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REVIEW |
Division of Endocrinology, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305-5103, USA
(Correspondence should be addressed to D Feldman; Email: dfeldman{at}stanford.edu)
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Abstract |
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B signaling that results in potent anti-inflammatory and anti-angiogenic effects. Other important direct effects of calcitriol as well as the consequences of its anti-inflammatory effects include the inhibition of tumor angiogenesis, invasion, and metastasis. We hypothesize that these anti-inflammatory actions, in addition to the other known anti-cancer effects of calcitriol, play an important role in its potential use as a therapeutic agent for PCa. Calcitriol or its analogs may have utility as chemopreventive agents and should be evaluated in clinical trials in PCa patients with early or precancerous disease.
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Introduction |
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Calcitriol (1,25-dihydroxyvitamin D3), 1,25(OH)2D3, the biologically most active metabolite of vitamin D, acts as a classical steroid hormone and regulates calcium homeostasis and bone metabolism through actions mediated by the vitamin D receptor (VDR) in intestine, bone, kidney, and the parathyroid glands (Feldman et al. 2007). However, calcitriol also exerts anti-proliferative and pro-differentiating effects in a number of malignant cells and retards tumor growth in animal models of cancer raising the possibility of its use as an anti-cancer agent. Calcitriol has been shown to inhibit the development and progression of PCa (Krishnan et al. 2003, Stewart & Weigel 2004, Beer & Myrthue 2006, Gombart et al. 2006, Deeb et al. 2007, Fleet 2008). U.V. light is essential for the synthesis of vitamin D in the skin, and epidemiological studies suggest that mortality rates due to PCa in the US are inversely related to sunlight exposure (Hanchette & Schwartz 1992, Schwartz & Skinner 2007). Many studies suggest that vitamin D deficiency, characterized by low circulating 25-hydroxyvitamin D levels, is associated with increased PCa risk and progression (Ahonen et al. 2000, Giovannucci 2005, Tretli et al. 2009, Trump et al. 2009), although all studies do not support such a correlation (Platz et al. 2004, Ahn et al. 2008).
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Inflammation and PCa |
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Molecular mechanisms of calcitriol actions |
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Anti-inflammatory actions of calcitriol |
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B (NFB), a transcription factor that regulates the expression of numerous genes involved in inflammatory and immune responses and cellular proliferation (McCarty 2004). NFB is thought to play a key role in the process leading from inflammation to carcinogenesis (Maeda & Omata 2008). In addition, calcitriol also exhibits important anti-angiogenic effects as detailed below. In the following sections, we will discuss the importance of these molecular pathways of inflammation in the development and progression of PCa and the therapeutic significance of the inhibition of these of pro-inflammatory signals by calcitriol. Regulation of PG metabolism and signaling
PGs have been shown to play a role in the development and progression of many cancers, and COX-2, the enzyme that regulates PG synthesis, is an important molecular target in cancer therapy (Badawi 2000, Hussain et al. 2003, Wang et al. 2005). PGs promote carcinogenesis by multiple mechanisms such as stimulating cellular proliferation, inhibiting apoptosis, promoting angiogenesis, and activating carcinogens (Dubois et al. 1998, Hawk et al. 2002). Calcitriol has been shown to regulate the expression of several key genes involved in the PG pathway causing a decrease in PG synthesis, an increase in PG catabolism, and the inhibition of PG signaling through their receptors in normal and malignant prostate cells (Moreno et al. 2005; Fig. 2).
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Local production of PGs at the tumor sites by infiltrating inflammatory cells also increases the risk of carcinogenesis and/or cancer progression (Zha et al. 2001, 2004, Nelson et al. 2004, Wang et al. 2005, De Marzo et al. 2007). In colon cancer, COX-2 expression is found in the carcinoma cells as well as infiltrating macrophages within the tumors (Bamba et al. 1999, Chapple et al. 2000). In other cancers, COX-2 expression has been demonstrated in vascular endothelial cells, fibroblasts, and smooth muscle cells around the cancer (Goluboff et al. 1999, Mifflin et al. 2002). Immunohistochemical analyses of COX-2 expression in prostate epithelium in tissue specimens from patients with PCa and benign prostatic hyperplasia (BPH) revealed high T-lymphocyte and macrophage densities in COX-2-positive areas raising the likelihood that pro-inflammatory cytokines released by these cells up-regulate COX-2 expression in the adjacent tumor cells (Wang et al. 2004, 2005). PGs generated by COX-2 act in an autocrine and paracrine manner to stimulate cell growth. At the cellular level, both arachidonic acid, the substrate for COX, and the product prostaglandin E2 (PGE2) stimulate proliferation by regulating the expression of genes that are involved in growth regulation including c-fos (Chen & Hughes-Fulford 2000). Studies in experimental models of cancer have shown that COX-2 enhances tumor development and progression by promoting resistance to apoptosis and stimulating angiogenesis and tumor invasion, and it is therefore regarded as an oncogene (Zha et al. 2004, Kundu & Surh 2008).
