Figure 2.
The activity of eftoza is enhanced in combination with the BCL-2 selective inhibitor venetoclax in AML cell lines. (A) AML cell lines were treated with eftoza and venetoclax in combination for 24 hours and cell viability was determined using CellTiter-Glo. Synergy was assessed using the Bliss independence model,32 in which Bliss sums represent the cumulative Bliss scores across the combination matrix. Data represent the mean ± SEM of n = ≥3 independent experiments. Red bars depict cell lines expressing TP53wt; green bars depict cell lines harboring TP53mut. (B-C) Live-cell quantification of caspase-3/7 activation in OCI-AML2 cell line over a time period was measured by adding caspase-3/7 green dye at the beginning of treatment and monitoring the cells every hour using IncuCyte ZOOM. (B) Time- and dose-dependent change in caspase-3/7–positive cells as a percentage of total cells per well. Data represent mean ± SEM; n = 3. (C) Caspase-3/7 activity as measured using the area under the concentration-time curve (AUC) from panel B. (D) Dose-response curves of OCI-AML5 parental and (E) BAK1–/–/BAX–/– OCI-AML5 cells, treated alone or in combination with eftoza and venetoclax for 24 hours. Viability was determined using CellTiter-Glo (mean ± SEM; n = 3). (F) Tumor volume change in mice bearing MV-4-11 tumor cells treated with eftoza (3 mg/kg, q2d × 3, IP), venetoclax (50 mg/kg, qd × 6, po), or eftoza and venetoclax in combination. Data represent the mean ± SEM of 8 mice per treatment group. (G) Tumor volume change in mice bearing OCI-AML2 tumor cells treated with eftoza (3 mg/kg, q7d × 2, IP), venetoclax (25 mg/kg, qd × 14, po), or eftoza and venetoclax in combination. Data represent the mean ± SEM of 8 mice per treatment group. (H-J) The plasma membrane expression of DR4, DR5, total DRs (DR4 + DR5), and total BCL-2 expression were measured using flow cytometry in the panel of AML cell lines, and the Spearman rank correlation with the Bliss sums from panel A was determined. IP, intraperitoneally; po, by mouth; qd, daily; q2d; every other day; q7d, every 7 days.

The activity of eftoza is enhanced in combination with the BCL-2 selective inhibitor venetoclax in AML cell lines. (A) AML cell lines were treated with eftoza and venetoclax in combination for 24 hours and cell viability was determined using CellTiter-Glo. Synergy was assessed using the Bliss independence model,32 in which Bliss sums represent the cumulative Bliss scores across the combination matrix. Data represent the mean ± SEM of n = ≥3 independent experiments. Red bars depict cell lines expressing TP53wt; green bars depict cell lines harboring TP53mut. (B-C) Live-cell quantification of caspase-3/7 activation in OCI-AML2 cell line over a time period was measured by adding caspase-3/7 green dye at the beginning of treatment and monitoring the cells every hour using IncuCyte ZOOM. (B) Time- and dose-dependent change in caspase-3/7–positive cells as a percentage of total cells per well. Data represent mean ± SEM; n = 3. (C) Caspase-3/7 activity as measured using the area under the concentration-time curve (AUC) from panel B. (D) Dose-response curves of OCI-AML5 parental and (E) BAK1–/–/BAX–/– OCI-AML5 cells, treated alone or in combination with eftoza and venetoclax for 24 hours. Viability was determined using CellTiter-Glo (mean ± SEM; n = 3). (F) Tumor volume change in mice bearing MV-4-11 tumor cells treated with eftoza (3 mg/kg, q2d × 3, IP), venetoclax (50 mg/kg, qd × 6, po), or eftoza and venetoclax in combination. Data represent the mean ± SEM of 8 mice per treatment group. (G) Tumor volume change in mice bearing OCI-AML2 tumor cells treated with eftoza (3 mg/kg, q7d × 2, IP), venetoclax (25 mg/kg, qd × 14, po), or eftoza and venetoclax in combination. Data represent the mean ± SEM of 8 mice per treatment group. (H-J) The plasma membrane expression of DR4, DR5, total DRs (DR4 + DR5), and total BCL-2 expression were measured using flow cytometry in the panel of AML cell lines, and the Spearman rank correlation with the Bliss sums from panel A was determined. IP, intraperitoneally; po, by mouth; qd, daily; q2d; every other day; q7d, every 7 days.

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