The Effects of Dietary Factors On The Androgen Receptor and Related Cellular Factors in Prostate Cancer

Current Medicinal Chemistry, 2004, 11, 909-923
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The Effects of Dietary Factors on the Androgen Receptor and Related Cellular Factors in Prostate Cancer
Charles Y.F. Young*, Aminah Jatoi, John F. Ward and Michael L. Blute
Departments of Urology, Medical Oncology, and Biochemistry and Molecular Biology, Mayo Medical Graduate School and Mayo Graduate School, Mayo Clinic/Foundation, Rochester, Minnesota, 55905, USA
Abstract: It has been strongly suggested that androgens and the cognate receptor (AR) may play important roles in the development and progression of prostate cancer. The AR is a transcription factor consisting of three major domains, i.e., N-terminal transactivation, middle DNA binding, and C-terminal steroid binding domains. Molecular events of androgen induced activation of the AR include conformation change, phosphorylation, acetylation, genomic DNA binding, and co-regulator recruiting. Many of these events can be manipulated in certain prostate cancer cells in favor of their progression. Dietary compounds and certain herbs have recently drawn a great deal of attention because of their relevance to development of several cancers including prostate cancer. We discuss in depth the findings from our and other laboratories of effects of dietary factors or herbs on the function of the AR and potential mechanisms on expression of the AR and AR regulated genes. We further discuss the potential implication of these dietary chemicals on prevention of development and progression of prostate cancer.
Keywords: androgen receptor, prostate cancer, dietary factors, phytochemicals, herbs. 1. INTRODUCTION The most common malignancy in men, prostate cancer is a formidable disease, responsible for over 30,000 deaths a year in the United States [1]. Such high rates of morbidity and mortality have spurred efforts to understand the clinical and biological aspects of this malignancy, especially as they pertain to the androgen receptor (AR) and its modulation. An evolving androgen-based hypothesis suggests that prostate cancer occurs as a result of an ongoing androgen onslaught that drives prostate cell proliferation, a process that allows for random genetic errors that eventually lead to malignant transformation. For example, in rats, Noble found that prostate adenocarcinoma leaped from a spontaneous development rate of 0.45% to a development rate of 20% after prolonged exposure to testosterone [2]. Consistent with this androgen-based hypothesis, androgen blockade provides an initially effective therapeutic strategy with 75% of patients with metastatic disease manifesting a tumor response with its use [3]. With time, however, and to complete this continuum, the cancer eventually becomes androgen independent, or refractory to hormonal manipulation, thus portending a median survival of only 2-3 years [3]. This androgen-based hypothesis provides the scientific infrastructure for a variety of epidemiological observations that discuss the etiology of prostate cancer. Not all studies are consistent, and admittedly epidemiologic studies suffer from the challenge of distinguishing between casual
*Address correspondence to this author at the Departments of Urology, Medical Oncology, and Biochemistry and Molecular Biology, Mayo Medical Graduate School and Mayo Graduate School, Mayo Clinic/Foundation, Rochester, Minnesota, 55905, USA; E-mail: youngc@mayo.edu 0929-8673/04 $45.00+.00
associations and cause-and-effect ones. However, some trends emerge, as recently reviewed by Kristal [4]. Dietary fat content may directly increase prostate cancer risk [5]. High amounts of dietary fat purportedly lead to greater androgen exposure within the prostate, thus predisposing to cancer. Similarly, high meat intake and total energy intake also appear to predispose to carcinogenesis [6, 7]. Carrying a presumed protective effect, such dietary factors as lycopene, cruciferous vegetables, selenium, soy, and vitamin E may either potentially inhibit the AR or scavenge free radicals to prevent random genetic errors [4]. The foregoing androgen-based hypothesis also takes into account emerging knowledge of genetic alterations as they pertain to prostate cancer. Although inherited prostate cancer constitutes only a small minority of incident cases, estimated recently at 5-10% by Bratt [8], genetic polymorphisms, coupled with such dietary factors as noted above, likely account for a far greater percentage. Several polymorphisms have been cited as predisposing to prostate cancer, and consistent with the hypothesis advanced above, either directly or indirectly impact on either the hosts hormonal status or the hosts ability to suppress random genetic errors. The AR gene itself is directly impacted. Shorter versions of the AR gene appear to make the receptor more functional, or more sensitive to the presence of androgens, thus predisposing to prostate cancer development. Again, not all studies are consistent, but Ingles and others recently described a case control study with 57 prostate cancer patients and 169 non-cancer controls [9]. Participants were genotyped for CAG repeats within the AR gene, and this shortened AR polymorphism was associated not only with prostate cancer development but also with a more aggressive form of the disease: adjusted odds ratio for cancer risk 2.10 (95% confidence interval 1.11, 3.88). Similarly, modulation
