Inhibition of Vitamin D3 Metabolism Enhances VDR Signalling in Androgen-independent Prostate Cancer Cells

Induction of growth arrest and differentiation by 1alpha,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) 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)(2)D(3). This appears to be due to increased 1,25-(OH)(2)D(3)-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 D(3) metabolising enzymes (IC(50) 3.5 microM), and was shown to be a more potent inhibitor than the broad spectrum P450 inhibitor ketoconazole (IC(50) 20 microM). The combination of the inhibitor and 1,25-(OH)(2)D(3) 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)(2)D(3) plus inhibitor of Vitamin D(3) metabolising enzymes co-ordinately upregulated CYP24, p21(waf1/cip1) and GADD45alpha.