apoptosis, suggesting that the synergy was mediated by p53 activation and XIAP inhibition. This is supported by data showing that inhibition of both MDM2 and XIAP by their respective ASOs induced significantly more cell death than either ASO alone. Importantly, p53 activation and XIAP inhibition enhanced apoptosis in blasts from patients with primary AML, even when the cells were protected by stromal cells. Mechanistic studies demonstrated that XIAP inhibition potentiates p53-induced apoptosis by decreasing p53-induced p21 and that p53 activation enhances XIAP inhibition-induced cell death by promoting mitochondrial release of SMAC and by inducing the expression of caspase-6. Since both XIAP and p53 are presently being targeted in ongoing clinical trials in leukemia, the combination strategy holds promise for expedited translation into the clinic. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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