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of androgen itself is effected by polymorphisms that participate in its metabolism. 5 alpha reductase type II converts testosterone to dihydrotestosterone. The latter magnifies hormonal signals that are mediated by testosterone. Again, studies have not been consistent, but some suggest that polymorphisms for this enzyme are associated with altered risk for prostate cancer. For example, one polymorphism for the gene that encodes the 5 alpha reductase type II polymorphism involves a substitution of alanine with threonine at codon 49. Associated with increased activity of 5 alpha reductase type II activity, some data suggest that this polymorphism might be associated with increased risk for prostate cancer [10, 11]. Along similar lines but aimed more at controlling random genetic errors, a multitude of epidemiologic studies have examined the genes involved with the cytochrome 450 enzyme system, some of which activate and others of which deactivate a variety of chemicals and hormones potentially involved in carcinogenesis. These studies have examined such genes as CYP1A1, CYP2D6, CYP17A2, CYP3A4, GST, and NAT1 [12-117], with studies again being provocative but not definitive in their ability to establish the role of these polymorphisms in defining prostate cancer risk. Taken together, however, the above androgen-based hypothesis lays the groundwork for understanding risk factors associated with prostate cancer and provides a framework for referencing hormonal and dietary factors in terms of their contribution to prostate cancer risk. 2. THE BIOLOGICAL FUNCTIONS OF THE ANDROGEN RECEPTOR AND THE DEVELOPMENT AND PROGRESSION OF PROSTATE CANCER Androgens play important roles in male sexual differentiation and development. Androgen action is mediated by the AR, a ligand dependent transcription factor of the nuclear receptor superfamily [18-20]. Testosterone and 5 alphadihydrotestosterone (DHT) are the two most important androgens exhibiting their tissue specific actions by the same AR. Mutations that totally disrupt AR function cause the well known testicular feminizing syndrome or complete androgen insensitivity syndrome of individuals with a 46 XY male genotype. Other mutations in the AR gene also result in a wide spectrum of milder insensitivity syndromes including ambiguous genitalia in newborn infants, and 'idiopathic' male infertility in otherwise normal males [19-22]. Polymorphisms in a trinucleotide repeat (CAG) tract, encoding a polyglutamine stretch in the Nterminal domain of AR associated with increased risk of defective spermatogenesis and undermasculinization as well as bulbar muscular-atrophy with an increase in the length of the CAG tract [21, 23]. Interestingly, shortening the CAG tract might have an association with an increasing risk of prostate cancer [9]. The prostate, a male sex accessory gland, requires DHT and the cognate receptor (AR) for its development and function [18-20]. Androgens/AR are also important players for the development and progression of prostate cancer [18, 20, 22]. Excessive androgens could be risky for early phase of the cancer development (22-24). Androgen deprivation
induces regression of prostate tumor due to programmed cell death and is usually the first line of treatment for patients with advanced prostatic carcinoma. This treatment is no longer effective when patients develop hormone-resistant or hormone-independent cancer cells [3]. Intriguingly, strong evidence suggests that the AR can still mediate recurrent tumor growth after androgen deprivation therapy. This is because amplification and mutations of the AR gene in conjunction with aberrant expression of some of AR coregulators and/or growth factors that facilitates the activation of AR in response to low levels of androgens or to nonandrogenic transducers [25-29]. Understanding the mechanisms that induce the aberrant transactivation abilities of AR may help find more efficient means for fighting prostate cancer. 2.1 The Function Domains of the Androgen Receptor The AR gene is located at chromosome Xq11-12 and contains 8 exons spanning approximately 90 kb in length [18, 19, 29]. The eight exons encode several major functional domains such as the transactivation domain at Nterminal half, comprising exon 1, the DNA binding domain, comprising exons 2 and 3, and the steroid binding domain (SBD), which comprises part of exon 4 and exons 5-8 of the carboxy terminus. The small area located between DNA domain and SBD is the hinge region. 