title: 19-Nor-1,25(OH)2D2 (a novel, noncalcemic vitamin D analogue), combined with arsenic trioxide, has potent antitumor activity against myeloid leukemia.
abstract: 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 alpha (RARalpha) 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-RARalpha in PR9 cells, and the combination of paricalcitol and As2O3 enhanced their monocytic differentiation in parallel with the As2O3-mediated decrease of PML-RARalpha. 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-RARalpha 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.
authors.affiliation: Division of Hematology/Oncology, University of California at Los Angeles School of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. kumamed1_2001@yahoo.co.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Kumagai
authors.forename: Lee-Yung
authors.initials: LY
authors.lastname: Shih
authors.forename: Susan V
authors.initials: SV
authors.lastname: Hughes
authors.forename: Julian C
authors.initials: JC
authors.lastname: Desmond
authors.forename: James
authors.initials: J
authors.lastname: O'Kelly
authors.forename: Martin
authors.initials: M
authors.lastname: Hewison
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D000208:Acute Disease; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage; D002454:Cell Differentiation / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004872:Ergocalciferols / Q000008:administration & dosage; D015870:Gene Expression / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors; D010087:Oxides / Q000008:administration & dosage; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D001152:Arsenicals; D065607:Cytochrome P-450 Enzyme Inhibitors; D004872:Ergocalciferols; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D010087:Oxides; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C084656:paricalcitol; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D000077237:Arsenic Trioxide