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.
Division of Medicinal Chemistry, Welsh School of Pharmacy, Cardiff University, UK.
Sook Wah
SW
Yee
Moray J
MJ
Campbell
Claire
C
Simons
D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018167:Receptors, Calcitriol / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013250:Steroid Hydroxylases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase; D000097642:GADD45 Proteins
D000728:Androgens; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007654:Ketoconazole; D009687:Nuclear Proteins; D018167:Receptors, Calcitriol; D013250:Steroid Hydroxylases; D014807:Vitamin D; D065668:Vitamin D3 24-Hydroxylase; C493956:CDKN1A protein, human; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C118756:dihydroxy-vitamin D3