2.1.1 Transactivation Domain The transactivation (N-terminal) domain of AR plays an important role in gene activation specificity and regulates the expression of these genes by interacting with accessory or co-regulator proteins [26, 27]. This domain has approximately 500 amino acids in length and its transactivation function mainly resides within amino acids 1-338. This N-terminal domain may also posses transrepression function and enhancement of DNA binding activity [30]. Moreover, two motif sequences, FXXLF and WXXLF, residing at amino acids 23 to 27 and 437 to 433, respectively, have been shown to interact with the steroid binding domain to stabilize the androgen-AR complex during its transactivation [31]. Intriguingly, polymorphism of the homopolymeric stretches of glutamine residues encoded by the trinucleotides, CAG, as described above [32, 33] in this domain also plays a role in prostate cancer. Although the biological function of this motif is not clear. it has been show that deletion of this CAG repeats can enhance transactivation [34]. It has been shown that the expansion of this CAG repeat decreases the binding to AR by an AR coactivator, a nuclear G-protein/ARA24 and reduce coactivation activity of ARA24 [35]. Recent genetic epidemiology studies reported that shorter CAG repeats may be correlated with an increased risk of prostate cancer [32, 33]. There are ethnic differences in the incidence of prostate cancer. African descent men have prostate cancer incidence twice more than white men. One of the possibilities for the ethnic difference in incidence of prostate cancer is because of short CAG lengths in the receptor. Short CAG alleles were noted to be most common in men of African American descent who are at higher risk of developing prostate cancer. Asians do not show short CAG alleles. In white population
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the presence of short CAG allele is intermediate and therefore have an intermediate risk of prostate cancer. On the average African-American have 18 repeats, Whites 21 repeats and Asians 22 repeats, the lowest in risk for prostate cancer [29, 32, 33]. 2.1.2 DNA Binding Domain Binding to a specific DNA motif sequence or an androgen responsive element or ARE is necessary for AR to control gene expression [36, 37]. A typical ARE contains a palindronic sequence to which AR binds as a homo-dimer in an antiparallel orientation and a cooperative fashion [36, 38]. The DNA binding domain is located at the carboxy terminal of the N-terminal (or transactivation) domain and contains a highly conserved sequence. It consists of approximately 70 amino acids with 20 invariant amino acid residues that form two zinc finger DNA binding motifs, providing the basis for the protein-ARE DNA binding interactions [18, 20]. Eight of the nine conserved cysteine residues in this domain interact in coordination to form two separate tetrahedral metal binding complexes or fingers. The four cysteine residues in each finger bind one zinc molecule, permitting interaction with the DNA. Amino acids adjacent to the cysteine define the specificity of binding the cognitive response elements. The functional role of the second zinc finger is less defined. It is suggested that it aids in the stability of the binding of the protein to the DNA. 2.1.3 Steroid Binding Domain SBD is critical for inducing AR function. Ligand binding to this domain induces the conformation change of the entire AR molecule, causing dissociation of heat shock protein complex [39], dimerization and phosphorylation and finally ARE binding and co-factor recruitment [27, 30, 40]. In addition, it has been suggested that there are two regions (amino acids 715 to 730 and 881 to 887) in SBD that are contributed to transactivation function of the receptor [41]. The latter region or AF-2 activation domain mediates an in vivo ligand dependent functional interaction between the AF-2 the NH2-terminal domain. This interaction might be either direct or indirect, requiring additional factors such as coactivators TIF2 and SRC-1 [41, 42]. AR has a higher affinity for DHT than for testosterone, and the AR-DHT complex is more stable than AR-testosterone complex. Hence trans-activational potential for DHT is much higher than for testosterone [43]. Deduced from crystal structure studies of several nuclear receptor ligand binding domains, a large hydrophobic cavity was predicted to form the ligand binding pocket of AR, comprised of hydrophobic amino acids between approximately 735 and 787, and 855 and 865 [44]. Many mutations identified in AR SBD is of clinical significance as they broaden the binding specificity and/or affinity of the AR to progesterone, glucocorticoid, estrogens or those weak adrenal androgens as well as reverse the antagonistic effect of antiandrogens causing drug resistant or dependent cells [45]. Anti-androgens given to patients with mutated AR may stimulate the receptor and increase acceleration potential of androgen independent prostate disease. For these patients, withdrawal of anti-androgens is of significant benefit [46]. A region of amino acids 617 634 (between DNA and ligand binding domains or hinge region) is responsible for AR nuclear localization [30, 47]. The above region functions independent of androgens.
