The Role of Vitamin D in Prostate Cancer
Prostate cancer (PCa) cells harbor receptors for vitamin D (VDR) as well as androgens (AR). 1,25-dihydroxyvitamin D3[1,(OH)2D3] increases AR expression and enhances androgen actions linking the two receptor systems.1,(OH)2D3exhibits antiproliferative acti
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stract Prostate cancer (PCa) cells harbor receptors for vitamin D (VDR) as well as androgens (AR). 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] increases AR expression and enhances androgen actions linking the two receptor systems. 1,25(OH)2D3 exhibits antiproliferative activity in both AR-positive and AR-negative PCa cells. Less calcemic analogs of 1,25(OH)2D3, with more antiproliferative activity, are being developed and will be more useful clinically. The mechanisms underlying differential analog activity are being investigated. In target cells, 1,25(OH)2D3 induces 24-hydroxylase, the enzyme that catalyzes its selfinactivation. Co-treatment with 24-hydroxylase inhibitors enhances the antiproliferative activity of calcitriol. Primary cultures of normal or cancer-derived prostatic epithelial cells express 1a-hydroxylase, the enzyme that catalyzes the synthesis of 1,25(OH)2D3, the levels being much lower in the cancerderived cells and in PCa cell lines. This finding raises the possibility of using 25-hydroxyvitamin D3 [25(OH)D3] as a chemopreventive agent in PCa. In LNCaP human PCa cells, 1,25(OH)2D3 and its analogs exert antiproliferative activity predominantly by cell cycle arrest, but also induce apoptosis, although to a much lesser degree. Growth arrest is mediated by induction of IGF binding protein-3 (IGFBP-3), which in turn increases the expression of the cell cycle inhibitor p21, leading to growth arrest. Other actions of 1,25(OH)2D3 in PCa cells include promotion of pro-differentiation effects and inhibition of tumor cell invasion, metastasis and angiogenesis. Combination therapy with retinoids, other anticancer agents or 24-hydroxylase inhibitors augments the inhibitory activity of 1,25(OH)2D3 in PCa and provides another effective approach in PCa treatment. Small clinical trials have shown that 1,25(OH)2D3 can slow the rate of prostate specific antigen (PSA) rise in PCa patients, demonstrating proof of concept that 1,25(OH)2D3 or its analogs will be clinically effective in PCa therapy. Current research involves further investigation of the role of 1,25(OH)2D3 and its analogs for the therapy or chemoprevention of PCa.
Recent Results in Cancer Research, Vol. 164 Springer-Verlag Berlin Heidelberg 2003
206
Aruna V. Krishnan et al.
Introduction 1a,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active form of vitamin D, is a secosteroid hormone that plays an important role in calcium and phosphate homeostasis through its actions in the intestine, kidney, bone and parathyroid glands (Feldman et al. 2001). In addition to its classic actions on calcium regulation, 1,25(OH)2D3 also exerts antiproliferative and pro-differentiating effects in many tumors and malignant cells, including prostate cancer cells (van Leeuwen and Pols 1997). PCa is the second most common malignancy in American men after skin cancer and causes approximately 40,000 deaths per year. Circulating androgens promote PCa growth and androgen deprivation therapy remains the mainstay of PCa treatment (Hellerstedt and Pienta 2002). However, many patients eve
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