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Editorial/Mini-Review: Vitamin D and Prostate Cancer

David Feldman

Xiao-Yan Zhao

Aruna V. Krishnan

Department of Medicine Stanford University School of Medicine Stanford, California 94305

Address all correspondence and requests for reprints to: David Feldman, M.D., Department of Medicine, Division of Endocrinology, Stanford University School of Medicine, Stanford, California 94305-5103. E-mail: feldman{at}cmgm.stanford.edu

	Introduction

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In this issue of Endocrinology, Blutt et al. describe the ability of 1,25-dihydroxyvitamin D₃ (calcitriol) to stimulate apoptosis in the human prostate cancer (CaP) cell line known as LNCaP (1). The study raises for discussion the subject of the wide spectrum of actions of calcitriol in CaP and its potential therapeutic use in a number of diseases. Over the past several years, it has become clear that calcitriol exhibits antiproliferative, prodifferentiating, and immunosuppressive properties in addition to its well known actions on mineral metabolism (2). This recent recognition of calcitriol’s expanded range of activities has raised the possibility that it may have utility in the treatment of a variety of malignancies, immune-mediated diseases, psoriasis, and a number of other conditions, including its more classical uses to treat osteoporosis and renal osteodystrophy. The findings of Blutt et al. support an additional mechanism by which calcitriol may have anticancer activity.

Because the therapeutic application of calcitriol is limited by its predictable proclivity to induce hypercalciuria and hypercalcemia, the advent of new therapeutic indications has spawned intense activity by pharmaceutical companies to develop vitamin D analogs with an improved therapeutic index so that the desired activity can be maximized while the tendency toward hypercalcemia can be minimized. Simultaneously, many laboratories have explored two basic and important biological questions: 1) to determine the various mechanisms by which calcitriol can exhibit cancer-inhibiting activity (which is the subject of the paper by Blutt et al.) as well as 2) the physiologic and molecular mechanisms by which analogs of calcitriol can differentially activate various pathways so that anticancer activity can be increased while calcemic activity can be reduced. In this mini-review of the subject, we shall try to touch on the high points of these two areas of vitamin D research but, because of space limitations, we will limit our comments to CaP and often cite recent reviews of this subject and the references therein (3, 4, 5, 6) rather than cite individual reports. In addition, we will begin by summarizing the history of the calcitriol hypothesis for CaP treatment to provide background and conclude by reviewing the clinical studies that have taken place using calcitriol and how we view the future.

	A. Scope of the prostate cancer problem

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Adenocarcinoma of the prostate gland is the most common malignancy in American males, after skin cancer. It is estimated that there will be approximately 180,000 new cases of CaP in the U.S. in 1999, which account for a significant proportion of newly diagnosed malignancies. These numbers are indeed impressive and may actually substantially underestimate the problem because clinically silent CaP is very common. Although CaP is generally a slow growing malignancy, mortality from this disease is nonetheless considerable, and CaP is the second leading cause of cancer death among U.S. males. Because CaP incidence rates increase with advancing age, it is expected that it will become an even greater problem as life expectancy continues to increase.

	B. Historical perspective of vitamin D and prostate cancer

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Epidemiology. Based upon epidemiological studies, several risk factors for CaP have been identified including age, race, and genetic factors (7). The disease has an increased prevalence in African-Americans and reduced prevalence among Asians. Environmental and dietary factors are also implicated in CaP risk. Of particular interest is an hypothesis on the role of sunlight being inversely related to CaP risk and the role of vitamin D (8). Based upon the observation that CaP mortality rates in the U.S. are inversely proportional to the geographically incident UV radiation exposure from the sun, and that UV light is essential for vitamin D synthesis in the skin, a role for vitamin D in decreasing the risk of developing CaP has been suggested. The hypothesis may also offer a potential partial explanation for the increased risk of African American men to develop CaP as a result of their darker skin pigmentation impairing endogenous vitamin D synthesis (2). Data suggesting that lower circulating levels of calcitriol are a risk factor for CaP have been presented; however, some studies do not agree on these findings (3, 4, 5, 6).

