Figure 7.
The ESRRB agonist GSK4716 synergizes with dexamethasone to induce human leukemic cell death. (A) Dexamethasone and DY131 dual treatment increase GC-induced apoptosis in human ALL cells in vitro. Human ALL cell lines were treated with vehicle (DMSO), dexamethasone (1 μM), DY131 (10 μM), or dexamethasone+DY131 for 72 hours, and apoptosis was assayed by annexin V-FITC/7-AAD staining followed by flow cytometry. Dexamethasone and DY131 dual treatment increase dexamethasone-induced gene expression in the human T-ALL cell line KOPTK1 in vitro. (B) Cells were treated with vehicle, dexamethasone (1 μM), DY131 (10 μM), or dexamethasone+DY131 for 24 hours, and NR3C1, BCL2L11, and TSC23D3 expression was analyzed by qRT-PCR. The copy number was normalized to β-actin by the ΔΔCT method. T-ALL patient samples are sensitive to dexamethasone and DY131 dual treatment. (C) Cells were treated with vehicle or dexamethasone (50 nM) and/or DY131 (50 μM), and cell viability was assayed by CellTiterGlo. Treatment with dexamethasone and GSK4716 increased GC-induced apoptosis in human ALL cells in vitro. (D) Human ALL cell lines were treated with vehicle (DMSO), dexamethasone (1 μM), GSK4716 (10 μM), or dexamethasone+GSK4716 for 72 hours, and apoptosis was assayed by annexin V-FITC/7-AAD staining followed by flow cytometry. The ESRRB agonists GSK4716 and DY131 require ESRRB to induce leukemic cell death. (E) NS or ESRRB-deficient mouse T-ALL cells were treated with DY131 or GSK4716 (10 μM) for 48 hours, and apoptosis was assayed by annexin V-FITC/7-AAD staining followed by flow cytometry. GSK4716 synergized with dexamethasone to induce human leukemic cell death. The human T-ALL cell lines KOPTK1 and DND-41 were treated with increasing doses of GSK4716 and dexamethasone, and cell viability was determined by CellTiterGlo. (F) The CI was calculated by using the formula a/A + b/B. Synergisms, additive effect, and antagonism of combined treatment assays were defined as CI < 1, CI = 1, and CI > 1, respectively. The results are averages of 3 independent experiments; error bars represent SEM. *P < .05; **P < .01; ***P < .001.

The ESRRB agonist GSK4716 synergizes with dexamethasone to induce human leukemic cell death. (A) Dexamethasone and DY131 dual treatment increase GC-induced apoptosis in human ALL cells in vitro. Human ALL cell lines were treated with vehicle (DMSO), dexamethasone (1 μM), DY131 (10 μM), or dexamethasone+DY131 for 72 hours, and apoptosis was assayed by annexin V-FITC/7-AAD staining followed by flow cytometry. Dexamethasone and DY131 dual treatment increase dexamethasone-induced gene expression in the human T-ALL cell line KOPTK1 in vitro. (B) Cells were treated with vehicle, dexamethasone (1 μM), DY131 (10 μM), or dexamethasone+DY131 for 24 hours, and NR3C1, BCL2L11, and TSC23D3 expression was analyzed by qRT-PCR. The copy number was normalized to β-actin by the ΔΔCT method. T-ALL patient samples are sensitive to dexamethasone and DY131 dual treatment. (C) Cells were treated with vehicle or dexamethasone (50 nM) and/or DY131 (50 μM), and cell viability was assayed by CellTiterGlo. Treatment with dexamethasone and GSK4716 increased GC-induced apoptosis in human ALL cells in vitro. (D) Human ALL cell lines were treated with vehicle (DMSO), dexamethasone (1 μM), GSK4716 (10 μM), or dexamethasone+GSK4716 for 72 hours, and apoptosis was assayed by annexin V-FITC/7-AAD staining followed by flow cytometry. The ESRRB agonists GSK4716 and DY131 require ESRRB to induce leukemic cell death. (E) NS or ESRRB-deficient mouse T-ALL cells were treated with DY131 or GSK4716 (10 μM) for 48 hours, and apoptosis was assayed by annexin V-FITC/7-AAD staining followed by flow cytometry. GSK4716 synergized with dexamethasone to induce human leukemic cell death. The human T-ALL cell lines KOPTK1 and DND-41 were treated with increasing doses of GSK4716 and dexamethasone, and cell viability was determined by CellTiterGlo. (F) The CI was calculated by using the formula a/A + b/B. Synergisms, additive effect, and antagonism of combined treatment assays were defined as CI < 1, CI = 1, and CI > 1, respectively. The results are averages of 3 independent experiments; error bars represent SEM. *P < .05; **P < .01; ***P < .001.

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