15-Hydroxyprostaglandin dehydrogenase
15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is the enzyme that catalyzes the conversion of PGs to their corresponding 15-keto derivatives, which exhibit greatly reduced biological activity. Therefore, 15-PGDH can be regarded as a physiological antagonist of COX-2. 15-PGDH has been described as an oncogene antagonist and plays a tumor-suppressive role in colon cancer (Yan et al. 2004, Myung et al. 2006). 15-PGDH is universally expressed in normal colon but is routinely absent or severely reduced in cancer specimens. Importantly, the stable transfection of a 15-PGDH expression vector into colon cancer cells greatly reduces the ability of the cells to form tumors and/or slows tumor growth in nude mice demonstrating that 15-PGDH functions as a tumor suppressor (Yan et al. 2004). 15-PGDH also acts as a tumor suppressor in breast cancer (Wolf et al. 2006).
PG receptors
Prostaglandin E (PGE) and prostaglandin F (PGF) are the major PGs stimulating the proliferation of PCa cells and they act by binding to G-protein-coupled membrane receptors (prostanoid receptors). There are eight members in the prostanoid receptor subfamily, which are distinguished by their ligand-binding profile and the signal transduction pathways that they activate, accounting for some of the diverse and often opposing effects of PGs (Breyer et al. 2001). PGE acts through four different receptor sub-types (EP1–EP4), while PGF acts through the FP receptor. PCa cells express both EP and FP receptors (Chen & Hughes-Fulford 2000, Moreno et al. 2005). PG receptors are also expressed in most endothelial cells, macrophages, and stromal cells found in the tumor microenvironment. PG interaction with its receptors can send a positive feedback signal to increase COX-2 mRNA levels (Tjandrawinata & Hughes-Fulford 1997, Tjandrawinata et al. 1997, Chen & Hughes-Fulford 2000). Therefore, irrespective of the initial trigger of COX-2 expression, PGs could mediate a wave of COX-2 expression at the tumor sites not only in the cancer cells themselves, but also in the surrounding stromal cells and infiltrating macrophages as well as endothelial cells thereby promoting tumor progression.
Calcitriol effects on the PG pathway in prostate cells
As depicted in Fig. 2, calcitriol regulates the expression of several PG pathway genes in multiple PCa cell lines as well as cultured primary prostate epithelial cells established from surgically removed prostate tissue from PCa patients (Moreno et al. 2005). The levels of COX-2 mRNA and protein are significantly decreased by calcitriol treatment of these cells (Moreno et al. 2005). Calcitriol increases 15-PGDH mRNA and protein expression in various PCa cells (Moreno et al. 2005). Calcitriol has also been shown to regulate COX-2 and 15-PGDH expression in other cells such as rat macrophages and human neonatal monocytes (Pichaud et al. 1997, Aparna et al. 2008). By inhibiting COX-2 and stimulating 15-PGDH expression in PCa cells, calcitriol decreases the levels of biologically active PGs, thereby reducing the growth stimulation due to PGs. Further calcitriol also decreases the expression of EP and FP PG receptor mRNA in PCa cells (Moreno et al. 2005). The calcitriol-induced decrease in PG receptor expression results in the attenuation of PG-mediated functional responses even when exogenous PGs are added to the cell cultures. Calcitriol suppresses the induction of the immediate-early gene c-fos and the growth stimulation seen following the addition of exogenous PGs or the PG precursor arachidonic acid to PCa cell cultures (Moreno et al. 2005). The down-regulation of PG receptors by calcitriol would inhibit the positive feedback exerted by PGs on COX-2, thereby limiting the wave of COX-2 expression at the tumor sites and slowing the rate of tumor progression. Thus, calcitriol inhibits the PG pathway in PCa cells by three separate mechanisms: decreasing COX-2 expression, increasing 15-PGDH expression, and reducing PG receptor levels (Fig. 2). We postulate that these actions contribute to the suppression of the proliferative and angiogenic stimuli provided by PGs in PCa. The regulation of PG metabolism and biological actions constitutes an important anti-inflammatory pathway of calcitriol action.
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). The analog causes significant decreases in COX-2 mRNA levels and PGE2 synthesis resulting in the suppression of cytokine-stimulated production of the pro-inflammatory chemokine interleukin-8 (IL-8), which is involved in BPH pathogenesis (Penna et al. 2009). Another study shows that a different calcitriol analog 1
,25-dihydroxy-16-ene-23-yne-vitamin D3 exhibits anti-inflammatory effects causing a reduction in the expression of inflammatory markers such as COX-2, inducible nitric oxide synthase, and IL-2 in experimental models of inflammation (Aparna et al. 2008). Interestingly, this study demonstrates that calcitriol and 1, 25-dihydroxy-16-ene-23-yne-vitamin D3 also directly inhibit COX-2 enzymatic activity (Aparna et al. 2008).