Genetics. A number of genetic loci have been linked to CaP risk, particularly in high risk families (7). Relevant to vitamin D and the prostate, it has recently been demonstrated that polymorphisms in the vitamin D receptor (VDR) gene may contribute to the risk of CaP, although not all studies can confirm this finding (5). These are the same polymorphisms that are considered to play a small but significant role in osteoporosis risk (2). The effect of polymorphisms on CaP risk may be the result of differential activity of the variant VDR alleles in transactivation of vitamin D target genes. Investigators have now begun to address the relevance of this observation in CaP as well as in osteoporosis. As in osteoporosis, it is likely that VDR polymorphisms represent one of the multiple polygenic elements contributing to CaP risk.

	C. The prostate as a vitamin D target organ

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Vitamin D receptor. The idea that the prostate represents a vitamin D target organ is supported by the presence of VDR within the epithelial cells of the prostate and the regulation of the expression of a number of prostate genes by calcitriol in both CaP cell lines as well as primary cultures of epithelial and stromal elements derived from normal, BPH, and CaP specimens (3, 4, 5, 6). The affinity of the VDR for calcitriol in CaP is similar to other vitamin D target organs. In all respects, the CaP VDR appears to be identical to the classical VDR.

In vitro studies. The antiproliferative effect of calcitriol on human CaP cells was first demonstrated by in vitro studies often focused on the three commonly used human CaP cell lines, LNCaP, PC-3, and DU 145 (3, 4, 5, 6). Both cell proliferation and clonal expansion assays demonstrate that calcitriol significantly inhibits the proliferation of LNCaP cells as well as primary cultures of CaP cells, has an intermediate effect to inhibit PC-3 cells, but only minimally inhibits DU 145 cells (9, 10). Because apoptosis was not detected in these early studies, it was felt that calcitriol induces cell cycle arrest.

VDR abundance does not correlate with histologic tumor grade, nor does it correlate with differential antiproliferative activity of calcitriol in various cancer cells (9, 10, 11). However, several studies have demonstrated that calcitriol-mediated growth inhibition of CaP cells requires the VDR (3, 4, 5, 6). For example, transfection of a VDR expression vector into the VDR-null JCA-1 cells restores calcitriol sensitivity (4). Conversely, an antisense plasmid for VDR that reduces expression levels of this receptor in ALVA31 cells, in turn, reduces the growth inhibitory effect of calcitriol (12).

With respect to differential cellular sensitivity to calcitriol, the growth of LNCaP cells can be inhibited by calcitriol at modest concentrations, whereas DU 145 cells respond minimally even at high concentrations. Interestingly, growth inhibition can be achieved by treating DU 145 cells with calcitriol in combination with liarozole, which is an inhibitor of P450 enzymes. By blocking the substantial 25-hydroxyvitamin D-24-hydroxylase activity induced by calcitriol in DU 145 cells, liarozole inhibits the rapid inactivation of calcitriol (13). These studies suggest that calcitriol metabolism in target cells contributes to calcitriol responsiveness. Also, studies using cell invasion assays reveal that the invasiveness of DU 145 cells can be inhibited by high concentrations of calcitriol, suggesting an additional mechanism of activity in some cell types (5). Taken together, the in vitro experiments demonstrate that the VDR is required, but not sufficient for potent calcitriol action, and that the growth inhibitory actions of calcitriol involve multiple mechanisms and multiple factors besides the VDR.

	D. Vitamin D analogs

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A number of less calcemic analogs of calcitriol have been synthesized by several pharmaceutical companies and investigated by various groups (2, 3, 4, 5, 6). Selected analogs exhibit enhanced antiproliferative activity with reduced tendency to cause hypercalcemia in vivo. Therefore, these compounds hold great promise for the treatment of a variety of neoplastic and hyperproliferative conditions including CaP. The main biologic effect of calcitriol is to maintain calcium homeostasis, but supraphysiologic concentrations lead to hypercalciuria, hypercalcemia, and renal stone formation. As demonstrated in the clinical trials to be described below, the dose of calcitriol needed to produce an antiproliferative effect appears to be high and difficult to achieve without causing hypercalcemia. Thus, there has been great interest in developing agents that have less calcemic activity and yet maintain the antiproliferative and prodifferentiating activities of calcitriol. The structure-function relationships that determine relative calcemic and prodifferentiating potencies of the vitamin D analogs have been extensively studied (2). Most of the analogs have alterations in the calcitriol side chain, although other modifications in the molecule are also being investigated.

