Anitcancer Activity of Vitamin D Analogs
From its discovery in 1920 to the late 1960s, vitamin D was considered to function as a nutritional cofactor for biologic processes related to calcium metabolism. Discovery and chemical characterization of the vitamin D plasma metabolites 25-hydroxy D3 [25(OH)D3] and 1,25-dihydroxy D3 [1,25(OH)2D3] led to recognition of the true significance of vitamin D3 as a precursor of a hormone, biosynthesis of which is tightly regulated, as in the case of other steroid hormones (Scheme 1). During the last 10 years, significant progress has been made at defining the molecular mechanism of 1,25(OH)2D3 activity in various cellular systems. 1,25(OH)2D3 as a hormone plays an essential role in a host of cellular processes involved in calcium-phosphate homeostasis, inhibition of cell growth, and induction of cell differentiation. It is now well established that this hormonally active form of vitamin D generates biologic responses by two distinct mechanistic pathways, via regulation of gene transcriptions mediated by 1,25(OH)2D3-specific nuclear receptors [the vitamin D receptor (VDR)], and a nongenomic mode initiated at cellular membranes. The genomic effects of 1,25(OH)2D3 are especially well portrayed by its multifaceted role in bone-forming processes, regulation of parathyroid hormone release, induction of differentiation of myeloid leukemia cells, and inhibition of proliferation of a large number of cancer cell lines, such as breast, prostate, and colon. As therapeutic agents, 1,25(OH)2D3 and some of its analogs are being used in the treatment of renal osteodystrophy, secondary hyperparathyroidism, osteoporosis, psoriasis, and scleroderma. These compounds also have the potential to be used in the treatment of leukemia and solid tumors based on the in vivo results discussed in this chapter. The immunosuppressive activity of 1,25(OH)2D3 and its analogs is defined by their downregulation of interleukin-12 (IL-12), interferon-γ (INF-γ), and IL-2 release, and it is also supported by disease suppression in in vivo models for experimental autoimmune encephalomyelitis, diabetes and lupus (1).
KeywordsExperimental Autoimmune Encephalomyelitis LNCap Cell Aberrant Crypt Focus Lithocholic Acid Volume Doubling Time
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