However, there is another nuclear localization sequence (a.a. 722 to 805) resided in SBD, which is androgen dependent. Different degrees of androgen dependence of the nuclear localization have been observed, depending on cell type used for the studies [30, 47]. 2.1.4 Phosphorylation and Acetylation AR is a phosphoprotein. AR contains more than two dozens of potential phosphorylation sites, some of which may be subjected to androgen regulation [48, 49]. Androgen treatment elevates phosphorylation of serines 16, 81, 256, 308, 424, and 650. But Ser-94 appears constitutively phosphorylated. The AR protein undergoes two posttranslational modifications during receptor activation. Firstly, upon synthesis the protein is rapidly phosphorylated to acquire hormone binding capacities and secondly, upon hormone binding an additional phosphorylation occurs during transformation to the DNA-binding transcription activation. On the other hand, phosphorylation/dephosphorylation may influence ligand binding and transcription activation of the mature receptor and hence the expression of androgen responsive genes [48-51]. For example, studies showed that substitution of two proline-directed phosphorylation sites Ser 81 and 94 with alanine had no effect on AR transactivation, whereas substitution of Ser650 with ala reduced 30% of transactivation. Moreover, recent data showed that phosphorylation/dephosphorylation of AR controlled by several kinases/phosphatases via extracellular factors/membrane receptors signaling pathways can activate AR independence of ligands [48-51]. Forskolin (a PKA activator), epidermal growth factor, and phorbol 12-myristate 13-acetate (a PKC activator) increase the phosphorylation of Ser-650. It has been demonstrated that activated Akt/protein kinase B can bind and phosphorylate AR at serines 213 and 791. The AKT activation of AR may contribute to development of a major subset of hormone refractory prostate cancer. In addition, it has been shown that acetylation of AR is also important for AR transactivation in an androgen dependent manner [52, 53]. Tat Tip60 (Tatinteractive protein, 60 kDa) has been shown (54) to be a bona fie co-activator protein for the AR. This co-activator as well as p300 or P/CAF can directly acetylate the AR at a conserved KLKK motif. 2.2 Mutation of AR Protein in Prostate Cancer It has been postulated that AR mutation may have a role leading to androgen-independent growth of prostate cancer cells. So far at least nearly 60 missense AR mutants have been identified in human prostate cancer (see http://www.mcgill.ca/androgendb). T877A mutant is the most frequently described AR mutation in prostate cancer samples and cancer cell lines that can be activated by, besides androgens, nonandrogenic steroids and the antiandrogen, hydrxyflutamide. Other mutations like V715M, V730M, and H874Y can respond to androgens and antiandrogens. A recent study (55) has made efforts to delineate the function of 44 mutant AR, many of which were mot characterized before. AR mutation seems to be rare in untreated early prostate cancer. However, the detected mutation rates are increased in advanced prostate cancer, especially being hormone therapy.
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2.3 Co-regulators for AR and their Roles in Prostate Cancer Up to date, more than two dozens of cellular proteins have been described [26, 27] to be able to physically interact with AR and affect ARs functions. It has been demonstrated that a large number of nuclear receptor-interacting proteins (co-activators or co-repressors) with no specific DNA binding activity are essential components for receptor mediated transactivation. A number of studies demonstrated that co-activators like ARA70, ARA55 and SRC-1 can increase ligand binding specificity of AR [27]. These studies showed that under over expression of these factors the wild type AR can be activated by, in addition to DHT, estrogens and weak adrenal androgens at physiologic concentrations. These novel and exciting findings were somewhat attenuated by the results obtained using ectopic over expression systems. Recently, a study [26] demonstrated that two coactivators, TIF2 and SRC-1 are actually overexpressed in advanced prostate tumors and a hormone refractory human prostate cancer xenograft, suggesting that the co-activator mediated alteration of steroid specificity of AR could actually happen and implicate prostate cancer recurrence after hormone therapy. A very recent study [58] suggested that overexpression of Rho GTPase in prostate cancer cells may induce nuclear localization of the LIM-only co-activator FHL-2 and subsequent activation of the AR. FHL-2 may act as a molecular transducer for non-androgen extracellular cues to cross talk with the AR. Interestingly, recent data showed that beta-catenin [59] and caveolin-1 [60] also play role in AR mediated action in prostate cancer cells. Beta-catenin can link alpha-catenin and