In vitro studies. The various analogs differ in their binding to vitamin D binding protein (DBP) and in their metabolic inactivation pathways, and therefore they vary in their pharmacokinetics and half-life (2). Metabolic products have differences in their agonist activity. At the molecular level, it is clear that modifications in ligand structure cause differences in interacting amino acids within the ligand binding pocket of the VDR, thus causing alterations in the structural conformation of the hormone-receptor complex. Studies of protease sensitivity of the ligand-occupied VDR indicate differences in the ability of various analogs to induce changes in the conformation of the VDR that correlate with activation of the ligand-receptor complex (14). Moreover, enhanced VDR-RXR heterodimerization by analogs has been demonstrated to explain some of their increased potency (15). Although it is generally believed that calcitriol and its analogs act through the same receptor to transactivate target genes, it is clear that conformational changes in the VDR-ligand complex induced by these different analogs in turn determine the particular profile of responsive genes that are activated. This is probably determined by differences in the pattern of the activated VDR complex interacting with tissue-specific co-activators (16). Collectively, these differences in pharmacokinetics, metabolism, structural interaction with the VDR, and recruitment of co-activators to the VDR-ligand complex all appear to act in concert to mediate the dissociation of the calcemic and antiproliferative action of the analogs. However, it should be emphasized that all of the analogs studied to date still have a tendency to cause hypercalcemia if used at high enough doses and the differences between the analogs and calcitriol are of degree and effective dose. However, with a widened therapeutic window, it is hoped that analogs with enhanced antiproliferative activity coupled with reduced calcemic effects will yield clinically useful anticancer agents.

In vivo studies. The analogs, like calcitriol, have shown efficacy both in cell culture experiments and in in vivo animal models. Most in vivo studies have investigated the effects of vitamin D analogs upon the growth of the three human CaP cell lines (LNCaP, PC 3, and DU-145) as xenografts in immuno-compromised mice (3, 4, 5, 6). Although the models are imperfect in their similarity to human CaP, they provide a system to demonstrate the potential of analogs to achieve anticancer activity with reduced tendency to cause hypercalcemia compared with calcitriol. As such, these studies are an important intermediate step between the basic investigation in molecular and cellular systems and the clinical trials in patients discussed below.

	E. Mechanisms of antiproliferative action

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The anticancer activity of calcitriol is in the nature of "differentiation therapy," inhibiting cancer cell growth and promoting a more differentiated phenotype. However, as indicated in the accompanying paper by Blutt et al., calcitriol also induces apoptosis in some CaP cells (1). As we will summarize below, the anticancer activities of calcitriol include multiple and diverse actions extending from cell cycle arrest to inhibition of metastatic potential, effects on angiogenesis, and induction of cell death.

1. Cell cycle arrest. LNCaP cells have been shown to accumulate in the G₁ phase of the cell cycle as a result of calcitriol treatment (17). Regulation of cellular progression from G₁ to S phase is governed by the phosphorylation status of the retinoblastoma (Rb) protein. The hyperphosphorylation of Rb by G₁ cyclins and their cyclin-dependent kinase (CDK) partners leads to the progression of cells from G₁ to S phase. Calcitriol seems to exert some of its effects on this key step in LNCaP cells (3, 4, 5, 6). The accumulation of the cells in G₀/G₁ involves an increase in the expression of the CDK inhibitor p21 and a decrease in CDK2 activity, a decrease in the phosphorylation of Rb, and repressed E2F transcriptional activity (18). However, in DU 145 cells, the lack of a functional Rb is not the critical reason for decreased sensitivity to calcitriol. As noted above, a recent report (13) shows that a combination of calcitriol and liarazole (an inhibitor of 24-hydroxylase activity) elicits a significant growth inhibitory response in DU 145 cells. Also, some analogs are more successful in inhibiting DU 145 cell growth than calcitriol, probably because they are less susceptible to 24-hydroxylase inactivation (19). Thus, alterations in Rb are unlikely to completely explain the major differences in calcitriol-mediated growth responses in various CaP cells.

