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

Bae,Ji-Yeon; Kim,Ji-Won; Kim,Inho

doi:10.3892/or.2013.2444

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

Authors:
- Ji-Yeon Bae
- Ji-Won Kim
- Inho Kim
View Affiliations

Affiliations: Cancer Research Institute, Seoul National University, Seoul, Republic of Korea, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
Published online on: May 9, 2013 https://doi.org/10.3892/or.2013.2444
Pages: 485-491

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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)2D3) 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 As2O3 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 As2O3 synergistically inhibited proliferation of HL-60 and K562 cells. In addition, this combination activated the apoptosis pathway more prominently than the single‑drug treatment.

View Figures

View References

1	Sanz MA and Lo-Coco F: Modern approaches to treating acute promyelocytic leukemia. J Clin Oncol. 29:495–503. 2011. View Article : Google Scholar : PubMed/NCBI
2	Miller WH Jr, Schipper HM, Lee JS, Singer J and Waxman S: Mechanisms of action of arsenic trioxide. Cancer Res. 62:3893–3903. 2002.PubMed/NCBI
3	Shen ZX, Chen GQ, Ni JH, et al: Use of arsenic trioxide (As₂O₃) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood. 89:3354–3360. 1997.PubMed/NCBI
4	Niu C, Yan H, Yu T, et al: Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood. 94:3315–3324. 1999.
5	Soignet SL, Maslak P, Wang ZG, et al: Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med. 339:1341–1348. 1998. View Article : Google Scholar : PubMed/NCBI
6	Nagpal S, Na S and Rathnachalam R: Noncalcemic actions of vitamin D receptor ligands. Endocr Rev. 26:662–687. 2005. View Article : Google Scholar : PubMed/NCBI
7	Deeb KK, Trump DL and Johnson CS: Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat Rev Cancer. 7:684–700. 2007. View Article : Google Scholar : PubMed/NCBI
8	Krishnan AV, Moreno J, Nonn L, et al: Novel pathways that contribute to the anti-proliferative and chemopreventive activities of calcitriol in prostate cancer. J Steroid Biochem Mol Biol. 103:694–702. 2007. View Article : Google Scholar : PubMed/NCBI
9	Abe E, Miyaura C, Sakagami H, et al: Differentiation of mouse myeloid leukemia cells induced by 1 alpha,25-dihydroxyvitamin D₃. Proc Natl Acad Sci USA. 78:4990–4994. 1981. View Article : Google Scholar : PubMed/NCBI
10	Zhou JY, Norman AW, Chen DL, Sun GW, Uskokovic M and Koeffler HP: 1,25-Dihydroxy-16-ene-23-yne-vitamin D₃ prolongs survival time of leukemic mice. Proc Natl Acad Sci USA. 87:3929–3932. 1990. View Article : Google Scholar : PubMed/NCBI
11	McCarthy DM, San Miguel JF, Freake HC, et al: 1,25-dihydroxyvitamin D₃ inhibits proliferation of human promyelocytic leukaemia (HL60) cells and induces monocyte-macrophage differentiation in HL60 and normal human bone marrow cells. Leuk Res. 7:51–55. 1983.
12	Studzinski GP, Bhandal AK and Brelvi ZS: Cell cycle sensitivity of HL-60 cells to the differentiation-inducing effects of 1-alpha,25-dihydroxyvitamin D₃. Cancer Res. 45:3898–3905. 1985.PubMed/NCBI
13	Muto A, Kizaki M, Yamato K, et al: 1,25-Dihydroxyvitamin D₃ induces differentiation of a retinoic acid-resistant acute promyelocytic leukemia cell line (UF-1) associated with expression of p21(WAF1/CIP1) and p27(KIP1). Blood. 93:2225–2233. 1999.PubMed/NCBI
