Low-dose 1,25-dihydroxyvitamin D3 combined with arsenic trioxide synergistically inhibits proliferation of acute myeloid leukemia cells by promoting apoptosis

Abstract

Arsenic trioxide (As2O3) has shown substantial efficacy in the treatment of patients with acute promyelocytic leukemia, a specific subtype of acute myeloid leukemia (AML). However, since not all patients can achieve remission after treatment, it is necessary to develop a novel method to overcome this problem. We investigated the anti-leukemic effect of low-dose 1,25-dihydroxyvitamin D3 (1,25(OH)2D 3) in combination with As2O3 on the human AML cell lines HL-60 and K562. The cell viability was in reverse proportion to As2O3 or 1,25(OH)2D3 concentration. In both HL-60 and K562 cells, after the combination treatment with As 2O3 and 1,25(OH)2D3 at a 10:1 ratio, the combination index (CI) values were <1 in all treatment groups. In the RT-PCR and western blot analysis, the combination treatment decreased Bcl-2 expression and increased Bax and caspase-3 expression more prominently than the single treatment. In the flow cytometric analysis performed in HL-60 cells, the proportion of late apoptotic cells was 4.9% in the control, 30.0% in cells treated with 1.0 μM As2O3, 8.1% in cells treated with 100 nM 1,25(OH)2D3, and 64.3% in cells treated with 1.0 μM As2O3 plus 100 nM 1,25(OH)2D3. In conclusion, low-dose 1,25(OH)2D3 combined with As 2O3 synergistically inhibited proliferation of HL-60 and K562 cells. In addition, this combination activated the apoptosis pathway more prominently than the single-drug treatment.