Studies have shown that the CDK inhibitor p21 is directly regulated by calcitriol in U937 leukemic cells through a putative vitamin D response element in the promoter of the p21 gene (20). However, in LNCaP cells, calcitriol increases p21 protein levels, possibly through translational or posttranslational mechanisms (18, 19). Calcitriol inhibits the growth of PC 3 and ALVA-31 cells without altering cell cycle distribution (18). Consistent with this, there is no change in the expression of p21 in these cells or in PC-3 cells stably transfected with VDR. Collectively these data suggest that the regulation of cell cycle distribution by calcitriol is cell specific and that multiple pathways of action are operative.

2. Differentiation. Calcitriol has been demonstrated to induce differentiation of a number of cell types such as leukemic myeloid cells, monocytic cells, osteoclasts, and small intestinal cells as well as the normal prostate and CaP cell lines (3, 4, 5, 6). Calcitriol treatment of LNCaP cells up-regulates the expression of the androgen receptor (AR) and increases the secretion of prostate-specific antigen (PSA), a differentiation marker for epithelial prostate cells, indicating that calcitriol may initiate differentiation of these cells (21), which decreases cellular proliferation.

3. Apoptosis. Induction of apoptosis has been implicated as an additional mechanism underlying calcitriol-mediated growth suppression of CaP (1). However, this is not a universal response in all cancer cells. In CaP, induction of apoptosis by calcitriol has mostly focused on LNCaP cells and the previous findings have been variable (18, 22, 23). The paper by Blutt et al. in the current issue (1) shows evidence for apoptosis in LNCaP cells treated with calcitriol for 6 days using TUNEL labeling followed by flow cytometric analysis to quantify DNA fragmentation. To explain the earlier negative findings by others (18), the authors (1) raise the possibility that the techniques used might not effectively analyze the poorly adherent and floating cells that are more likely to show apoptosis.

In addition, the Blutt et al. study shows down-regulation of the levels of Bcl-2 and Bcl-X_L proteins that are antiapoptotic factors (1). However, a decrease in the expression of the Bcl-2 proto-oncogene does not necessarily result in apoptosis. For instance, in HL-60 leukemic cells, calcitriol caused a reduction in the levels of Bcl-2 messenger RNA (mRNA) and protein even though the cells became more resistant to death by apoptosis (24). Blutt et al., however, proceed to demonstrate the involvement of Bcl-2 in calcitriol-mediated apoptosis by stably over-expressing the Bcl-2 gene in LNCaP cells (1). In the LNCaP-Bcl-2 cell line, calcitriol does not induce apoptosis, and there is also a reduction in the number of cells arrested in G₁ after calcitriol treatment. Thus, both the growth inhibitory and pro-apoptotic actions of calcitriol in LNCaP cells seem to involve the down-regulation of Bcl-2. Overall, the data indicate that the effect of calcitriol on apoptosis is cell specific, and in LNCaP cells, both growth arrest and apoptosis are stimulated.

4. Growth factors. Several growth factors, including epidermal growth factor, keratinocyte growth factor, basic fibroblast growth factor, and insulin-like growth factor (IGF), play an important role in the regulation of prostate epithelial cell growth by both autocrine and paracrine mechanisms (3, 5). Evidence that calcitriol decreases the availability of IGF to CaP cells by up-regulating the expression of its binding proteins (IGFBP-3 and IGFBP-5) was reported in PC-3 cells and HPV-transformed CaP cells (5, 6). On the other hand, calcitriol induces transforming growth factor-ß in PC-3 cells, which is known to inhibit the growth of epithelial cells. Transforming growth factor-ß may thus mediate some of the growth inhibitory action of calcitriol in these cells (3, 5).

5. PTH-related peptide (PTHrP). PTHrP has been demonstrated in clinical specimens of prostate carcinoma and CaP cell lines (3) and may play a role in prostate growth and differentiation. It may also be an important mediator of osteolytic bone metastases. Although calcitriol inhibits PTHrP expression in a number of cell types, calcitriol does not regulate PTHrP mRNA levels in primary cultures of human prostate epithelial cells derived from BPH or carcinoma despite the presence of VDR in these cells (3). However, PTHrP has been shown to stimulate growth in several prostatic epithelial cell lines, suggesting a role for PTHrP in prostatic cell growth.