the actin cytoskeleton to membrane bound cadherin, an important event for cell-cell adhesion. Beta-catenin is also a key downstream effector in the Wnt/Wingless signaling pathway which has been implicated in oncogenesis. Upon the activation of Wnt/Wingless signaling pathway, betacatenin can enter into nucleus and interact with and activate transcription factors TCF/LEF [61]. Unexpectedly, betacatenin now shows to act as a coactivator for AR and, like SRC1 and ARA70, to broaden steroid binding specificity [58]. Beta-catenin is overexpressed in some prostate tumors. This suggests that beta-catenin may play a role in the development of some hormone refractory tumors [62]. Another surprise is that the membrane associated protein, caveolin-1, evidently becomes a co-activator for AR [60]. Caveolin-1 is a major component of the caveolae membrane domain that is enriched with cholesterol and glycosphingolipid. In lung and breast cancer cell systems, it is suggested that caveolin-1 is a tumor suppressor [63]. However, in prostate cancer, caveolin-1 is thought to have anti-apoptotic activity and to promote tumor progression after hormone therapy [64]. Caveolin-1 is negative in benign or normal prostate tissues but overexpressed in some advanced tumor. Over expression of this protein may seemingly reduce androgen dependence of the cancer cells, this may be because of enhanced androgen sensitivity of AR by caveolin-1 [60]. This is partly because caveolin-1 can directly interact with AR and lower androgen requirement for AR transactivation. However, since caveolin-1 is a membrane associated protein it is not clear if the interaction occurs in the vicinity of the plasma membrane
2.4 Growth Factors/Receptors and AR Activation in Prostate Cancer Several growth factors [65] including epidermal growth factor (EGF), transforming growth factor- (TGF- ), insulin-like growth factor-1 (IGF-1) keratinocyte growth factor, and fibroblast growth factor and can stimulate proliferation of prostate cells. Some of these factors are overexpressed in prostate cancer. In addition, growth factor receptors like HER-2/neu and platelet growth factor receptor are overexpressed in prostate cancer [66]. Deletion mutation of EGF receptor that becomes constitutively activated and oncogenic is found overexpressed in over 60% of advanced prostate cancer [67]. Recent studies demonstrated that these growth factor/receptor systems can activate AR without ligands or enhance AR transactivation in an androgen dependent fashion. Growth factors/receptors influence AR activation via second messenger pathways [66, 68, 69]. Other peptide factors such bombesin, neurotensin, gastrin releasing peptide, and luteinizing hormone-releasing hormone (LHRH) can also activate the AR independent of androgens (70). An important aspect of these findings is that activation of AR by the ligand-independent mechanisms via aberrant expression and activity of growth factors/receptors could lead to androgen independent prostate cancer. HER-2/neu/erbB2, a 185,000 kDA transmembrane glycoprotein, belongs to the EGF receptor family with intrinsic receptor tyrosine kinase activity. Over expression of HER-2, due to gene amplification, is found in 20 30 % of breast and ovarian cancers [66]. In a cell line system and patient cancer tissue studies, it has been suggested that HER-2 expression seems to increase with progression to androgen independence [66]. However, HER-2 gene amplification appears to be rare in prostate cancer. One study [69] showed that HER-2 activates Akt/protein kinase B which in turn binds and activates AR by phosphorylating serine 213 and 791 of AR. Another report demonstrated that HER-2 induces AR transactivation via the MAP kinase pathway by phosphorylating AR at serine 514 [71]. These results seem to suggest that HER-2 uses multi-pathways to activate AR. Another extensively studied example is the interleukin-6 (IL-6) mediated AR activation. IL-6 is a pleiotropic cytokine that can regulate the growth of many cancer cells [72]. It has been shown that IL-6 can activate AR in the androgenindependent manner [72]. IL-6 receptor is expressed in prostate cancer tissues and prostate cell lines [73]. Correlation studies [74] showed the frequent association of high serum IL-6 levels with androgen-independent prostate cancer, implicating the potential role of IL-6/receptor in the progression of the androgen-independent cancer. IL-6 via its receptor can activate two major transducers, STAT3 and MAPK/ERK following the activation of JAK [75]. STAT3 activated by IL-6 mediated phosphorylation binds AR in the nucleus and turns on AR regulated gene expression in either androgen-dependent or -independent manner. The same study further demonstrated that activated MAPK/ERK is not the transducer of IL-6 for AR activation. Interestingly, a different study [76] demonstrated that in some prostate cancer cells HER-2/neu receptor system is required for IL-6 activation.
