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Inhibition of vitamin D3 metabolism enhances VDR signalling in androgen-independent prostate cancer cells

Simons, Claire, Yee, S. W. and Campbell, M. J. 2006. Inhibition of vitamin D3 metabolism enhances VDR signalling in androgen-independent prostate cancer cells. The Journal of Steroid Biochemistry and Molecular Biology 98 (4-5) , pp. 228-235. 10.1016/j.jsbmb.2005.11.004

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Abstract

Induction of growth arrest and differentiation by 1α,25-dihydroxyvitamin D3 (1,25-(OH)2D3) occurs in non-malignant cell types but is often reduced in cancer cells. For example, androgen-independent prostate cancer cells, DU-145 and PC-3, are relatively insensitive to the anti-proliferative action of 1,25-(OH)2D3. This appears to be due to increased 1,25-(OH)2D3-metabolism, as a result of CYP24 enzyme-induction, which in turn leads to decreased anti-proliferative efficacy. In the in vitro rat kidney mitochondria assay, the 2-(4-hydroxybenzyl)-6-methoxy-3,4-dihydro-2H-naphthalen-1-one (4) was found to be a potent inhibitor of Vitamin D3 metabolising enzymes (IC50 3.5 μM), and was shown to be a more potent inhibitor than the broad spectrum P450 inhibitor ketoconazole (IC50 20 μM). The combination of the inhibitor and 1,25-(OH)2D3 caused a greater inhibition of proliferation in DU-145 cells than when treated with both agents alone. Examination of the regulation of VDR target gene mRNA in DU-145 cells revealed that co-treatment of 1,25-(OH)2D3 plus inhibitor of Vitamin D3 metabolising enzymes co-ordinately upregulated CYP24, p21waf1/cip1 and GADD45α.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: Vitamin D3 metabolising enzymes; Tetralone; Prostate cancer cells
Publisher: Elsevier
ISSN: 0960-0760
Last Modified: 04 Jun 2017 01:37
URI: http://orca.cf.ac.uk/id/eprint/950

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