FIGURE 5.

Combination of venetoclax and thioridazine in t(6;11)-rearranged acute myeloid leukemia (AML). (A) Cell viability of t (6; 11) SHI-1 and non-t (6; 11) HL-60 after treatment with thioridazine (TDZ) combined with venetoclax (Ven) at 48 h after treatment. The synergy scores were represented by pseudocoloring 2-dimensional contour plots over the dose matrix (red indicates synergy and green indicates antagonism) and calculated using the ZIP model (synergy when >10, n = 2). Stars indicate the concentrations selected for subsequent experiments. (B) Cell viability of t (6; 11) SHI-1 and non-t (6; 11) HL-60 after treatment with venetoclax, thioridazine, or the combination at 48 h after treatment (CI, combination index; synergy when CI <1. ANOVA test was performed by applying Bonferroni correction for multiple statistical hypotheses testing. **p < 0.01, ***p < 0.001; ****p < 0.0001; n = 2). (C) Mitochondrial depolarization evaluated by tetramethylrhodamine ethyl fluorescence measurement at 20 h after Ven (5 µM), TDZ (10 µM), or combination treatment compared with dimethyl sulfoxide in SHI-1 (n = 2). (D) Cell viability of PDX-derived ex vivo t (6; 11) and non-t (6; 11) AML after treatment with venetoclax (1 µM), thioridazine (10 µM) or the combination at 24 h after treatment. ANOVA test was performed by applying Bonferroni correction for multiple statistical hypotheses testing.*p < 0.05; **p < 0.01. (E) Colony-forming assay performed on viable ex vivo cells seeded at 24 h after the combination treatment [venetoclax (1 µM) + thioridazine (10 μM), n = 2].