19-Nor-1,25(Oh)(2)D-2 (A Novel, Noncalcemic Vitamin D Analogue), Combined With Arsenic Trioxide, Has Potent Antitumor Activity Against Myeloid Leukemia

Recently, we reported that a novel, noncalcemic vitamin D analogue (19-nor-1,25(OH)(2)D-2; 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 anti-proliferative 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 (RAR alpha) 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 alpha in PR9 cells, and the combination of paricalcitol and As2O3 enhanced their monocytic differentiation in parallel with the As2O3-mediated decrease of PML-RAR alpha. 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 D-3-24-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 alpha fusion protein and the vitamin D metabolizing protein, 25-hydroxyvitamin D-3-24-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.