Combination of calcitriol and NSAIDs as a therapeutic approach in PCa
NSAIDs are a class of drugs that decrease PG synthesis by inhibiting COX-1 and COX-2 enzymatic activities. Several NSAIDs nonselectively inhibit both the constitutively expressed COX-1 and the inducible COX-2, while others have been shown to be more selective in preferentially inhibiting COX-2 enzymatic activity. Based on our studies in PCa cells (Moreno et al. 2005), we hypothesized that the action of calcitriol at the genomic level to reduce COX-2 expression, leading to decreased COX-2 protein levels, would allow the use of lower concentrations of NSAIDs to inhibit COX-2 enzyme activity (Fig. 2). Further, an increase in the expression of 15-PGDH and a decrease in PG receptor levels due to calcitriol actions would lower the concentrations and biological activity of PGs thereby enhancing the NSAID effect (Fig. 2). Therefore, we hypothesized that the combination of calcitriol and NSAIDs would exhibit an additive/synergistic activity to inhibit PCa cell growth. Combinations of calcitriol with the COX-2-selective NSAIDs, NS398 and SC-58125, and the nonselective NSAIDs, naproxen and ibuprofen, caused a synergistic enhancement of the inhibition of PCa cell proliferation, compared to the individual agents (Moreno et al. 2005). These results led us to further hypothesize that the combination of calcitriol and NSAIDs may have clinical utility in PCa therapy (Moreno et al. 2005). As discussed below (see the section on Clinical studies), we have conducted a small clinical trial examining the effects of a combination of high-dose calcitriol and the nonselective NSAID naproxen in PCa patients with far advanced disease, and the results suggest a beneficial effect of the combination to slow the course of disease progression.
Induction of MKP5 and inhibition of stress-activated kinase signaling
Data from cDNA microarray studies in normal human prostate epithelial cells (Peehl et al. 2004) revealed another novel calcitriol-responsive gene, MKP5, also known as DUSP10. MKP5 is a member of the dual specificity MKP family of enzymes that dephosphorylate, and thereby inactivate, mitogen-activated protein kinases (MAPKs). MKP5 specifically dephosphorylates p38 MAPK and the stress-activated protein kinase Jun-N-terminal kinase (JNK), leading to their inactivation (Fig. 3). Calcitriol up-regulates MKP5 expression leading to downstream anti-inflammatory effects in cells derived from normal prostatic epithelium and primary, localized adenocarcinoma, supporting a role for calcitriol in the prevention and/or early treatment of PCa (Nonn et al. 2006). In primary cultures of normal prostatic epithelial cells from the peripheral zone, calcitriol increases MKP5 transcription. A putative positive vitamin D response element in the MKP5 promoter mediates the stimulation of MKP5 transcription by calcitriol. Interestingly, calcitriol up-regulation of MKP5 is seen in primary cells derived from normal prostatic epithelium and primary, localized adenocarcinoma, but not in the established PCa cell lines derived from PCa metastasis. Calcitriol inhibits the phosphorylation and activation of p38 in normal primary prostate cells in a MKP5-dependent manner as MKP5 siRNA completely abolished p38 inactivation by calcitriol (Nonn et al. 2006). A consequence of p38 stress-induced kinase activation is an increase in the production of pro-inflammatory cytokines that sustain and amplify the inflammatory response (Park et al. 2003). IL-6 is a p38-regulated pro-inflammatory cytokine implicated in PCa progression (Culig et al. 2005). Stimulation of primary prostate cells with the pro-inflammatory molecule tumor necrosis factor (TNF) increases IL-6 mRNA stability and concentrations of IL-6 in the conditioned media. Pre-treatment of the cells with calcitriol significantly attenuates the increase in IL-6 production following TNF treatment, adding inhibition of IL-6 production to the spectrum of calcitriol-mediated actions (Nonn et al. 2006).
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(Nonn et al. 2006; Fig. 3). These observations provide evidence for significant anti-inflammatory effects of calcitriol in prostate cells. Interestingly, established PCa cell lines derived from metastasis such as LNCaP, PC-3, and DU145 exhibit low basal levels of MKP5, and calcitriol is unable to induce MKP5 expression. We therefore speculate that a loss of MKP5 expression might occur during PCa progression, as a result of a selective pressure to eliminate the tumor suppressor activity of MKP5 and/or calcitriol.
