10347199

pubmed:Citation

23

We examined the effects of two novel 1alpha,25-dihydroxyvitamin D3-26,23-lactone (1alpha,25-lactone) analogues on human promyelocytic leukemia cell (HL-60) differentiation using the evaluation system of the vitamin D nuclear receptor (VDR)/vitamin D-responsive element (DRE)-mediated genomic action stimulated by 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) and its analogues. We found that the 1alpha,25-lactone analogues (23S)-25-dehydro-1alpha-hydroxyvitamin-D3-26,23-lactone (TEI-9647), and (23R)-25-dehydro-1alpha-hydroxyvitamin-D3-26,23-lactone (TEI-9648) bound much more strongly to the VDR than the natural (23S, 25R)-1alpha,25(OH)2D3-26,23-lactone, but did not induce cell differentiation even at high concentrations (10(-6) M). Intriguingly, the differentiation of HL-60 cells induced by 1alpha,25(OH)2D3 was inhibited by either TEI-9647 or TEI-9648 but not by the natural lactone. In contrast, retinoic acid or 12-O-tetradecanoylphorbol-13-acetate-induced HL-60 cell differentiation was not blocked by TEI-9647 or TEI-9648. In separate studies, TEI-9647 (10(-7) M) was found to be an effective antagonist of both 1alpha,25(OH)2D3 (10(-8) M) mediated induction of p21(WAF1, CIP1) in HL-60 cells and activation of the luciferase reporter assay in COS-7 cells transfected with cDNA containing the DRE of the rat 25(OH)D3-24-hydroxylase gene and cDNA of the human VDR. Collectively the results strongly suggest that our novel 1alpha,25-lactone analogues, TEI-9647 and TEI-9648, are specific antagonists of 1alpha, 25(OH)2D3 action, specifically VDR/DRE-mediated genomic action. As such, they represent the first examples of antagonists, which act on the nuclear VDR.

http://linkedlifedata.com/resource/pubmed/journal/2985121R

http://linkedlifedata.com/resource/pubmed/chemical/1,25-dihydroxyvitamin..., http://linkedlifedata.com/resource/pubmed/chemical/CDKN1A protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Calcitriol, http://linkedlifedata.com/resource/pubmed/chemical/Cdkn1a protein, rat, http://linkedlifedata.com/resource/pubmed/chemical/Cholecalciferol, http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinase Inhibitor..., http://linkedlifedata.com/resource/pubmed/chemical/Cyclins, http://linkedlifedata.com/resource/pubmed/chemical/Cytochrome P-450 Enzyme System, http://linkedlifedata.com/resource/pubmed/chemical/Luciferases, http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Calcitriol, http://linkedlifedata.com/resource/pubmed/chemical/Steroid Hydroxylases, http://linkedlifedata.com/resource/pubmed/chemical/vitamin D 24-hydroxylase

Jun

pubmed-author:GajTT, pubmed-author:IshizukaSS, pubmed-author:ManabeKK, pubmed-author:MiuraDD, pubmed-author:NormanA WAW, pubmed-author:OzonoKK, pubmed-author:SaitoMM

4

NLM

16392-9

pubmed-meshheading:10347199-Animals, pubmed-meshheading:10347199-COS Cells, pubmed-meshheading:10347199-Calcitriol, pubmed-meshheading:10347199-Cell Differentiation, pubmed-meshheading:10347199-Cell Nucleus, pubmed-meshheading:10347199-Cholecalciferol, pubmed-meshheading:10347199-Cyclin-Dependent Kinase Inhibitor p21, pubmed-meshheading:10347199-Cyclins, pubmed-meshheading:10347199-Cytochrome P-450 Enzyme System, pubmed-meshheading:10347199-Genes, Reporter, pubmed-meshheading:10347199-HL-60 Cells, pubmed-meshheading:10347199-Humans, pubmed-meshheading:10347199-Luciferases, pubmed-meshheading:10347199-Models, Chemical, pubmed-meshheading:10347199-Rats, pubmed-meshheading:10347199-Receptors, Calcitriol, pubmed-meshheading:10347199-Steroid Hydroxylases, pubmed-meshheading:10347199-Transfection

Antagonistic action of novel 1alpha,25-dihydroxyvitamin D3-26, 23-lactone analogs on differentiation of human leukemia cells (HL-60) induced by 1alpha,25-dihydroxyvitamin D3.

Journal Article