Promise of vitamin D analogues in the treatment of hyperproliferative conditions

Abstract

Abstract1A,25-Dihydroxyvitamin D 3 [1A,25-(OH) 2 D 3 ; calcitriol] is best known as a hormone involved in calcium homeostasis but is also a potent antiproliferative agent in many cell types, particularly epithelial cells. 1A,25(OH) 2 D 3 mediates its actions through a classic steroid hormone-like transcriptional mechanism by influencing the expression of hundreds of genes. Effects of 1A,25(OH) 2 D 3 have been observed on expression of cell cycle regulators, growth factors and their receptors, apoptotic machinery, metastatic potential, and angiogenesis; all of which have some effect on hyperproliferative conditions. This minireview focuses on the anticancer potential of 1A,25(OH) 2 D 3 and its analogues by summarizing the promising data from animal and human trials of 1A,25(OH) 2 D 3 and some of the more interesting synthetic vitamin D analogues in the treatment of a variety of different animal cancer models and in human patients with advanced cancer. Optimal administration of vitamin D analogues is only just being achieved with high-dose intermittent administration overcoming bioavailability and hypercalcemia problems and combination therapy with cytotoxic agents (taxols and cisplatins), antiresorptive agents (bisphosphonates), or cytochrome P450 inhibitors being attempted. Although the potential of vitamin D as an antiproliferative drug has been realized in the treatment of psoriasis and in parathyroid cell hyperplasia associated with secondary hyperparathyroidism, the search for an anticancer treatment incorporating a vitamin D analogue remains elusive. [Mol Cancer Ther 2006;5(4):797 -808]

25-Hydroxyvitamin D3 is a natural chemopreventive agent against carcinogen induced precancerous lesions in mouse mammary gland organ culture

“…These results suggest that maintenance of normal physiological concentration of 25(OH)D 3 in the serum will generate protective effect against carcinogenesis, providing direct evidence in support of the epidemiological research [7]. Regarding the physiological concentration of 25(OH)D 3 , generally 80-200 nmol/l (32-80 ng/ml) is considered as vitamin D sufficient physiological concentration [38]. In our studies we used 250 nM 25(OH)D 3 which is considered physiologically achievable and not toxic concentration for this prohormone.…”

Molecular pathways mediating the anti-inflammatory effects of calcitriol: implications for prostate cancer chemoprevention and treatment

“…Calcitriol analogs are being developed to find a therapeutic substitute that would have increased anti-cancer efficacy and decreased side effects of hypercalcemia (Masuda & Jones 2006). A recent study reports that the calcitriol analog elocalcitol also exhibits anti-inflammatory effects on human BPH cells (Penna et al 2009).…”

Hybrid homology modeling and mutational analysis of cytochrome P450C24A1 (CYP24A1) of the Vitamin D pathway: Insights into substrate specificity and membrane bound structure–function

“…This includes the most hormonally-active form, 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 or calcitriol) that alters gene expression in numerous target tissues to regulate multiple cellular functions including calcium homeostasis, immune function an normal cellular proliferation and differentiation processes (as reviewed) [11]. Vitamin D and related drug analogs are potent inducers of cellular differentiation, making them promising targets for the treatment of antiproliferative disorders, including psoriasis and cancer [12]. In addition, there is growing evidence for a global epidemic of vitamin D deficiency underlying numerous diseases, which can be partially attributed to vitamin D resistance caused by altered regulation of CYP24A1 [13].…”