Inhibition of NFB activation and signaling
NFB comprises a family of inducible transcription factors ubiquitously present in all cells that are important regulators of innate immune responses and inflammation (Karin & Lin 2002). In the basal state, most NFB dimers are bound to specific inhibitory proteins called IB. Many pro-inflammatory signals activate NFB mainly through IB kinase-dependent phosphorylation and degradation of the inhibitory IB proteins (Maeda & Omata 2008). Free NFB then translocates to the nucleus and activates the transcription of pro-inflammatory cytokines, chemokines, and anti-apoptotic factors (Ghosh & Karin 2002). In contrast to normal cells, many cancer cells have elevated levels of active NFB (Sovak et al. 1997, Palayoor et al. 1999), and constitutive activation of NFB has been observed in AIPC (Gasparian et al. 2002, Ismail et al. 2004, Suh & Rabson 2004). The NFB protein RelB is uniquely expressed at high levels in PCa with high Gleason scores (Lessard et al. 2005). NFB plays a major role in the control of immune responses and inflammation and promotes malignant behavior by increasing the transcription of the anti-apoptotic gene BCL-2 (Catz & Johnson 2001), cell cycle progression factors such as c-MYC and cyclin D1, proteolytic enzymes such as matrix metalloproteinase 9 (MMP-9) and urokinase-type plasminogen activator, and angiogenic factors such as VEGF and IL-8 (Huang et al. 2001, Suh & Rabson 2004). IL-8, an angiogenic factor and a downstream target of NFB, is also a potent chemotactic factor for neutrophils and is associated with the initiation of the inflammatory response (Ferrer et al. 1998).
Calcitriol is known to directly modulate basal and cytokine-induced NFB activity in many cells including human lymphocytes (Yu et al. 1995), fibroblasts (Harant et al. 1998), and peripheral blood monocytes (Stio et al. 2007). A reduction in the levels of the NFB-inhibitory protein IB has been reported in fibroblasts derived from knockout mice lacking the VDR (Sun et al. 2006). Calcitriol and its analogs block NFB activation by increasing the expression of IB in macrophages and peripheral blood mononuclear cells (Cohen-Lahav et al. 2006, 2007, Stio et al. 2007). VDR appears to play an inhibitory role in the regulation of basal NFB signaling in colon cancer cells, and the VDR antagonist ZK191732 increases NFB activity by decreasing IB (Schwab et al. 2007). Calcitriol and its analogs also inhibit NFB activation in different types of immune cells (Dong et al. 2003, Giarratana et al. 2004, Penna et al. 2007). There is considerable evidence for the inhibition of NFB signaling by calcitriol in PCa cells. Calcitriol decreases the levels of the angiogenic and pro-inflammatory cytokine IL-8 in immortalized normal human prostate epithelial cell lines (HPr-1 and RWPE-1) and established PCa cell lines (LNCaP, PC-3, and DU145; Bao et al. 2006a). The suppression of IL-8 by calcitriol appears to be due to the inhibition of NFB signaling. Calcitriol reduces the nuclear translocation of the NFB subunit p65 thereby inhibiting the NFB complex from binding to its DNA response element and consequently suppressing the NFB stimulation of transcription of downstream targets such as IL-8 (Bao et al. 2006a). Thus, calcitriol could delay the progression of PCa by suppressing the expression of angiogenic and pro-inflammatory genes such as VEGF and IL-8 (Fig. 4). The calcitriol analog elocalcitol inhibits the production of IL-8 by human BPH cells by arresting NFB p65 nuclear translocation (Penna et al. 2009). NFB also provides an adaptive response to PCa cells against cytotoxicity induced by redox-active therapeutic agents and is implicated in radiation resistance of cancers (Kimura et al. 1999, Criswell et al. 2003). Calcitriol significantly enhances the sensitivity of PCa cells to ionizing radiation by selectively suppressing radiation-mediated RelB activation (Xu et al. 2007). Thus, calcitriol may serve as an effective agent for sensitizing PCa cells to radiation therapy via suppression of the NFB pathway.
