The active form of
vitamin D3,
1,25-dihydroxyvitamin D3, is a major regulator of bone and
calcium homeostasis. In addition, this
hormone also inhibits the proliferation and stimulates the differentiation of normal as well as malignant cells. Supraphysiological doses of
1,25-dihydroxyvitamin D3 are required to reduce
cancer cell proliferation. However, these doses will lead in vivo to calcemic side effects such as
hypercalcemia and
hypercalciuria. During the last 25 years, many structural analogs of
1,25-dihydroxyvitamin D3 have been synthesized by the introduction of chemical modifications in the A-ring, central CD-ring region or side chain of
1,25-dihydroxyvitamin D3 in the hope to find molecules with a clear dissociation between the beneficial antiproliferative effects and adverse calcemic side effects. One example of such an analog with a good dissociation ratio is
calcipotriol (Daivonex®), which is clinically used to treat the hyperproliferative
skin disease psoriasis. Other
vitamin D analogs were clinically approved for the treatment of
osteoporosis or
secondary hyperparathyroidism. No
vitamin D analog is currently used in the clinic for the treatment of
cancer although several analogs have been shown to be potent drugs in animal models of
cancer. Transcriptomics studies as well as in vitro cell
biological experiments unraveled basic mechanisms involved in the
antineoplastic effects of
vitamin D and its analogs.
1,25-dihydroxyvitamin D3 and analogs act in a cell type- and tissue-specific manner. Moreover, a blockade in the transition of the G0/1 toward S phase of the cell cycle, induction of apoptosis, inhibition of migration and invasion of
tumor cells together with effects on angiogenesis and
inflammation have been implicated in the pleiotropic effects of
1,25-dihydroxyvitamin D3 and its analogs. In this review we will give an overview of the action of
vitamin D analogs in
tumor cells and look forward how these compounds could be introduced in the clinical practice.