title: Altered Vitamin D receptor-coactivator interactions reflect superagonism of Vitamin D analogs.
abstract: The active form of Vitamin D, 1alpha,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], has potent antiproliferative actions on various normal and malignant cells. Calcemic effects, however, hamper therapeutic application of 1,25-(OH)(2)D(3) in hyperproliferative diseases. Two 14-epi-analogs of 1,25-(OH)(2)D(3) namely 19-nor-14-epi-23-yne-1,25-(OH)(2)D(3) (TX522) and 19-nor-14,20-bisepi-23-yne-1,25-(OH)(2)D(3) (TX527), display reduced calcemic effects coupled to an (at least 10-fold) increased antiproliferative potency when compared with 1,25-(OH)(2)D(3). Altered cofactor recruitment by the Vitamin D receptor (VDR) might underlie the superagonism of these 14-epi-analogs. Therefore, this study aims to evaluate their effects at the level of VDR-coactivator interactions. Mammalian two-hybrid assays with VDR and the coactivators TIF2 and DRIP205 showed the 14-epi-analogs to be more potent inducers of VDR-coactivator interactions than 1,25-(OH)(2)D(3). TX522 and TX527 require 30- and 40-fold lower doses to obtain the VDR-DRIP205 interaction induced by 1,25-(OH)(2)D(3) at 10(-8)M. Evaluation of additional 1,25-(OH)(2)D(3)-analogs and their impact on VDR-coactivator interactions revealed a strong correlation between the antiproliferative potency of an analog and its ability to induce VDR-coactivator interactions. In conclusion, these data show that altered coactivator binding by the VDR is one possible explanation for the superagonistic action of the two 14-epi-analogs TX522 and TX527.
authors.affiliation: Laboratorium voor Experimentele Geneeskunde en Endocrinologie, Katholieke Universiteit Leuven, Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Eelen
authors.forename: Lieve
authors.initials: L
authors.lastname: Verlinden
authors.forename: Mark
authors.initials: M
authors.lastname: Van Camp
authors.forename: Frank
authors.initials: F
authors.lastname: Claessens
authors.forename: Pierre
authors.initials: P
authors.lastname: De Clercq
authors.forename: Maurits
authors.initials: M
authors.lastname: Vandewalle
authors.forename: Roger
authors.initials: R
authors.lastname: Bouillon
authors.forename: Annemieke
authors.initials: A
authors.lastname: Verstuyf
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation; D006801:Humans; D008968:Molecular Conformation; D016133:Polymerase Chain Reaction; D018167:Receptors, Calcitriol / Q000378:metabolism*; D014807:Vitamin D / Q000819:agonists* / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D018167:Receptors, Calcitriol; C118756:dihydroxy-vitamin D3; D014807:Vitamin D