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B signaling by up-regulating the expression of other proteins that interfere with NFB activation such as IGFBP-3 and clusterin (CLU) as discussed below. Calcitriol up-regulates the expression of IGFBP-3 (Boyle et al. 2001, Peng et al. 2004), which has been shown to interfere with NFB signaling in PCa cells by suppressing p65 NFB protein levels and the phosphorylation of IB (Jogie-Brahim et al. 2009; Fig. 4). Apart from its ability to inhibit NFB, IGFBP-3 has multiple anti-PCa actions including inhibition of proliferation, stimulation of apoptosis, and a variety of anti-inflammatory effects (Boyle et al. 2001, Ali et al. 2003, Peng et al. 2004, 2008, Jogie-Brahim et al. 2009; Fig. 4). NFB activity is also modulated by apolipoprotein J or CLU. CLU is a protein expressed in virtually all tissues and is regulated in inflammation, apoptosis, and cancer. Its nuclear form (nCLU) is implicated in apoptosis (Gleave & Chi 2005, Shannan et al. 2006). In human neuroblastoma cells and mouse embryonic fibroblasts, CLU has been shown to strongly inhibit NFB activity through the stabilization of IB proteins (Santilli et al. 2003). Calcitriol and its analogs up-regulate CLU expression with an accompanying apoptotic response in several cells including human BPH cells (Crescioli et al. 2004) and human breast cancer cells (Simboli-Campbell et al. 1997). Inhibition of angiogenesis
Angiogenesis is the process of formation of new blood vessels from existing vasculature and is a crucial step in continued tumor growth, progression, and metastasis (Folkman 1995). VEGF is the most potent stimulator of angiogenesis. PGs, as discussed below, are also important pro-angiogenic factors. The initiation of angiogenesis is controlled by local hypoxia, which induces the synthesis of pro-angiogenic factors that activate signaling pathways leading to the structural reorganization of endothelial cells favoring new capillary formation (Sakamoto et al. 2008). Stimulation of angiogenesis in response to hypoxia is mediated by hypoxia-inducible factor 1 (HIF-1), which directly increases the expression of several pro-angiogenic factors including VEGF (Giaccia et al. 2003, Rankin & Giaccia 2008). Early studies indicate that calcitriol is a potent inhibitor of tumor cell-induced angiogenesis in experimental models (Majewski et al. 1996). Calcitriol inhibits VEGF-induced endothelial cell tube formation in vitro and decreases tumor vascularization in vivo in mice bearing xenografts of breast cancer cells overexpressing VEGF (Mantell et al. 2000). Calcitriol and its analogs also directly inhibit the proliferation of endothelial cells (Bernardi et al. 2002, Furigay & Swamy 2004, Ben-Shoshan et al. 2007, Chung et al. 2009) leading to the inhibition of angiogenesis.
At the molecular level, calcitriol exerts its anti-angiogenic effects by regulating the expression of key factors that control angiogenesis. Calcitriol reduces the expression of VEGF in several malignant cells including PCa cells through transcriptional repression of HIF-1 (Ben-Shoshan et al. 2007). Furthermore, as discussed above, calcitriol inhibits PCa cell-induced angiogenesis by suppressing the expression of the pro-angiogenic factor IL-8 in an NFB-dependent manner (Bao et al. 2006a). Chung et al. (2009) established transgenic adenocarcinoma of the mouse prostate (TRAMP) -2 tumors in wild-type mice and VDR knockout mice and found enlarged vessels and increased vessel volume in TRAMP tumors in the VDR knockout mice, suggesting an inhibitory role for VDR and calcitriol in tumor angiogenesis. The study further showed increased expression of pro-angiogenic factors such as HIF-1, VEGF, angiopoietin-1, and platelet-derived growth factor in the tumors in the VDR knockout mice (Chung et al. 2009).
Interestingly, another important mechanism by which COX-2 promotes tumor progression is through the stimulation of angiogenesis, and COX-2 inhibitors have been used to block angiogenesis and tumor proliferation (Sahin et al. 2009). The pro-angiogenic effect of COX-2-generated PGE2 might be due to its action to increase HIF-1 protein synthesis in cancer cells (Fukuda et al. 2003). In PCa cells, PGE2 mediates hypoxic effects on VEGF by promoting the translocation of HIF-1 protein to the nucleus (Liu et al. 2002). The selective COX-2 inhibitor NS398 has been shown to suppresses the growth of PC-3 xenografts in vivo by a combination of the direct induction of tumor cell apoptosis and the down-regulation of tumor VEGF, leading to the inhibition of angiogenesis as demonstrated by decreased microvessel density of the tumors (Liu et al. 2000). An immunohistochemical analysis of human PCa specimens by Wang et al. (2005) reveals that increased COX-2 immunostaining is associated with an increased infiltration of T-lymphocytes and macrophages and increased CD31-marked microvessel density, indicating a positive correlation between COX-2 expression and inflammation and angiogenesis. The authors postulate that pro-inflammatory cytokines released by tumor-adjacent inflammatory cells such as T-lymphocytes and macrophages may induce COX-2 in the epithelial cells in prostate atrophic lesions promoting tumor progression (Wang et al. 2004). Suppression of COX-2 expression by calcitriol therefore provides an important indirect mechanism by which calcitriol inhibits angiogenesis, in addition to its direct suppressive effects on pro-angiogenic factors such as HIF-1 and VEGF. It has been suggested that VEGF induction of p38 and JNK pathways is necessary for COX-2 expression in endothelial cells (Wu et al. 2006). As discussed above, calcitriol inactivates the p38 pathway by inducing MKP5 expression. Thus, MKP5 induction and VEGF suppression by calcitriol could further contribute to its anti-angiogenic effects through p38 inactivation.
MMPs promote angiogenesis by mediating the degradation of the basement membrane of the vascular epithelium and the extracellular matrix, thereby creating a passageway in these barriers for the formation of new capillaries (Sakamoto et al. 2008). In human PCa cells, calcitriol decreases the expression and activity of MMP-9 while increasing the activity of its counterpart tissue inhibitor of metalloproteinase-1 (TIMP-1), thereby decreasing the invasive potential of these cells (Bao et al. 2006b).
