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19-Nor-1,25(OH)₂D₂ (a Novel, Noncalcemic Vitamin D Analogue), Combined with Arsenic Trioxide, Has Potent Antitumor Activity against Myeloid Leukemia

¹ Division of Hematology/Oncology, University of California at Los Angeles School of Medicine, Cedars-Sinai Medical Center, Los Angeles, California; ² Department of Internal Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan; ³ Chang Gung University, Taoyuan, Taiwan; ⁴ Department of Medical Sciences, University of Birmingham, Birmingham, United Kingdom; and ⁵ Department of Hematology, Ohme Municipal General Hospital, Tokyo, Japan

Requests for reprints: Takashi Kumagai, Division of Hematology/Oncology, University of California at Los Angeles School of Medicine, Cedars-Sinai Medical Center, Davis Building 5068, 8700 Beverly Boulevard, Los Angeles, CA 90048. Phone: 310-423-7736; Fax: 310-423-0225; E-mail: kumamed1_2001{at}yahoo.co.jp.

Recently, we reported that a novel, noncalcemic vitamin D analogue (19-nor-1,25(OH)₂D₂; paricalcitol) had anticancer activity. In this study, we explored if paricalcitol enhanced anticancer effects of other clinically useful drugs in vitro against a large variety of cancer cells. Paricalcitol, when combined with As₂O₃, showed a markedly enhanced antiproliferative effect against acute myeloid leukemia (AML) cells. This combination induced monocytic differentiation of NB-4 acute promyelocytic leukemia (APL) cells and HL-60 AML cells and caused both to undergo apoptosis associated with down-regulation of Bcl-2 and Bcl-x_L. Paricalcitol induced monocytic differentiation of U937 AML cells, which was partially blocked by inducing expression of APL-related PML-retinoic acid receptor (RAR) chimeric protein in the U937 cells containing a Zn²⁺-inducible expression vector coding for this fusion protein (PR9 cells). Exposure to As₂O₃ decreased levels of PML-RAR in PR9 cells, and the combination of paricalcitol and As₂O₃ enhanced their monocytic differentiation in parallel with the As₂O₃-mediated decrease of PML-RAR. Furthermore, As₂O₃ increased the transcriptional activity of paricalcitol probably by increasing intracellular levels of paricalcitol by decreasing the function of the mitochondrial enzyme 25-hydroxyvitamin D₃-24-hydroxylase, which functions to metabolize the active vitamin D in cells. In summary, the combination of paricalcitol and As₂O₃ potently decreased growth and induced differentiation and apoptosis of AML cells. This probably occurred by As₂O₃ decreasing levels of both the repressive PML-RAR fusion protein and the vitamin D metabolizing protein, 25-hydroxyvitamin D₃-24-hydroxylase, resulting in increased activity of paricalcitol. The combination of both of these Food and Drug Administration–approved drugs should be considered for treatment of all-trans retinoic acid–resistant APL patients as well as those with other types of AML.

Key Words: paricalcitol • arsenic trioxide • PML-RAR • 24-hydroxylase (CYP-24) • MAPK