Publication
20-Hydroxyvitamin D2is a noncalcemic analog of vitamin D with potent antiproliferative and prodifferentiation activities in normal and malignant cells
Publisher:
American Physiological Society
Date:
03-2011
DOI:
10.1152/AJPCELL.00203.2010
Abstract: 20-hydroxyvitamin D 2 [20(OH)D 2 ] inhibits DNA synthesis in epidermal keratinocytes, melanocytes, and melanoma cells in a dose- and time-dependent manner. This inhibition is dependent on cell type, with keratinocytes and melanoma cells being more sensitive than normal melanocytes. The antiproliferative activity of 20(OH)D 2 is similar to that of 1,25(OH) 2 D 3 and of newly synthesized 1,20(OH) 2 D 2 but significantly higher than that of 25(OH)D 3 . 20(OH)D 2 also displays tumorostatic effects. In keratinocytes 20(OH)D 2 inhibits expression of cyclins and stimulates involucrin expression. It also stimulates CYP24 expression, however, to a significantly lower degree than that by 1,25(OH) 2 D 3 or 25(OH)D 3 . 20(OH)D 2 is a poor substrate for CYP27B1 with overall catalytic efficiency being 24- and 41-fold lower than for 25(OH)D 3 with the mouse and human enzymes, respectively. No conversion of 20(OH)D 2 to 1,20(OH) 2 D 2 was detected in intact HaCaT keratinocytes. 20(OH)D 2 also demonstrates anti-leukemic activity but with lower potency than 1,25(OH) 2 D 3 . The phenotypic effects of 20(OH)D 2 are mediated through interaction with the vitamin D receptor (VDR) as documented by attenuation of cell proliferation after silencing of VDR, by enhancement of the inhibitory effect through stable overexpression of VDR and by the demonstration that 20(OH)D 2 induces time-dependent translocation of VDR from the cytoplasm to the nucleus at a comparable rate to that for 1,25(OH) 2 D 3 . In vivo tests show that while 1,25(OH) 2 D 3 at doses as low as 0.8 μg/kg induces calcium deposits in the kidney and heart, 20(OH)D 2 is devoid of such activity even at doses as high as 4 μg/kg. Silencing of CY27B1 in human keratinocytes showed that 20(OH)D 2 does not require its transformation to 1,20(OH) 2 D 2 for its biological activity. Thus 20(OH)D 2 shows cell-type dependent antiproliferative and prodifferentiation activities through activation of VDR, while having no detectable toxic calcemic activity, and is a poor substrate for CYP27B1.