Arsenic trioxide-induced cell apoptosis and cell cycle arrest are potentiated by 1,25-dihydroxyvitamin D3 in human...

The interaction between 1,25-dihydroxyvitamin [1,25(OH)2D3] and vitamin D receptor (VDR) plays a critical role in regulating cell proliferation and programmed cell death. The present study aimed to investigate the effects of 1,25(OH)2D3 in combination with arsenic trioxide (As₂O₃) on the proliferation and cell cycle of a K562 leukemia cell line. K562 cells were treated with 100 nM 1,25(OH)2D3, 2.5 µM As₂O₃, and 100 nM 1,25(OH)2D3 combined with 2.5 µM As₂O₃. Cell proliferation was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt/phenazine ethosulfate method. Cell cycle progression and apoptosis were detected by flow cytometry. The expression levels of genes associated with the cell cycle and apoptosis were analyzed by reverse transcription-quantitative PCR and western blotting analyses. The present findings indicated that combined treatment of 1,25(OH)2D3 and As₂O₃ led to a significant increase in cytotoxicity, apoptotic cell death and G₁ cell cycle arrest when compared to those treated with 1,25(OH)2D3 or As₂O₃ alone. The downregulation of the Bax/Bcl-2 ratio and decreased survivin expression may be involved in combined treatment-mediated apoptosis. G₀/G₁ cell cycle arrest induced by combined treatment was associated with the activation of p21 and p27. In addition, the increased expression of VDR was found to participate in the anticancer effect of combination treatment. The data suggested that the combination of 1, 25-(OH)₂D₃ and As₂O₃ had clear synergistic effects on the inhibition of K562 cell proliferation, which could provide a novel therapeutic approach for the treatment of acute myeloid leukemia.