Inhibition of invasion and metastasis
Calcitriol reduces the invasive and metastatic potential of many malignant cells including PCa cells. The mechanisms underlying this effect include the inhibition of angiogenesis (discussed above) and regulation of the expression of key molecules involved in invasion and metastasis (Osborne & Hutchinson 2002). Calcitriol decreases the tumor size and lung metastasis of the highly metastatic Mat-ly lu and R 3327-AT-2 Dunning PCa cells in vivo (Getzenberg et al. 1997). Calcitriol inhibits the invasiveness and migration potential of metastatic PCa cells such as DU145 and PC-3, due in part to decreasing the expression of 6 and β4 integrins (Sung & Feldman 2000). In PCa cells, calcitriol and its analogs also increase the expression of E-cadherin, a tumor suppressor gene whose expression is inversely correlated to metastatic potential (Campbell et al. 1997). Calcitriol-mediated suppression of MMP-9 activity and increase in TIMP-1 also decrease the invasive potential of PCa cells (Bao et al. 2006b).
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The role of anti-inflammatory effects of calcitriol in PCa prevention and treatment |
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B signaling and tumor angiogenesis suggest that calcitriol exhibits significant anti-inflammatory and anti-angiogenic effects in vitro and in vivo (Fig. 4). Therefore, calcitriol has the potential to be useful as a chemopreventive agent in PCa (Chen & Holick 2003, Banach-Petrosky et al. 2006, Krishnan et al. 2007a,b). Foster et al. have demonstrated that administration of high-dose calcitriol (20 µg/kg), intermittently 3 days/week for up to 14–30 weeks, suppresses prostate tumor development in TRAMP mice (Alagbala et al. 2005, 2006). The efficacy of calcitriol as a chemopreventive agent has been examined in Nkx3.1; Pten mutant mice, which recapitulate stages of prostate carcinogenesis from PIN lesions to adenocarcinoma (Banach-Petrosky et al. 2006). The data reveal that calcitriol significantly reduces the progression of PIN from low-grade to high-grade lesions. Calcitriol is more effective when administered before, rather than subsequent to, the initial occurrence of PIN. These animal studies as well as in vitro observations suggest that clinical trials in PCa patients with PIN or early disease evaluating calcitriol and its analogs as agents that prevent and/or delay PCa progression are warranted. |
Clinical studies of calcitriol in PCa |
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Many academic investigators and pharmaceutical companies have undertaken intense research to develop structural analogs of calcitriol, which exhibit increased anti-proliferative activity and reduced tendency to cause hypercalcemia (Ma et al. 2006, Masuda & Jones 2006). A phase II study in PCa patients with advanced hormone-refractory PCa evaluated the calcitriol analog 1-OH-D2 that had exhibited a reduced calcemic effect but an equal or greater anti-proliferative effect in comparison to calcitriol in preclinical studies (Liu et al. 2003). PSA response was not considered a surrogate marker in this study. Although no objective responses were seen, 30% of the patients experienced stable disease for >6 months, suggesting possible cytostatic activity (Liu et al. 2003). In a phase I/II study of the calcitriol analog 19-nor-1-25(OH)2D2 (paricalcitol) in patients with AIPC, no PSA or objective responses were seen (Schwartz et al. 2005). However, the data suggested that paricalcitol might be beneficial in the reduction of skeletal morbidity (Schwartz et al. 2005). Administration of the VDR agonist elocalcitol (BXL-628) has been shown to arrest prostate growth in patients with BPH (Maggi et al. 2006).
Calcitriol and its analogs have also been tested in PCa patients and in other cancers in combination with various therapeutic agents. Preclinical (Torrance et al. 2000) and clinical studies (Meyskens et al. 2008) on colon and other cancers have successfully used the strategy of combining low doses of two active drugs to achieve a more effective chemoprevention and therapeutic outcome compared to the individual agents (Sporn & Hong 2008). The combination approach would also minimize the toxicities of the individual drugs by allowing them to be used at lower doses while achieving a significant therapeutic effect. Calcitriol is also being used in combination therapy with other agents that may enhance its anti-proliferative activity while reducing its hypercalcemic tendency (Trump et al. 2006, Beer et al. 2007). Trump et al. (2006) carried out a phase II trial in patients with AIPC using high-dose oral calcitriol (12 µg/day 3 times/week) with dexamethasone (4 mg/day 4 times/week), and the results showed a 50% reduction in PSA in 28% of the patients and no hypercalcemia. Another phase II trial tested the combination of calcitriol, dexamethasone, and carboplatin in patients with hormone-refractory PCa and found a PSA response in 13 out of 34 patients (Flaig et al. 2006).
