Mechanism and Potential of the Growth-Inhibitory Actions of Vitamin D and Analogs

Abstract

1alpha,25-Dihydroxyvitamin D(3) [1,25-(OH) (2)D(3)] can exert its biological actions through binding with the nuclear vitamin D receptor (VDR), a ligand-activated transcription factor. Next to control of bone and mineral homeostasis, these actions include an immunomodulatory effect and a potent growth-inhibitory, antiproliferative or prodifferentiating action on a wide variety of cell types. The molecular mechanisms underlying this antiproliferative action form an intriguing research topic and they remain, although thoroughly studied, not completely understood. Important cell cycle regulators are involved such as cyclins, cyclin dependent kinases and their corresponding inhibitors as well as E2F transcription factors and accompanying pocket proteins. Whether 1,25-(OH)(2)D(3) influences the expression of all these proteins directly through the nuclear VDR or rather in an indirect manner is not always clear. The antiproliferative action makes 1,25-(OH) (2)D(3) a possible therapeutic tool to treat hyperproliferative disorders, among which different types of cancer. Clinical application, however, is severely hampered by calcemic effects such as hypercalcemia, hypercalciuria and increased bone resorption. Rational design of chemically modified 1,25-(OH) (2)D(3)-analogs tries to overcome this problem. As such, several thousands of analogs have been synthesized and evaluated, some of which display the desired dissociation between beneficial antiproliferative and unwanted calcemic effects. A number of those analogs are 'superagonistic' and have a several-fold stronger antiproliferative action than the parent compound. This review focuses on recent findings about the complex mechanisms behind the antiproliferative and prodifferentiating effect of 1,25-(OH) (2)D(3). Furthermore, the mode of action and possible clinical application of chemically modified 1,25-(OH) (2)D(3)-analogs will be discussed.

From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health

“…In 1975, journals published only Ȃ100 articles per year that included the term vitamin D in the title or abstract; by 2007, the rate of publication had increased to 1400 articles per year. Another driving factor for this increased publication rate was the chemical synthesis by academic chemists and by 4 pharmaceutical companies of 2000 analogues of 1␣,25(OH) 2 D; most of these analogues were targeted toward selective responses in diseases such as osteoporosis, renal osteodystrophy, and psoriasis, and the authors reported their biological properties in a multitude of publications (8,26 Figure 2 emphasizes the structural differences between vitamins D 3 and D 2 and provides a clear description and comparison of the biological properties of these 2 key molecules. This figure shows that 1) vitamin D 3 is the only naturally occurring form of vitamin D in humans and other animals and 2) vitamin D 2 has only one-third the biological activity of vitamin D 3 in humans (7).…”

SPROUTY-2 and E-cadherin regulate reciprocally and dictate colon cancer cell tumourigenicity

“…Many epidemiological and animal studies indicate that the active vitamin D metabolite 1a, 25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) affords protection against colon cancer (Campbell and Adorini, 2006;Deeb et al, 2007;Eelen et al, 2007). A causal link between vitamin D deficiency and colon cancer has recently been considered probable by the International Agency for Research on Cancer (IARC, 2008).…”

Inhibition of prostaglandin synthesis and actions contributes to the beneficial effects of calcitriol in prostate cancer

“…9,10 In vivo studies have demonstrated inhibitory effects of calcitriol and its analogs on the growth of human PCa xenografts in immunocompromised mice causing significant reduction in tumor size and volume. 5,[11][12][13] Transgenic models of PCa have also been developed in animals to study the chemopreventive effects of calcitriol and its analogs.…”