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3. DIETARY FACTORS AND PROSTATE CANCER Prostate cancer exceeds lung cancer as the most commonly diagnosed cancer in males and is the second leading cause of male cancer death in this country. Although significant improvement in early detection and treatment of prostate cancer has been made in recent years, the mortality rate of the disease still remains high [77]. The initiation and progression of prostate cancer is a complex disease process that involves multiple variables ranging from hereditary causes to environmental influences. Although the exact etiology of this disease still needs to be elucidated, factors such as diet and hormonal status are known to play critical roles in the development, treatment, and prevention of prostate cancer. Several hypotheses have been proposed to explain these observations. Increased genomic instability, either inherent or induced by exogenous agents (mutagens or carcinogens), has been considered as a primary event leading to neoplastic transformation [78]. It is in general agreement that the mortality of prostate cancer in Asian countries may be 10 times lower than that in the west [79]. It has been suggested that frequent consumption of plant foods and other dietary constituents with less animal food products may contribute in part to such low rates of prostate cancer [79, 80]. Increase incidence of prostate cancer is noted in Japanese and Chinese men who migrated from area of low risk to an area of high risk, matching that of the indigenous population within a few generations. Dietary factors may play a role in prostate cancer development and prevention including animal fat, vitamins, minerals, and natural occurring nutrients. Since the central theme of this article is around the androgens and receptor in prostate cancer, we might want to emphasize that our discussion throughout this review article will be more or less restricted to the potential effects of compounds on androgen action in prostate cancer cells. 3.1 Phyto-Chemicals and Herbs 3.1.1 Phyto-Chemicals There are hundreds of phenolic chemicals in the plants used for human foods [81-85]. These plant phenols are present in various fruits and vegetables at relatively low concentration (10 mg/kg or less), but some can be as high as 400 mg/kg. Their functions in the plants are mainly as (i) antioxidants to remove radical species, (ii) antimicrobial and antiviral agents to ward off microbial or viral infections, (iii) food colors and (iv) building-blocks for plant cell structures (89, 91). It is believed that the anti-cancer effects of these plant phenols are largely due to their antioxidant activities. Recent studies [81, 82] have demonstrated that these compounds have broader biological effects in animal and human systems. These effects include growth inhibition, apoptosis, inhibition of protein kinase and topoisomerase activities, activation (as ligands) of the estrogen receptors, inhibition of enzyme activities involved in metabolisms of steroid hormones and arachidonic acid. Plant phenols include three major groups, i.e., (i) simple phenols and phenolic acids, (ii) hydroxycinnamic acid derivatives and (iii) flavonoids [82, 84]. The simple phenols
contain monophenols such as p-cresol in raspberry and blackberry, 3-ethylphenol and 3,4-dimethylphenol in cocoa beans and diphenols such as hydroquinone. The most common member in hydroxycinnamic acid derivatives is chlorogenic acid, an ester of caffeic acid with the sugar quinic acid, which is the key substrate for enzymatic browning in apples and pears. The flavonoids consist of catechins, anthocyanidins, flavones, flavonoids and their glycosides. Catechins are particularly enriched in tea leaves. The potential utilization of these phenols in the prevention of chronic diseases has been documented. In addition, animal studies and epidemiological studies indicate consumption of plant phenols may help prevent cancers [8186]. It is worthwhile mentioning the potential estrogen-like activities of some plant phenols (or so called phytoestrogens) [84], because evidence began to accumulate that estrogen receptors (ER) may play important roles in prostate cancer development and progression [87-90]. Although the exact role of ER in the prostate and its cancer is still not clear, it has been shown that estrogens/cognate receptors can stimulate or inhibit the in vitro growth of human prostate cancer cells [91, 92]. Neonatal exposure of rats to estrogens (or the neonatal estrogen imprinting) can retard prostate growth and alter secretory function in part due to a permanent decrease in AR expression [93]. The mechanism by which the neonatal estrogen imprint affects AR expression in the adult prostate is not understood. However, no evidence shows that the activated estrogen receptor can directly affect AR expression in the same cells. More recent data show that ER is down-regulated in prostate cancer which may be related to prostate cancer progression [89]. In the past several decades, estrogens have been used in hormonal therapy for prostate cancer. Phytoestrogens such as the soya isoflavones genisten and daidzein, are plant derived non-steroidal