vitamin-d-2 and Leukemia--Myeloid

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.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Cell Differentiation; Cell Growth Processes; Cell Line, Tumor; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Screening Assays, Antitumor; Drug Synergism; Ergocalciferols; Gene Expression; HL-60 Cells; Humans; Leukemia, Myeloid; Mitochondria; Neoplasm Proteins; Oncogene Proteins, Fusion; Oxides; Steroid Hydroxylases; Vitamin D3 24-Hydroxylase

Topics: Carboxylesterase; Carboxylic Ester Hydrolases; Cell Differentiation; Cell Division; Dose-Response Relationship, Drug; Ergocalciferols; Humans; In Vitro Techniques; Leukemia, Myeloid; Superoxides; Tumor Cells, Cultured

Topics: Busulfan; Diagnosis, Differential; Ergocalciferols; Humans; Leukemia; Leukemia, Myeloid; Neoplasms; Pulmonary Fibrosis; Toxicology