Comparison of Calcipotriol with Selected Metabolites and Analogues of Vitamin D<sub>3</sub>: Effects on Cell Growth Regulation in Vitro and Calcium Metabolism in Vivo

Binderup, Lise

doi:10.1111/j.1600-0773.1993.tb01643.x

Cited by 33 publications

(16 citation statements)

References 24 publications

(20 reference statements)

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“…The 20-epi analogs KH1060 and MC1288 protected human VDR much better than calcitriol, whereas protection with MC903 and EB1089 was about the same as with calcitriol. The analogs studied are several orders of magnitude more potent in their anti- proliferative action than calcitriol [ 10,[17][18][19][20][21][22]. However, their calcemic activities are not proportionally higher and their relative affinities for human VDR can be even less than that of calcitriol.…”

Section: Discussionmentioning

confidence: 99%

Conformational Studies of Human Vitamin‐D Receptor by Antipeptide Antibodies, Partial Proteolytic Digestion and Ligand Binding

Vaïsänen

Juntunen

Itkonen

et al. 1997

European Journal of Biochemistry

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We have studied conformational changes of human vitamin-D receptor by using antipeptide antibodies, partial proteolytic digestion and binding of the natural ligand calcitriol or its synthetic analogs. Before exposing either ['sS]methionine-labelled in vitro translated human vitamin-D receptor or a recombinant human vitamin-D receptor produced either in Escherichia coli or in 5 ' ' insect cells to limited proteolysis by trypsin or chymotrypsin, the proteins were treated with calcitriol or its synthetic analogs. The digestion products were analyzed by SDS/PAGE, immunoblotting with polyclonal antipeptide antibodies targeted against different domains of the receptor, and Edman N-terminal sequencing. After limited proteolysis with trypsin, two fragments of M , 21 000 and M , 34000 could be localized into N-terminus and C-terminus of the receptor, respectively, by antipeptide antibodies. We found that treatment with calcitriol or its synthetic analogs leads to differential resistance of the ligand-binding domain of the recombinant receptor to partial proteolysis in vitro. We suggest that this is due to distinct conformational changes in the domain induced by the different ligands. The short N-terminal region and the Zn-finger domain form, however, a protease-resistant structure which is independent on the presence or absence of the ligand. When the C-terminal fragment of M , 34000 was further analyzed by Edman N-terminal sequencing, the major cleavage site in the receptor between amino acids Arg173 and His174 was revealed. Recently, interest has arisen in numerous synthetized analogs of calcitriol, human VDR ligands, because of their potential uses for cancer and psoriasis therapies. Many of these analogs are several orders of magnitude more potent in their antiproliferative action than calcitriol, but their calcemic effects are not proportionally higher and their relative affinities for human VDR do not differ notable from that of calcitriol [17-221. It has been recently determined that the reason for the better antiproliferative action of the 20-epi analogs may be a ligand-induced conformational change of human VDR that differs from the conformational change induced by calcitriol. This change in conformation may enhance dimerization of human VDR with RXR and therefore render it more active in transcription [lo].We have studied the conformational changes of human VDR by using antipeptide antibodies, partial proteolytic digestion, and the natural ligand calcitriol or its synthetic analogs. We report here that human VDR has ligand-dependent resistance to proteolysis and that the whole ligand-binding domain, including the C-terminal end of the hinge region, participates in the obvious ligand-induced conformational change of human VDR. We suggest that the binding of the ligand leads to a conformational change similar to that found in RXR-a, RAR-y, and thyroidhormone receptor-a, and that treatment with specific ligands causes slightly different changes in the conformation of human VDR.

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Section: Discussionmentioning

confidence: 99%

Conformational Studies of Human Vitamin‐D Receptor by Antipeptide Antibodies, Partial Proteolytic Digestion and Ligand Binding

Vaïsänen

Juntunen

Itkonen

et al. 1997

European Journal of Biochemistry

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“…Accordingly, the expression of IL-8 mRNA as well as the production of IL-8 by IL-1-stimulated cultured human keratinocytes, fibroblasts, monocytes and endothelial cells is inhibited by vitamin D, derivatives (80,81). In addition, vitamin D, analogues are potent regulators of cell growth, since they inhibit the proliferation of T lymphocytes in the Gl phase (82), inhibit growth and induce differentiation in human histioeytic U 937 lymphoma cells (83) and cultured human keratinocytes (84). In the antipsoriatic effect of vitamin D3 analogues the down-regulation of IL-8 receptors may also be involved (85).…”

Section: Vitatnin D Analoguesmentioning

confidence: 99%

Cytokine system as potential target for antipsoriatic therapy

Kemény

Michel

Ruzicka

1994

Experimental Dermatology

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Cytokines are produced by a variety of cells and have numerous of overlapping activities. There is increasing evidence that cytokines play a crucial role in the pathogenesis of psoriasis and of other dermatologic diseases. This review summarizes current knowledge as to how the altered cytokine network is involved in the accumulation of inflammatory cells in lesional skin, and how the cytokines are involved in epidermal hyperproliferation. The actions of the most important therapeutic compounds, such as corticosteroids, dithranol, cyclosporine, retinoids, vitamin D3 analogues and ultraviolet radiation, on the cytokine system are also discussed. Consideration is given as to how the effects on the production of cytokines and/or cytokine receptors contribute to their therapeutic action.

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“…Calcipotriol has low DBP affinity, and the small amount of the topically applied analog that is absorbed into the circulation is rapidly cleared, allowing higher amounts to be applied to psoriatic lesions without causing hypercalcemia (Binderup, 1993).…”

Section: Interaction With the Serum Vitamin D Binding Protein (Dbp)mentioning

confidence: 99%

Vitamin D analogs: Therapeutic applications and mechanisms for selectivity

Brown

Slatopolsky

2008

Molecular Aspects of Medicine

140

100

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Comparison of Calcipotriol with Selected Metabolites and Analogues of Vitamin D₃: Effects on Cell Growth Regulation in Vitro and Calcium Metabolism in Vivo

Cited by 33 publications

References 24 publications

Conformational Studies of Human Vitamin‐D Receptor by Antipeptide Antibodies, Partial Proteolytic Digestion and Ligand Binding

Conformational Studies of Human Vitamin‐D Receptor by Antipeptide Antibodies, Partial Proteolytic Digestion and Ligand Binding

Cytokine system as potential target for antipsoriatic therapy

Vitamin D analogs: Therapeutic applications and mechanisms for selectivity

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Comparison of Calcipotriol with Selected Metabolites and Analogues of Vitamin D3: Effects on Cell Growth Regulation in Vitro and Calcium Metabolism in Vivo

Cited by 33 publications

References 24 publications

Conformational Studies of Human Vitamin‐D Receptor by Antipeptide Antibodies, Partial Proteolytic Digestion and Ligand Binding

Conformational Studies of Human Vitamin‐D Receptor by Antipeptide Antibodies, Partial Proteolytic Digestion and Ligand Binding

Cytokine system as potential target for antipsoriatic therapy

Vitamin D analogs: Therapeutic applications and mechanisms for selectivity

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Product

Resources

About

Comparison of Calcipotriol with Selected Metabolites and Analogues of Vitamin D₃: Effects on Cell Growth Regulation in Vitro and Calcium Metabolism in Vivo