Mechanism and Potential of the Growth-Inhibitory Actions of Vitamin D and Analogs
Authors: G. Eelen; C. Gysemans; L. Verlinden; E. Vanoirbeek; P. De Clercq; D. Van Haver; C. Mathieu; R. Bouillon; A. Verstuyf
Source: Current Medicinal Chemistry, Volume 14, Number 17, July 2007 , pp. 1893-1910(18)
Publisher: Bentham Science Publishers
Abstract:1α,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] 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)2D3 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)2D3 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)2D3-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)2D3. Furthermore, the mode of action and possible clinical application of chemically modified 1,25-(OH)2D3-analogs will be discussed.
Document Type: Research Article
Affiliations: Laboratorium voor Experimentele Geneeskunde en Endocrinologie (LEGENDO), Katholieke Universiteit Leuven, Herestraat 49, B-3000 Leuven, Belgium.
Publication date: 2007-07-01
- Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.