oestrogen mimics that are being extensively studied to determine their prevention/therapeutic potential for cancers [86]. Soybean is a well-known legume that contains high levels of phytoestrogens. It contains conjugates of the isoflavonoids, genistein and daidzein. Isoflavonoids, as a weak estrogen, compete with estradiol for binding of ER [86]. In addition, it stimulates synthesis of sex hormone binding globulin (SHBG) in the liver. SHBG binds free testosterone in the serum, therefore, increase in serum SHBG in effect decreases free circulating testosterone [94, 95]. Isoflavonoids also effect 5-[alpha]-reductase, an androgen related enzyme found in prostate that converts testosterone to 5[alpha]-dihydrotestosterone (DHT), a derivative of testosterone that has greater affinity for the androgen receptor in prostate cells. Both genistein and daidzein have shown to inhibit prostate cancer cell growth, lending to their roles as chemopreventive agents. Genistein is a potent inhibitor of tyrosine-kinase, an important enzyme that regulates several growth factor receptors and oncogenes [96]. Studies also indicated inhibitory effects of genistein on endothelial cell proliferation and angiogenesis, two important processes essential in tumor growth, and metastasis [95]. As mentioned above many plant phenols in vegetables and fruits are daily consumed by humans. It is undoubtful that plant phenols as environmental factors will be increasingly encountered in our body due to (i) the awareness
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of benefit of consumption of plant foods to health and (ii) increasing in use of herbs in alternative medicine. However, it is largely unclear what exactly the biological effects of plant phenols occur in cells and tissues. It is important to address the potential utility and the molecular mechanisms of plant phenols for prostate cancer. Three commonly studied plant phenols are described below in more details. Tea is the most commonly used beverage in the world. Active compounds for antitumor effects in tea are mainly tea polyphenols [85, 97]. The major green tea polyphenols (GTP) including (-)-epigallocatechin gallate (EGCG), (-)epicatechin gallate (ECG), (-)-epigallocatechin (EGC), (-)epicatechin (EC),(+)-gallocatechin (GC) and (+)-catechin constitute up to 30% of the dry green tea leaf. Theaflavins, a major component in black tea, is also an active polyphenol. However, EGCG is the most active anticarcinogensis compound among tea catechins tested [88, 97]. Tea mediated inhibition of tumorigenesis by various carcinogens has been attributed to (i) its ability as a competitive inhibitor for enzymes involved in activation of various carcinogens, (ii) its antioxidant activity to scavenge reactive oxygen species or (iii) its ability to increase activities of Phase II detoxifying enzymes [85, 97]. Recently, it has been reported [98, 99] that EGCG can bind and block proteolytic activity of urokinase which plays an important role in spreading of cancer cells. More recently, it has been suggested that EGCG and other tea polyphenols can inhibit tumor promoter (e. g., phorbol ester)-induced AP-1 activities [101, 102]. The activation of AP-1 by tumor promoter plays an important role in tumor promotion. In addition, green tea polyphenols can inhibit cancer cell growth in vitro [100, 101] by arresting cells at G1 phase. At high concentrations (over 200 uM), it induces apoptosis [102-104]. EGCG can differentially modulate the expression and/or function of nuclear factor kappa B in some cancer cells [105]. While we are studying the molecular mechanism of tea polyphenol effects on androgen action, Gupta S. et al. [106] have shown that tea polyphenols can inhibit the androgen up-regulation of ornithine decarboxylase in vivo, suggesting that tea polyphenols may exhibit repression effects on in vivo androgen action. However, mechanisms by which these substances exhibit their anti-androgen activity were not described in this study. A more recent study [107] showed that the i.p. administration of EGCG can modulate endocrine system of rats by lowering several circulating hormones, and reducing body weight and the size of the prostate and others organs. Moreover, a recent survey study reported that, among several beverages consumed, only drinking tea can significantly reduce the risk for prostate cancer [108]. Elucidating molecular mechanisms of antiproliferative and cancer-preventive activities of GTP and its components may help us design more effective means for preventing and combating cancer. Finally, we need to keep in mind that these so called tea polyphenols also exist in many plants consumed by humans. Quercetin is one of the most abundant, naturally occurring flavonoids. It has been estimated that about 25-50 mg of quercetin are consumed from the daily diet. Quercetin, like other flavonoids, displays a wide range of pharmacological properties including anti-inflammatory, anti-mutagenic, anti-carcinogenic and anti-cancer effects. The flavonoid intake has been linked to the prevention of human
