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

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.

• Authors: 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
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 106 Issue 2 Pg. djt440 (Feb 2014) ISSN: 1460-2105 [Electronic] United States
• PMID: 24526787 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Apoptosis Regulatory Proteins
• DIABLO protein, human
• Dipeptides
• Indoles
• Inhibitor of Apoptosis Proteins
• Intracellular Signaling Peptides and Proteins
• Mitochondrial Proteins
• birinapant
• Caspase 8
• Azacitidine

Topics

• Adult
• Aged
• Antimetabolites, Antineoplastic (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Apoptosis Regulatory Proteins
• Azacitidine (administration & dosage)
• Blotting, Western
• Caspase 8 (metabolism)
• DNA Methylation (drug effects)
• Dipeptides (administration & dosage)
• Drug Synergism
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Indoles (administration & dosage)
• Inhibitor of Apoptosis Proteins (antagonists & inhibitors)
• Intracellular Signaling Peptides and Proteins (agonists, metabolism)
• Leukemia, Myeloid, Acute (drug therapy)
• Male
• Middle Aged
• Mitochondrial Proteins (agonists, metabolism)
• Neoplastic Stem Cells
• Protein Array Analysis