Figure 1.

AMG 900 exhibits potent anti-leukemia activity on AML cell lines with a distinct sensitivity profile relative to isoform-selective AKIs. A and B, AML cell lines were treated with DMSO or test agents at eleven concentrations [three-point dilution, high concentration AMG 900 (0.1 μmol/L), MLN8054 and AZD1152-hQPA (5 μmol/L), Ara-C and daunorubicin (20 μmol/L)] for 72 hours. Cell count and apoptosis/DNA content analysis. A, Cell count potency determined for individual AML lines (n = 11), with mean and median EC₅₀ values noted below. *OCI-AML-3 data not included in graph for Ara-C (EC₅₀ > 1 μmol/L). B, AKI dose-response profiles for MOLM-13, KG-1a, and HL-60 cells showing percentage of ≥ 4N DNA content and total cell death (subG₁ + cl-caspase-3) populations (mean ± SD). C, MOLM-13, KG-1, HEL, and MEGAL cells treated with AMG 900, MLN8054, and AZD1152-hQPA or DMSO for 48 hours. Heatmaps showing p-histone H3 positivity represented as a mean percentage of control (POC). SAC activation (p-histone H3 POC > 100, white to red) and SAC silencing (p-histone H3 POC < 100, white to blue). D, Histogram of MOLM-13, KG-1, HEL cells stained with P-gp (blue) and isotype (red) antibodies, and unstained control (black). MES-SA/Dx5 cells were included as P-gp control. E, DNA content analysis of HEL cells treated with AMG 900 or AZD1152-hQPA ± P-gp inhibitor GF120918. Dose-response of AKI alone (blue) and in combination with P-gp inhibitor (red).