Studies suggest that the addition of calcitriol to chemotherapy drugs might be beneficial in the management of advanced, hormone-refractory PCa (Berry & Eisenberger 2005, Kantoff 2005). The ASCENT I clinical trial in advanced CRPC patients who had failed other therapies studied the administration of a very high dose (45 µg) of calcitriol (DN101, Novacea, South San Francisco, CA, USA), administered once weekly along with the chemotherapy drug docetaxel (Taxotere, sanofi-aventis, Bridgewater, NJ, USA) at the usual regimen in use at the time of that trial (once weekly) compared to docetaxel alone. The results of the trial appeared to indicate that the combination caused a very significant improvement in overall survival and time to progression, suggesting that calcitriol could enhance the efficacy of active drugs in cancer treatment (Beer et al. 2007, 2008). The ASCENT I trial did not meet its primary endpoint, i.e. a lowering of serum PSA. However, based on the promising survival results (16.4 months in the docetaxel arm versus 24.5 months in the docetaxel plus calcitriol arm), a larger phase III trial (ASCENT II) with survival as an endpoint was initiated. A new, improved docetaxel regimen (every 3 week dosing) was used in the control arm of the ASCENT II trial, which was compared to DN101 plus the older docetaxel dose regimen (once a week), resulting in an asymmetric study design. Unfortunately, the improved survival due to the combination demonstrated in the ASCENT I trial could not be confirmed in the ASCENT II trial (Press Release, June 04, 2008, http://novacea.com/). In fact, the trial was prematurely stopped by the data safety monitoring committee after 900 patients were enrolled, when an excess number of deaths were noted in the study arm (DN101 plus old docetaxel regimen) versus the control arm (new docetaxel regimen). This negative result eventually led to the company Novacea ending its DN-101 PCa program.
Another recent study has tested the combination of high-dose calcitriol (DN-101) with mitoxantrone and prednisone in patients with metastatic AIPC without previous chemotherapy, and has concluded that calcitriol did not significantly add to the activity of mitoxantrone and prednisone as assessed by the decline in serum PSA levels (Chan et al. 2008). In a randomized, double-blinded phase II study in a similar patient population, the addition of daily doses of doxercalciferol (1-hydroxyvitamin D2) to weekly docetaxel did not enhance the PSA response rate or survival (Attia et al. 2008). Interestingly, another study testing the effect of the combination of weekly high-dose calcitriol and docetaxel in PCa patients whose disease progressed after first-line chemotherapy using docetaxel alone showed that high-dose calcitriol restored the sensitivity to chemotherapy with docetaxel (Petrioli et al. 2007).
Preclinical observations in prostate cell cultures (Moreno et al. 2005) suggested that a combination of calcitriol with a NSAID would be a beneficial approach in PCa therapy. The combination strategy would allow the use of lower concentrations of NSAIDs thereby minimizing their undesirable side effects. It has become clear recently that the long-term use of COX-2-selective inhibitors such as rofecoxib (Vioxx) causes an increase in cardiovascular complications in patients (Ray et al. 2002, Antman et al. 2005, Graham et al. 2005, Solomon et al. 2006). Very recently, even the use of nonselective NSAIDs has been shown to increase cardiovascular risk in patients with heart disease (Gislason et al. 2009). However, in comparison to COX-2-selective inhibitors, nonselective NSAIDs such as naproxen may be associated with fewer cardiovascular adverse effects (Bombardier et al. 2000, Gislason et al. 2009). Preclinical data showed that the combinations of calcitriol with nonselective or selective NSAIDs were equally effective in inducing synergistic growth inhibition (Moreno et al. 2005). Based on these data, we have recently carried out a single-arm, open-label phase II study evaluating the combination of the nonselective NSAID naproxen and calcitriol in patients with early recurrent PCa (Srinivas & Feldman 2009). Patients in this study had no evidence of metastases. All of the patients received 45 µg of calcitriol (DN-101) orally once a week and 375 mg naproxen twice a day for 1 year. The trial was prematurely stopped after 21 patients had been enrolled when the FDA put a temporary hold on DN-101 based on the preliminary data from the ASCENT II trial described above. The therapy was well tolerated by most patients in the trial. Serum PSA levels were monitored every 2 months. Bone scans were done every 3 months along with ultrasound of the kidney to assess the possibility of asymptomatic renal stones. One patient developed a small asymptomatic renal stone and was removed from the study. He required no intervention for his renal stone. Only four patients showed evidence of progression and they were removed from the study and offered other therapy. Changes in PSA doubling time (PSA-DT) post intervention were compared to baseline PSA-DT values. A prolongation of the PSA-DT was achieved in 75% of the patients suggesting a potential beneficial effect of the combination therapy (Krishnan et al. 2009, Srinivas & Feldman 2009).
