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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

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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 Research Article 19-Nor-1,25(OH)2D2 (a Novel, Noncalcemic Vitamin D Analogue), Combined with Arsenic Trioxide, Has Potent Antitumor Activity against Myeloid Leukemia Takashi Kumagai,1,5 Lee-Yung Shih,2,3 Susan V. Hughes,4 Julian C. Desmond,1 James O’Kelly,1 Martin Hewison,4 and H. Phillip Koeffler1 1Division of Hematology/Oncology, University of California at Los Angeles School of Medicine, Cedars-Sinai Medical Center, Los Angeles, California; 2Department of Internal Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan; 3Chang Gung University, Taoyuan, Taiwan; 4Department of Medical Sciences, University of Birmingham, Birmingham, United Kingdom; and 5Department of Hematology, Ohme Municipal General Hospital, Tokyo, Japan Abstract Introduction Recently, we reported that a novel, noncalcemic vitamin D Cancer therapies are usually toxic for normal cells. Induction of analogue (19-nor-1,25(OH)2D2; paricalcitol) had anticancer differentiation is sometimes a useful, less toxic cancer therapy activity. In this study, we explored if paricalcitol enhanced that can supplement more aggressive approaches. For example, anticancer effects of other clinically useful drugs in vitro the use of all-trans retinoic acid for the treatment of acute against a large variety of cancer cells. Paricalcitol, when promyelocytic leukemia (APL) often induces complete remissions combined with As2O3, showed a markedly enhanced anti- as well as its use in the treatment of head and neck cancers and proliferative effect against acute myeloid leukemia (AML) neuroblastomas (1–3). cells. This combination induced monocytic differentiation of 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] is a member of the NB-4 acute promyelocytic leukemia (APL) cells and HL-60 seco-steroid hormone family, which controls calcium homeostasis AML cells and caused both to undergo apoptosis associated and bone metabolism. It can inhibit the growth of various types of with down-regulation of Bcl-2 and Bcl-xL. Paricalcitol induced malignant cells, including breast, prostate, colon, skin, and brain monocytic differentiation of U937 AML cells, which was cancers as well as myeloid leukemia, by inducing differentiation, partially blocked by inducing expression of APL-related apoptosis, and cell cycle arrest. In a clinical study, orally A A PML-retinoic acid receptor (RAR ) chimeric protein in administrated 1,25(OH)2D3 showed some activity for preleukemic 2+ the U937 cells containing a Zn -inducible expression vector patients (4). Because of the calcemic side effect of 1,25(OH)2D3, the coding for this fusion protein (PR9 cells). Exposure to As2O3 dosage that could be safely given to these individuals was less than decreased levels of PML-RARA in PR9 cells, and the theoretically required for an anticancer effect as noted in vitro (5, 6). combination of paricalcitol and As2O3 enhanced their mono- Therefore, novel, potent, but less calcemic analogues of vitamin D cytic differentiation in parallel with the As2O3-mediated are being synthesized and tested (7–15). decrease of PML-RARA. Furthermore, As2O3 increased the 19-Nor-1,25(OH)2D2 (paricalcitol) is a synthetic analogue of transcriptional activity of paricalcitol probably by increasing 1,25(OH)2D2 that is currently approved by the Food and Drug intracellular levels of paricalcitol by decreasing the function of Administration for the clinical treatment of secondary hyperpara- the mitochondrial enzyme 25-hydroxyvitamin D3-24-hydroxy- thyroidism. This compound has very little calcemic potential as lase, which functions to metabolize the active vitamin D in shown by several randomized clinical trials (16, 17). Antiprolifer- cells. In summary, the combination of paricalcitol and As2O3 ative effects of paricalcitol were reported recently against human potently decreased growth and induced differentiation and prostate, leukemia, myeloma, and colon cancer cells in vitro and apoptosis of AML cells. This probably occurred by As2O3 in vivo (18–20). These studies suggest that clinical trails of this decreasing levels of both the repressive PML-RARA fusion analogue are reasonable; to this end, we are examining its effects in protein and the vitamin D metabolizing protein, 25- individuals with myelodysplastic syndrome. hydroxyvitamin D3-24-hydroxylase, resulting in increased In this study, we investigated the combinations of paricalcitol and activity of paricalcitol. The combination of both of these Food either chemotherapeutic or related agents against human myeloid and Drug Administration–approved drugs should be consid- leukemia, myeloma, prostate, breast, and colon cancer in vitro.We ered for treatment of all-trans retinoic acid–resistant APL