Increasing evidence has accumulated to suggest that
vitamin D may reduce the risk of
cancer through its biologically active metabolite, 1α,25(
OH)2D3, which inhibits proliferation and angiogenesis, induces differentiation and apoptosis, and regulates many other cellular functions. Thus, it is plausible to assume that rapid clearance of 1α,25(
OH)2D3 by highly expressed
CYP24A1 could interrupt the normal physiology of cells and might be one cause of
cancer initiation and progression. In fact, enhancement of
CYP24A1 expression has been reported in literature for many
cancers. Based on these findings, CYP24A1-specific inhibitors and
vitamin D analogs which are resistant to CYP24A1-dependent catabolism might be useful for
cancer treatment. CYP24A1-specific inhibitor
VID400, which is an
azole compound, markedly enhanced and prolonged the antiproliferative activity of 1α,25(
OH)2D3 in the human keratinocytes. Likewise, CYP24A1-resistant analogs such as 2α-(3-hydroxypropoxy)-1α,25(OH)2D3 (O2C3) and its C2-epimer
ED-71 (
Eldecalcitol), and 19nor- 2α-(3-hydroxypropyl)-1α,25(OH)2D3 (MART-10) showed potent
biological effects. Our in vivo studies using rats revealed that
MART-10 had a low calcemic effect, which is a suitable property as an anticancer
drug. Much lower affinity of
MART-10 for
vitamin D binding protein (DBP) as compared with 1α,25(
OH)2D3 may be related to its more potent cellular activities. Based on these results, we conclude that (1) high affinity for VDR, (2) resistance to CYP24A1-dependent catabolism, (3) low affinity for DBP, and (4) low calcemic effect may be required for designing potent
vitamin D analogs for
cancer treatment.