title: Low-dose 1,25-dihydroxyvitamin D(3) combined with arsenic trioxide synergistically inhibits proliferation of acute myeloid leukemia cells by promoting apoptosis.
abstract: Arsenic trioxide (As(2)O(3)) 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 D(3) (1,25(OH)(2)D(3)) in combination with As(2)O(3) on the human AML cell lines HL-60 and K562. The cell viability was in reverse proportion to As(2)O(3) or 1,25(OH)(2)D(3) concentration. In both HL-60 and K562 cells, after the combination treatment with As(2)O(3) and 1,25(OH)(2)D(3) 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 As(2)O(3), 8.1% in cells treated with 100 nM 1,25(OH)(2)D(3), and 64.3% in cells treated with 1.0 µM As(2)O(3) plus 100 nM 1,25(OH)(2)D(3). In conclusion, low-dose 1,25(OH)(2)D(3) combined with As(2)O(3) synergistically inhibited proliferation of HL-60 and K562 cells. In addition, this combination activated the apoptosis pathway more prominently than the single-drug treatment.
authors: Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.
authors: Ji-Yeon
authors: JY
authors: Bae
authors: Ji-Won
authors: JW
authors: Kim
authors: Inho
authors: I
authors: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D002117:Calcitriol / Q000494:pharmacology*; D053148:Caspase 3 / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+); D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D010087:Oxides / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001152:Arsenicals; D050071:Bone Density Conservation Agents; D010087:Oxides; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+); D053148:Caspase 3; D002117:Calcitriol; D000077237:Arsenic Trioxide