Antileukemic effect of a synthetic vitamin D3 analog, HY-11, with low potential to cause hypercalcemia

  • Authors:
    • Jin Sun Yoon
    • Ju Young Kim
    • Hyun Ki Park
    • Eun Shil Kim
    • Kwang Sung Ahn
    • Sung Soo Yoon
    • Cheon Gyu Cho
    • Byoung Kook Kim
    • Young Yiul Lee
  • View Affiliations

  • Published online on: February 1, 2008     https://doi.org/10.3892/ijo.32.2.387
  • Pages: 387-396
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Abstract

1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] is capable of inhibiting the proliferation of acute myelogenous leukemia (AML). However, toxicity of hypercalcemia has limited the use of 1,25(OH)2D3 in clinical trials. We have evaluated 11 synthesized vitamin D3 analogs for their ability to inhibit clonal growth of HL-60 myeloid leukemic cells. Among the 11 vitamin D3 analogs, HY-11 (code name) showed the most potent antileukemic activity with 2.5x10−6 M of IC50, however, it did not affect the cellular growth of normal peripheral blood mononuclear cells until 10−6 M. Flow cytometric analysis indicated that HY-11 induced the G1 arrest in a dose-dependent manner, which was mediated via inactivation of CDK4 and CDK6 in association with up-regulation of CDKI (cyclin-dependent kinase inhibitor), p27 and Rb protein. Induction of apoptosis was mediated via caspase-3 pathway in HY-11-treated HL-60. In addition, HY-11 enhanced the expression of TGF-β1, TGF-β receptor type I and II and vitamin D3 receptor (VDR). VDR expression was increased by TGF-β1, suggesting that TGF-β1 might be involved in the antiproliferative effect of HY-11 on HL-60 cells by autocrine and paracrine regulation. Serum calcium levels were within normal limit when HY-11 was given intraperitoneally (i.p.) every other day for 5 weeks to BALB/c mice at the doses of 10−7, 10−6and 10−5 M. HY-11 inhibited the growth of WEHI-3BD+ mouse leukemic cells in vitro, and syngeneic BALB/c mice that received WEHI-3BD+ mouse leukemic cells and HY-11 had a significantly longer survival without producing hypercalcemia compared to control group. In summary, HY-11 is a vitamin D3 analog that inhibited the proliferation of human AML cell line, HL-60, through induction of cell cycle arrest, triggering apoptosis as well as modulation of TGF-β1 and its receptors. In particular, HY-11 significantly increased the survival of mice that had myeloid leukemia without producing hypercalcemia.

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February 2008
Volume 32 Issue 2

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Yoon JS, Kim JY, Park HK, Kim ES, Ahn KS, Yoon SS, Cho CG, Kim BK and Lee YY: Antileukemic effect of a synthetic vitamin D3 analog, HY-11, with low potential to cause hypercalcemia. Int J Oncol 32: 387-396, 2008.
APA
Yoon, J.S., Kim, J.Y., Park, H.K., Kim, E.S., Ahn, K.S., Yoon, S.S. ... Lee, Y.Y. (2008). Antileukemic effect of a synthetic vitamin D3 analog, HY-11, with low potential to cause hypercalcemia. International Journal of Oncology, 32, 387-396. https://doi.org/10.3892/ijo.32.2.387
MLA
Yoon, J. S., Kim, J. Y., Park, H. K., Kim, E. S., Ahn, K. S., Yoon, S. S., Cho, C. G., Kim, B. K., Lee, Y. Y."Antileukemic effect of a synthetic vitamin D3 analog, HY-11, with low potential to cause hypercalcemia". International Journal of Oncology 32.2 (2008): 387-396.
Chicago
Yoon, J. S., Kim, J. Y., Park, H. K., Kim, E. S., Ahn, K. S., Yoon, S. S., Cho, C. G., Kim, B. K., Lee, Y. Y."Antileukemic effect of a synthetic vitamin D3 analog, HY-11, with low potential to cause hypercalcemia". International Journal of Oncology 32, no. 2 (2008): 387-396. https://doi.org/10.3892/ijo.32.2.387