Synergistic targeting of AML Stem/progenitor cells with IAP antagonist birinapant and demethylating agents

Bing Z. Carter, Po Yee Mak, Duncan H. Mak, Yuexi Shi, Yihua Qiu, James M. Bogenberger, Hong Mu, Raoul Tibes, Hui Yao, Kevin R. Coombes, Rodrigo O. Jacamo, Teresa McQueen, Steven M. Kornblau, Michael Andreeff

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

Background Acute myeloid leukemia (AML) therapy has limited long-term efficacy because patients frequently develop disease relapse because of the inability of standard chemotherapeutic agents to target AML stem/progenitor cells. Here, we identify deregulated apoptotic components in AML stem/progenitor cells and investigate the individual and combinatorial effects of the novel inhibitor of apoptosis (IAP) protein antagonist and second mitochondrial-derived activator of caspases (SMAC) mimetic birinapant and demethylating epigenetic modulators. Methods Protein expression was measured by reversed-phase protein array in AML patient (n = 511) and normal (n = 21) samples and by western blot in drug-treated cells. The antileukemic activity of birinapant and demethylating agents was assessed in vitro and in an in vivo AML mouse xenograft model (n = 10 mice per group). All statistical tests were two-sided. Results Compared with bulk AML cells, CD34+38- AML stem/progenitors expressed increased cIAP1 and caspase-8 levels and decreased SMAC levels (one-way analysis of variance followed by Tukey s multiple comparison test, P > .001). Birinapant induced death receptor /caspase-8 mediated apoptosis in AML cells, including in AML stem/ progenitor cells, but not in normal CD34+ cells. Demethylating agents modulated extrinsic apoptosis pathway components and, when combined with birinapant, were highly synergistic in vitro (combination index > 1), and also more effective in vivo (P > .001, by Student t test, for the median survival of birinapant plus 5-azacytadine vs birinapant alone or vs controls). Conclusions cIAP1, SMAC, and caspase-8 appear to play a role in AML stem cell survival, and synergistic targeting of these cells with birinapant and demethylating agents shows potential utility in leukemia therapy.

Original languageEnglish (US)
Article numberdjt440
JournalJournal of the National Cancer Institute
Volume106
Issue number2
DOIs
StatePublished - Feb 1 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Carter, B. Z., Mak, P. Y., Mak, D. H., Shi, Y., Qiu, Y., Bogenberger, J. M., Mu, H., Tibes, R., Yao, H., Coombes, K. R., Jacamo, R. O., McQueen, T., Kornblau, S. M., & Andreeff, M. (2014). Synergistic targeting of AML Stem/progenitor cells with IAP antagonist birinapant and demethylating agents. Journal of the National Cancer Institute, 106(2), [djt440]. https://doi.org/10.1093/jnci/djt440