The use of calcitriol or various vitamin D analogs in trials in men with PCa has thus far been disappointing. Based on preclinical data from cell culture and animal models showing substantial benefits, the modest efficacy thus far achieved in patients is underwhelming. The most promising study, ASCENT I, using very high doses of calcitriol intermittently (to avoid complicating side-effects) in combination with docetaxel had very encouraging findings since the data showed improved survival and not just changes in the surrogate marker PSA (Beer et al. 2007). However, the expanded follow-up trial, ASCENT II, not only failed to show any benefit but put a shadow over the use of calcitriol for PCa therapy when it was stopped prematurely because of increased deaths in the calcitriol arm. However, the trial was poorly designed with asymmetric placebo and treatment arms. Since the halting of the trial, further analysis (Press Release, September 11, 2008, http://novacea.com/) suggested that the increased deaths in the treatment arm compared to the control arm were not due to calcitriol toxicity, but due to better survival in the control arm that had received the new and improved docetaxel regimen compared to the older docetaxel regimen. Although both ASCENT trials seemed to indicate little problem with toxicity using very high but intermittent doses, the benefits of calcitriol were decidedly unimpressive or nonexistent in the larger ASCENT II trial. Thus, data from clinical studies using calcitriol are not as hopeful as that predicted by epidemiological and preclinical studies. One obvious and major difference in the approaches is that many of the clinical studies including the ASCENT trials were carried out in men with far advanced PCa or in men who had failed all other therapies. This suggests that calcitriol may be better used in early disease and/or in chemoprevention.
However, when used in early disease, an efficacy trial would require very large numbers of subjects and long-term studies to demonstrate improved survival or prolonged time to progression. This has led many trials examining patients with early disease to rely on changes in PSA levels as a surrogate biomarker to demonstrate benefit. There is much discussion in the urology field about whether declines in absolute PSA levels, the rate of PSA rise, PSA velocity, or PSA doubling time are valid indicators of efficacy, and criteria have been established to utilize PSA change as a biomarker of efficacy (Petrylak et al. 2006, Scher et al. 2008). However, in clinical trials in men with early recurrent disease, whose prostates have been surgically removed or irradiated, changes in PSA levels remain a useful although not perfect tumor biomarker. Some studies do show a PSA benefit due to calcitriol by various criteria, at least in some men. Based on the strong rationale from preclinical data and epidemiological studies described in this review on control of inflammation and the many other actions of calcitriol that predict efficacy, it is our opinion that it would be premature to conclude from the limited number of clinical trials completed thus far that calcitriol has little or no efficacy in men with PCa. We need to determine the optimum regimen of calcitriol or its analogs to be used and the time during the course of PCa that is best to intervene. Since calcitriol has mild anti-proliferative and differentiating actions that are more cytostatic than cytolytic, we believe therapy would be most effectively used in chemoprevention or early disease, at the highest dose tolerated without side effects and probably in combination with other drugs.
The epidemiological studies indicating increased risk of cancer in vitamin D deficiency (Giovannucci 2005, Garland et al. 2006) and the high frequency of vitamin D deficiency in the population (Tangpricha et al. 2002) indicate that at a minimum, vitamin D status should be assessed and deficiency should be vigorously treated with vitamin D supplements in men at high risk for PCa or those that have already been diagnosed with cancer. The available data suggest that the likelihood of vitamin D or calcitriol having a beneficial effect in the prevention of PCa development or in treatment of early disease is better than its effects on advanced disease. Therefore, the detection and correction of vitamin D deficiency in the population at large is worthwhile for this and many other reasons. In the future, improved vitamin D analogs with increased efficacy and decreased tendency to cause hypercalcemia may be the best therapeutic option (Ma et al. 2006, Masuda & Jones 2006). However, in the interim until those drugs are developed and become available, treatment with high doses of dietary vitamin D seems to be a safe and worthwhile approach. The prostate expresses 25-hydroxyvitamin D3-1-hydroxylase, the enzyme that can convert circulating 25-hydroxyvitamin D to calcitriol (Schwartz et al. 1998, Hsu et al. 2001, Chen et al. 2003). Thus, dietary vitamin D supplements can lead to local calcitriol production within the prostate where it acts as a paracrine hormone to inhibit prostate growth and perhaps to delay or prevent the progression to cancer (Schwartz et al. 1998, Chen et al. 2003). This seems a worthwhile strategy for a safe and effective approach until new, more potent drugs become available.
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Conclusions |
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). The data suggest that calcitriol has several anti-inflammatory actions in addition to its other well-known therapeutic and cancer-preventive effects in PCa. We conclude that calcitriol or its analogs may have the best utility as chemopreventive agents in PCa and/or when used in early disease. Studies in animal models suggest that calcitriol is more effective when administered before, rather than subsequent to, the initial occurrence of PIN. We believe that calcitriol and its analogs should therefore be further evaluated in clinical trials in PCa patients with early or precancerous disease. The avoidance of vitamin D deficiency should be a goal for reducing the incidence of PCa. Additional trials in men with minimal or early disease, treating with high doses of dietary vitamin D, new potent analogs or, combination therapy may finally demonstrate the promise of benefit of vitamin D in the prevention and treatment of PCa. |
Declaration of interest |
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References |
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Abstract
Introduction
