Figure 1.
Figure 1. Sequence-dependent ATRA/FK228 effects on cytotoxicity of DOX in NB4 cells. (A) Dose-dependent inhibition of cell growth by DOX, ATRA, and FK228 in NB4 cells. NB4 cells were cultured in the presence of different concentrations of DOX (8.5, 17.0, 34.0, and 68.0 nM), ATRA (0.125, 0.25, 0.5, and 1.0 μM), and FK228 (1.0, 2.0, 3.0, 4.0, and 8.0 nM) for 72 hours. The effects on cell growth were determined by viable cell counts using trypan blue exclusion method. Graphs show the mean ± SD of results of 3 independent experiments. Cont indicates control. (B) Inhibition of cell growth depends on the sequence of DOX and FK228/ATRA treatment of NB4 cells. ATRA (1.0 μM), FK228 (3.0 nM), or their combination were either given 24 hours prior to DOX (17.0 nM) treatment (i-iii) or 24 hours after initiation of DOX therapy (iv-vi). The timing of each agent exposure is shown by arrows. The effects on cell growth were determined by cell counts. Graphs show the mean ± SD of results of 3 independent experiments. (C) Sequence-dependent ATRA/FK228 effects on cytotoxicity of DOX in NB4 cells. The effects on cytotoxicity of ATRA (1.0 μM), FK228 (3.0 nM), or their combination were either given 24 hours prior to DOX (17.0 nM) treatment or 24 hours after initiation of DOX therapy and were defined as the percentage of annexin V–positive flow cytometry analysis (i) or trypan blue–positive cells detected by cell count (ii). (iii) ATRA (0.125, 0.25, and 0.5 μM) and FK228 (1.0, 2.0, and 4.0 nM) were given at a fixed ratio either 24 hours prior to DOX (8.5, 17.0, and 34.0 nM) treatment or 24 hours after initiation of DOX therapy. The pharmacologic interactions between 3 agents were analyzed by isobologram analysis using Calcusyn software (Table 1). Total time of DOX treatment was 72 hours in all experiments. The effects on cytotoxicity were defined as the percentage of annexin V–positive cells detected by flow cytometry analysis. Graphs show the mean ± SD of results from 3 independent experiments. Statistically significant differences were determined by ANOVA and Fisher post hoc tests (*P < .05).

Sequence-dependent ATRA/FK228 effects on cytotoxicity of DOX in NB4 cells. (A) Dose-dependent inhibition of cell growth by DOX, ATRA, and FK228 in NB4 cells. NB4 cells were cultured in the presence of different concentrations of DOX (8.5, 17.0, 34.0, and 68.0 nM), ATRA (0.125, 0.25, 0.5, and 1.0 μM), and FK228 (1.0, 2.0, 3.0, 4.0, and 8.0 nM) for 72 hours. The effects on cell growth were determined by viable cell counts using trypan blue exclusion method. Graphs show the mean ± SD of results of 3 independent experiments. Cont indicates control. (B) Inhibition of cell growth depends on the sequence of DOX and FK228/ATRA treatment of NB4 cells. ATRA (1.0 μM), FK228 (3.0 nM), or their combination were either given 24 hours prior to DOX (17.0 nM) treatment (i-iii) or 24 hours after initiation of DOX therapy (iv-vi). The timing of each agent exposure is shown by arrows. The effects on cell growth were determined by cell counts. Graphs show the mean ± SD of results of 3 independent experiments. (C) Sequence-dependent ATRA/FK228 effects on cytotoxicity of DOX in NB4 cells. The effects on cytotoxicity of ATRA (1.0 μM), FK228 (3.0 nM), or their combination were either given 24 hours prior to DOX (17.0 nM) treatment or 24 hours after initiation of DOX therapy and were defined as the percentage of annexin V–positive flow cytometry analysis (i) or trypan blue–positive cells detected by cell count (ii). (iii) ATRA (0.125, 0.25, and 0.5 μM) and FK228 (1.0, 2.0, and 4.0 nM) were given at a fixed ratio either 24 hours prior to DOX (8.5, 17.0, and 34.0 nM) treatment or 24 hours after initiation of DOX therapy. The pharmacologic interactions between 3 agents were analyzed by isobologram analysis using Calcusyn software (Table 1). Total time of DOX treatment was 72 hours in all experiments. The effects on cytotoxicity were defined as the percentage of annexin V–positive cells detected by flow cytometry analysis. Graphs show the mean ± SD of results from 3 independent experiments. Statistically significant differences were determined by ANOVA and Fisher post hoc tests (*P < .05).

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