In a study reported in the Journal of the National Cancer Institute, Carter and colleagues identified deregulated apoptotic components in acute myeloid leukemia (AML) stem/progenitor cells and investigated the effects of the novel inhibitor of apoptosis (IAP) protein antagonist and SMAC mimetic birinapant and demethylating agents in AML.
Measurement of protein expression in AML patient and normal samples showed that CD34-positive/CD38-negative AML stem/progenitors expressed significantly higher cIAP1 and caspase-8 levels and decreased SMAC levels compared with bulk AML cells. Birinapant caused death receptor/caspase-8–mediated apoptosis in AML cells, including AML stem/progenitor cells, but not in normal CD34-positive cells.
Demethylating agents modulated extrinsic apoptosis pathway components, and the combination of demethylating agents and birinapant was highly synergistic against AML cells in vitro (combination index < 1) and resulted in prolonged median survival in AML mouse xenograft models (P < .001 for birinapant plus azacitadine vs birinapant alone or vs controls).
The investigators concluded, “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.” ■