6. AR regulation. The AR mediates the physiological actions of androgens that are involved in the development, growth, and progression of CaP. Several lines of evidence indicate significant cross-talk between calcitriol and androgen signaling in CaP cells (21, 22). For instance, calcitriol treatment of LNCaP cells increases AR gene expression at both the mRNA and protein levels (21). As a result, the secretion of PSA by these cells is synergistically enhanced by a combination of calcitriol and the androgen dihydrotestosterone. Moreover, the pure AR antagonist Casodex effectively blocks the antiproliferative action of calcitriol in LNCaP cells. This study suggests that calcitriol actions in the LNCaP cell line are androgen-dependent. This androgen-dependent mechanism may be specific to LNCaP cells because calcitriol also inhibits the growth of other CaP cells that do not express the AR (3, 4, 5, 6).

7. Other actions. Additionally, calcitriol has a number of different actions that provide potential anticancer activity. Calcitriol inhibits telomerase activity by reducing hTERT mRNA expression during the induction of leukemia cell differentiation, indicating that calcitriol may change the life span of cells in culture (25). Also, calcitriol and its analogs stimulate E-cadherin, a tumor suppressor gene whose expression suggests a more differentiated phenotype and a reduced metastatic potential (19). Recently, calcitriol also has been shown to be a potent inhibitor of angiogenesis (26). It has been reported that calcitriol and its analogs inhibit embryonic angiogenesis in chicks, and tumor-cell-induced angiogenesis in mice as well as retinoblastoma angiogenesis in transgenic animals. In vivo, calcitriol might inhibit tumor growth and progression by its antiangiogenic activity, and this needs to be tested in CaP.

	F. Clinical studies

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Because of the importance of CaP and because of the relative safety of vitamin D therapy compared with alternatives, investigators have begun clinical trials to evaluate the role of calcitriol and its analogs in the treatment of patients with CaP. Osborn et al. (27) reported a small phase II trial of calcitriol in 13 patients with hormone refractory metastatic prostate carcinoma. No objective responses (>50% reduction in PSA or >30% reduction in measurable tumor mass) were observed and median time to progression was 10.6 weeks.

Gross et al. (28) used increasing doses of calcitriol to treat 7 patients with early recurrent CaP following x-ray therapy or prostatectomy. The patients under therapy had no evidence of metastases and the only sign of recurrent disease was a rising level of PSA. The doubling time of PSA after calcitriol was compared with the doubling time at baseline. In 7 of 7 patients, the rate of PSA rise was substantially decreased by calcitriol. This was the first evidence that vitamin D could be effective in slowing the progression of CaP in patients.

Another important finding in both clinical trials was the rather high incidence of hypercalciuria or hypercalcemia and the development of renal stones in some patients (27, 28). This finding underscores the fact that hypercalcemia constrains the maximal dose of calcitriol that may be given safely and limits its therapeutic benefit that may only be realized at very high doses. As discussed above, numerous analogs of vitamin D have been developed that are less calcemic and more antiproliferative than calcitriol and these agents are attractive candidates for the treatment of CaP. Currently a multicenter trial is in progress employing the less calcemic and more potent calcitriol analog EB-1089.

	G. Future directions and conclusions

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The role of calcitriol as an antiproliferative, prodifferentiating, and proapoptotic agent has been established in a variety of cell types including CaP. Among the many challenges facing investigators is the complete determination of the mechanisms of calcitriol-mediated anticancer activity and in particular identifying the calcitriol-regulated genes that are important in controlling cell growth, differentiation, and apoptosis. Another related challenge is to fully understand the mechanisms by which the various vitamin D analogs maintain potent anticancer effects yet are less calcemic. Progress in these areas will hopefully pave the way to rational drug design that might lead to the development of more potent and safer anticancer agents. Although clinical studies have begun to address the role of calcitriol in treating patients with CaP, hypercalcemia remains a major limiting factor to efficacy. Therefore, the less calcemic analogs provide an appealing alternative to calcitriol. A second approach is the use of combination therapy because addition of a second effective agent such as retinoids or suramin to calcitriol or one of its analogs has already been demonstrated to exhibit enhanced antiproliferative activity (5, 29, 30).

In conclusion, the vitamin D analogs take advantage of diverging pathways to produce more of an antiproliferative response while causing less of a calcemic response. The expanded role of stimulating apoptosis, as raised in the accompanying paper by Blutt et al. (1), opens additional opportunities for anticancer therapy that remain to be investigated. We believe that calcitriol and its analogs hold great promise as an important addition to the therapeutic arsenal available for the treatment of CaP.

Received November 9, 1999.

	References

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