found that the combination of paricalcitol and As2O3 had a strong patients as well as those with other types of AML. (Cancer Res antiproliferative effect against myeloid leukemia in vitro, and we 2005; 65(6): 2488-97) studied the mechanism of action of this combination. Materials and Methods Cells and Samples. Cell lines were obtained from American Type Culture Collection (Rockville, MD) and maintained according to their recommendations. Myeloid leukemia cell lines (HL-60, NB-4, and U937), Note: H.P. Koeffler is Mark Goodson Endowed Chair in Oncology Research and is a member of the Jonsson Cancer Center and Molecular Biology Institute, University of myeloma cell lines (RPMI-8226, ARH-77, and NCI-H929), lung cancer cell California at Los Angeles. lines (NCI-H125 and NCI-H520), and prostate cancer cell lines (LNCaP and Requests for reprints: Takashi Kumagai, Division of Hematology/Oncology, PC-3) were grown in RPMI 1640 with 10% FCS. Breast cancer cell lines University of California at Los Angeles School of Medicine, Cedars-Sinai Medical (MCF-7 and MDA-MB-231), colon cancer cell lines (HT-29 and SW837), a Center, Davis Building 5068, 8700 Beverly Boulevard, Los Angeles, CA 90048. Phone: 310-423-7736; Fax: 310-423-0225; E-mail: [email protected]. prostate cancer cell line (DU145), and endometrial cancer cell lines #2005 American Association for Cancer Research. (Ishikawa, HEC59, and HEC1B) were maintained in DMEM with 10% FCS. Cancer Res 2005; 65: (6). March 15, 2005 2488 www.aacrjournals.org Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2005 American Association for Cancer Research. Paricalcitol and As2O3 Against Myeloid Leukemia The U937 cell line (PR9) that stably expressed PML-retinoic acid receptor a temperature, because SYBR Green intercalates nonspecifically into PCR (RARa)inaZn2+-inducible fashion was described previously (21) and was products. Melting curve analysis included 95jC for 5 seconds, 65jC for kindly provided by Dr. Pelicci (Perugia University, Perugia, Italy). For 15 seconds, and heating to 95jC at a rate of 0.1jC/2 seconds with induction of PML-RARa in PR9 cells, 0.1 mmol/L ZnSO4 was added to the continuous reading of fluorescence. The signal in this study was generated culture medium. Viable cell numbers were counted using trypan blue by the binding of the fluorophore SYBR Green (Biozym, Hess. Oldendorf, solution (Sigma-Aldrich, St. Louis, MO). The paricalcitol was generously Germany) to dsDNA. Baseline and threshold calculations were done with provided by Scott Toner (Abbott Laboratories, Chicago, IL). PD98059 was the iCycler software. The chemical composition of the PCR assays was obtained from LC Laboratories (Woburn, MA). Other compounds were according to the descriptions of the Taq polymerases. The amplification obtained from Sigma-Aldrich. followed a three-step PCR with denaturation at 94jC for 20 seconds, 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide annealing at 60jC for 10 seconds, elongation at 65jC for 25 seconds, and Assays. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide 20 seconds at melting temperature. PCR products were separated on a 2% (MTS, 5 mg/mL, Sigma-Aldrich) was used to measure cellular proliferation. agarose gel, stained with ethidium bromide, and photographed. Briefly, 103 cells were incubated in culture medium containing test Determination of Mitochondrial Membrane Potential. Mitochondrial compounds for 96 hours followed the MTS assay as described before (19). membrane potential was analyzed with a lipophilic cationic dye 5,5V,6,6V- Soft Agar Colony Assay. Trypsinized and washed single-cell suspen- tetrachloro-1,1V,3,3V-tetraethylbenzimidazol carbocyanine iodide (JC-1, Sig- sions were enumerated and plated into 24-well flat-bottomed plates using a ma-Aldrich) using a method described previously (22). JC-1 selectively two-layer soft agar system with a total of 1 Â 103 cells per well in a volume incorporates into mitochondria. Intact mitochondrial membranes display of 400 AL/well as described previously (11). a negative charge, which attracts positively charged JC-1 molecules. JC-1 Cell Cycle Analysis. After treatment of 5 Â 104 of cells with experimental aggregates form as a result of accumulation in the mitochondria. The compounds, cell cycle analysis was done as described previously (19). monomeric form emits green fluorescence at 527 nm, whereas Western Blot Analysis. Western blot was done as noted previously (19). aggregated JC-1 molecules emit red fluorescence at 590 nm. Therefore, Briefly, cells were washed and suspended in lysis buffer. After centrifugation, red fluorescence emission, assayed by fluorescence-activated cell sorting, the suspension was collected. Protein (40 Ag) was used for SDS-PAGE, is interpreted as a function of mitochondrial membrane potential. Cells transferred to a polyvinylidene difluoride
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