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 cells and stimulate the differentiation of myeloid leukemia cells. 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. 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. 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. VDR−/− mice crossed with APC heterozygous mice (Apc−/+), develop more colonic aberrant crypt foci. 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. 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. 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 interactions and co-crystallization studies show that inecalcitol forms closer contact points with the human VDR-LBD.

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, prostate cancer 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. 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.