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 language | English (US) |
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Article number | djt440 |
Journal | Journal of the National Cancer Institute |
Volume | 106 |
Issue number | 2 |
DOIs | |
State | Published - Feb 1 2014 |
Externally published | Yes |
ASJC Scopus subject areas
- Oncology
- Cancer Research