14	Koeffler HP, Hirji K and Itri L: 1,25-Dihydroxyvitamin D₃: in vivo and in vitro effects on human preleukemic and leukemic cells. Cancer Treat Rep. 69:1399–1407. 1985.
15	Chou TC and Talalay P: Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 22:27–55. 1984. View Article : Google Scholar : PubMed/NCBI
16	Chen GQ, Zhu J, Shi XG, et al: In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As₂O₃) in the treatment of acute promyelocytic leukemia: As₂O₃ induces NB4 cell apoptosis with downregulation of Bcl-2 expression and modulation of PML-RAR alpha/PML proteins. Blood. 88:1052–1061. 1996.PubMed/NCBI
17	Jing Y, Dai J, Chalmers-Redman RM, Tatton WG and Waxman S: Arsenic trioxide selectively induces acute promyelocytic leukemia cell apoptosis via a hydrogen peroxide-dependent pathway. Blood. 94:2102–2111. 1999.PubMed/NCBI
18	Yedjou C, Tchounwou P, Jenkins J and McMurray R: Basic mechanisms of arsenic trioxide (ATO)-induced apoptosis in human leukemia (HL-60) cells. J Hematol Oncol. 3:282010. View Article : Google Scholar : PubMed/NCBI
19	Vandewalle B, Wattez N and Lefebvre J: Effects of vitamin D₃ derivatives on growth, differentiation and apoptosis in tumoral colonic HT 29 cells: possible implication of intracellular calcium. Cancer Lett. 97:99–106. 1995.
20	Mathiasen IS, Sergeev IN, Bastholm L, Elling F, Norman AW and Jäättelä M: Calcium and calpain as key mediators of apoptosis-like death induced by vitamin D compounds in breast cancer cells. J Biol Chem. 277:30738–30745. 2002. View Article : Google Scholar : PubMed/NCBI
21	Guzey M, Kitada S and Reed JC: Apoptosis induction by 1alpha,25-dihydroxyvitamin D₃ in prostate cancer. Mol Cancer Ther. 1:667–677. 2002.PubMed/NCBI
22	Sergeev IN: Calcium as a mediator of 1,25-dihydroxyvitamin D₃-induced apoptosis. J Steroid Biochem Mol Biol. 89–90:419–425. 2004.PubMed/NCBI
23	Sergeev IN: 1,25-Dihydroxyvitamin D₃ induces Ca²⁺-mediated apoptosis in adipocytes via activation of calpain and caspase-12. Biochem Biophys Res Commun. 384:18–21. 2009.
24	Richard C, Mazo E, Cuadrado MA, et al: Treatment of myelodysplastic syndrome with 1.25-dihydroxy-vitamin D₃. Am J Hematol. 23:175–178. 1986. View Article : Google Scholar
25	Scholz C, Wieder T, Stärck L, et al: Arsenic trioxide triggers a regulated form of caspase-independent necrotic cell death via the mitochondrial death pathway. Oncogene. 24:1904–1913. 2005. View Article : Google Scholar : PubMed/NCBI
26	Florea AM, Splettstoesser F and Busselberg D: Arsenic trioxide (As₂O₃) induced calcium signals and cytotoxicity in two human cell lines: SY-5Y neuroblastoma and 293 embryonic kidney (HEK). Toxicol Appl Pharmacol. 220:292–301. 2007.
27	Günes DA, Florea AM, Splettstoesser F and Büsselberg D: Co-application of arsenic trioxide (As₂O₃) and cisplatin (CDDP) on human SY-5Y neuroblastoma cells has differential effects on the intracellular calcium concentration ([Ca²⁺]i) and cytotoxicity. Neurotoxicology. 30:194–202. 2009.
28	Cai BZ, Meng FY, Zhu SL, et al: Arsenic trioxide induces the apoptosis in bone marrow mesenchymal stem cells by intracellular calcium signal and caspase-3 pathways. Toxicol Lett. 193:173–178. 2010. View Article : Google Scholar : PubMed/NCBI