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

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.