The antiproliferative and pro-apoptotic effects of 1α,25-dihydroxycholecalciferol (
1,25(OH)2D3, 1,25D3,
calcitriol) have been demonstrated in various
tumor model systems in vitro and in vivo. However, limited antitumor effects of 1,25D3 have been observed in clinical trials. This may be attributed to a variety of factors including overexpression of the primary 1,25D3 degrading
enzyme,
CYP24A1, in
tumors, which would lead to rapid local inactivation of 1,25D3. An alternative strategy for improving the antitumor activity of 1,25D3 involves the combination with a selective
CYP24A1 inhibitor. The validity of this approach is supported by numerous preclinical investigations, which demonstrate that
CYP24A1 inhibitors suppress 1,25D3 catabolism in
tumor cells and increase the effects of 1,25D3 on gene expression and cell growth. Studies are now required to determine whether selective
CYP24A1 inhibitors+1,25D3 can be used safely and effectively in patients.
CYP24A1 inhibitors plus 1,25D3 can cause dose-limiting toxicity of
vitamin D (
hypercalcemia) in some patients.
Dexamethasone significantly reduces 1,25D3-mediated
hypercalcemia and enhances the antitumor activity of 1,25D3, increases VDR-
ligand binding, and increases VDR
protein expression. Efforts to dissect the mechanisms responsible for
CYP24A1 overexpression and combinational effect of 1,25D3/
dexamethasone in
tumors are underway. Understanding the cross talk between
vitamin D receptor (VDR) and
glucocorticoid receptor (GR) signaling axes is of crucial importance to the design of new
therapies that include 1,25D3 and
dexamethasone. Insights gained from these studies are expected to yield novel strategies to improve the efficacy of 1,25D3 treatment.