title: Studies on the mechanisms of superagonistic pro-differentiating activities             of side-chain modified analogs of vitamin D2.
abstract: 1,25-Dihydroxyvitamin D3 (1,25D) is implicated in many cellular functions             including cell proliferation and differentiation, thus, exerting potential antitumor             effects. A major limitation for therapeutic use of 1,25D are its potent calcemic             and phosphatemic activities. Therefore, synthetic analogs of 1,25D for use in             anticancer therapy should retain cell differentiating potential, with calcemic             activity being reduced. Previously, we described pro-differentiating effects of             vitamin D2 analogs with extended and branched side-chains. Analogs with side-chains             extended by a pair of one (PRI-1906) or two carbon units (PRI-1907) displayed             elevated cell-differentiating activity towards some acute leukemia cell lines             (AML) in comparison to 1,25D. In this study, the potential mechanism of this superagonistic             activity of the analogs was addressed. At first, possible differences in the expression             of CYP24A1, a major catabolizing enzyme for vitamin D compounds and resulting             differences in the degradation of analogs were investigated. In addition, interactions             of the analogs with vitamin D receptor (VDR) and resulting activation of CCAAT-enhancer-binding             protein β (C/EBPβ) were studied. The results obtained show that superagonistic             pro-differentiating activities of analogs PRI-1906 and PRI-1907 do not seem to             be caused by their altered catabolism, but most probably by altered interactions             with VDR and resulting downstream proteins.
authors: Department of Biotechnology, University of Wroclaw, 50-137 Wroclaw,                     Poland.
authors: Hanna
authors: H
authors: Baurska
authors: Aleksandra
authors: A
authors: Marchwicka
authors: Anna
authors: A
authors: Kłopot
authors: Andrzej
authors: A
authors: Kutner
authors: Ewa
authors: E
authors: Marcinkowska
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D004872:Ergocalciferols / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D007700:Kinetics; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects; D021381:Protein Transport; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D065668:Vitamin D3 24-Hydroxylase
chemical_list: C533599:24a-homo-1,15-dihydroxyergocalciferol; D000970:Antineoplastic Agents; D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; D004872:Ergocalciferols; D018950:Lipopolysaccharide Receptors; D018167:Receptors, Calcitriol; D047488:Retinoid X Receptors; C003564:1,25-dihydroxyergocalciferol; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol; D007654:Ketoconazole