Vitamin D and cancer

Already in the eighties it was shown that the active form of vitamin D₃, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], can inhibit the proliferation of melanoma cells¹ and stimulate the differentiation of myeloid leukemia cells.² The almost universal presence of the vitamin D receptor (VDR) and the presence of 1α-hydroxylase (CYP27B1) activity in non-classical tissues together with the antiproliferative and prodifferentiating effects suggests a paracrine role for 1,25(OH)₂D₃. 1,25(OH)₂D₃ directly regulates the expression of a whole set of genes through binding to the VDR which heterodimerizes to the retinoid X receptor (RXR), and 1,25(OH)₂D₃-VDR/RXR complexes bind to vitamin D response elements in the promoter region of target genes. In most cancer cell types that express a functional VDR, exposure to 1,25(OH)₂D₃ results in the accumulation of cells in the G₀/G₁ phase of the cell cycle. This effect is not due to one single gene or a single pathway but depend on a multiple pathways among which epidermal growth factor, insulin like growth factor, transforming growth factor, prostaglandins and Wnt-β-catenin signaling cascades.³ In VDR^−/− mice there is no apparent increase in spontaneous cancer but these mice have an increased rate of proliferation of colonic, prostate and breast cells.⁴ If VDR^−/− mice are challenged with carcinogenic agents the incidence of skin tumors increase or more pre-neoplastic lesions in the mammary glands are present. Mouse mammary tumor virus (MMTV)-neu mice on VDR heterozygous background also show accelerated mammary tumorigenesis compared with MMTV-neu mice on VDR wild type background.⁵ VDR^−/− mice crossed with APC heterozygous mice (Apc^−/+), develop more colonic aberrant crypt foci.⁶ Similarly VDR^−/− mice develop more skin tumors when exposed to UV-B. These data suggest that vitamin D deficiency may be a predisposing environmental factor for cancer. Cross-sectional and especially prospective studies indicate that a low vitamin D status (25-hydroxyvitamin D₃ levels) is associated with a higher risk for several types of cancer, particularly colorectal cancer.⁶ Whether vitamin D supplements may decrease the risk of cancer (prevention) awaits the results of ongoing randomized controlled trials as the limited number of available studies are inconsistent. A different question is whether 1,25(OH)₂D₃ can be used to treat cancer but supraphysiologic doses are needed and leads to calcemic side effects. To overcome this problem analogs of the parent compound have been synthesized with a clear dissociation between antiproliferative and calcemic activity. One such promising superagonistic analog is the 14-epi analog inecalcitol being 10-fold more potent to inhibit the proliferation of breast cancer cells and 400 fold less calcemic than 1,25(OH)₂D₃.⁷ Inecalcitol is 100 times more potent than 1,25(OH)₂D₃ to protect keratinocytes of UV-B induced damage. Trump et al. show in the present issue that inecalcitol is 30× more active to inhibit squamous cell carcinoma (SCC) proliferation and the induction of apoptosis by inecalcitol is much higher compared with 1,25(OH)₂D₃. The superagonistic action of inecalcitol correlates with its ability to induce coactivator-VDR interactions⁷ and co-crystallization studies show that inecalcitol forms closer contact points with the human VDR-LBD.⁷

The potential clinical use of 1,25(OH)₂D₃ analogs such as inecalcitol as an anti-cancer drug has been demonstrated in in vivo animals models of breast cancer,⁷ prostate cancer⁸ and by the current study of Trump in SCC. Moreover a phase II study in patients with hormone-refractory prostate cancer demonstrated that 27 of the 31 patients treated with inecalcitol (at doses up to 600 µg/day) and Taxotere during 18 weeks showed a decrease in prostate specific antigen levels of more than 30% within 3 m of initiation of treatment without any changes in calcium parameters.⁷ Although these preliminary results look promising more clinical trials are needed to evaluate 1,25(OH)₂D₃ and its analogs as compounds that prevent and/or delay cancer progression. As can be expected from nearly all anti-cancer drugs combination therapies are more likely to generate long-term effects than single therapy.

Ma Y, Yu WD, Hidalgo AA, Luo W, Delansorne R, Johnson CS, et al. Inecalcitol, an analog of 1,25D₃, displays enhanced antitumor activity through the induction of apoptosis in a squamous cell carcinoma model system. Cell Cycle. 2013;12:743–52. doi: 10.4161/cc.23846.