diseases including cancer. The chemopreventive effect of quercetin on dietary carcinogen has been intensely studied in animal models. It has been shown that quercetin suppresses benzo[a]pyrene (B[a]P)-induced DNA damage in human Hep G2 cells by inhibiting cytochrome P-450 1A1 (CYP1A1) gene expression [109]. On the other hand, quercetin can also increase the expression of CYP1A1 gene in different cell types [110]. However, knowledge regarding the molecular mechanism is still limited. Immunocytochemical and northern blotting studies have revealed that quercetin reduced the steady state levels of p21-ras proteins in both colon cancer cell lines and primary colorectal tumors [111]. Quercetin may affect the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase9 (MMP-9) and the function of EGFR [112]. Studies showed that both quercetin and soya isoflavone genistein down-regulated cytoplasmic ER levels and promoted a tighter nuclear association of the ER in a breast cancer cell line [113]. Apparently, the mechanisms by which these two phytochemicals affect estrogen action are different. In in vitro binding experiments, genistein competed with oestradiol for binding to the ER, but quercetin did not [113]. Other study also indicated that quercetin has little ER binding activity. Resveratrol (3,5,4-trihydroxy-trans-stilbene), a natural non-flavanoid phenol product found in at least 70 plant species, has significant anti-cyclooxygenase (COX) activity [114]. The anti-COX of resveratrol may be relevant to cancer chemoprevention since COX can catalyze the conversion of arachidonic acid to prostaglandins, which may stimulate tumor cell growth. COX can also activate carcinogens to damage DNA. Resveratrol also induces phase II enzymes, e. g., quinone reductase, which are capable of metabolically detoxifying carcinogens. Resveratrol may also inhibit the activation of the I kappa B kinase [115]. As mentioned, like some other plant phenols, resveratrol exhibits weak estrogen activities and/or estrogen antagonist activities via ER [116, 117]. This phytoestrogen property may be beneficial for preventing/treating estrogen related tumors [113, 117]. Resveratrol can be found in common food components such as peanut, mulberries, grapes and among others. The concentrations of resveratrol in fresh grape skin can be as high as 50 to 100 ug per gram. A recent study [114] suggested that resveratrol exhibits cancer chemopreventive activity on carcinogen-treated mouse mammary glands and a mouse skin cancer model. More recent studies [118, 119] including ours also indicate that resveratrol may have antiprostate cancer properties. In summary, plant phenols represent a large group of dietary factors with some extents of similarity in chemical structures and biological activities. Many of these compounds may exhibit anti-tumor activities which are in part attributed to their antioxidant properties. However, they also show many diversified biological activities, relatively depending on cell types. Their biological activities on prostate cells are largely unknown. One important issue is the bio-availability of these polyphenols in vivo. In vivo concentrations of major forms of polyphenols after maximal oral administration in humans and experimental animals have been surveyed to certain extents and appear to be relatively low when compared to the effective doses found in vitro (82), however, their in vivo anticancer effects are quite
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comparable to that predicted by in vitro studies with low concentrations [82, 85, 102, 114]. As mentioned above, tea polyphenols seem to be able to modulate in vivo androgen action [107, 120] and to reduce the size of the normal prostate [107]. However, further studies to resolve the issue regarding this in vivo bioavailability are necessary. 3.1.2 Effects of Phytochemicals on the AR and its Gene Regulation Androgens via their nuclear receptor (AR) may be involved in the development and progression of prostate cancer as mentioned above. Recently, inhibition of AR function has become the focal point in the study of prostate cancer treatment and prevention. Animal studies using the transgenic adenocarcinoma of the mouse prostate (TRAMP) model showed that flutamide, an anti-androgen agent, has the ability to suppress T-antigen-driven carcinogenesis by androgens, resulting in significant reduction in the incidence and an increase in the latency period of cancer development [121]. In a case control study comparing two groups of prostate cancer patients matched for age and stage of disease, a marked decrease in the prevalence and extent of high-grade intraepithelial neoplasia was noted in the prostatectomy specimens of patients receiving pre-operative androgen deprivation therapy compared with untreated patients [122]. Finasteride, a 5 -reductase inhibitor, is currently being investigated as potential chemopreventive agent in an ongoing 10-year clinical trial, the Prostate Cancer Prevention Trial [123]. The difficulty in treating patients with advanced prostate cancer is that despite initial tumor regression with hormone deprivation, prostate cancers usually relapse within 1-2 years [124]. Various molecular mechanisms have been proposed that might be responsible for the development of recurrent hormone-refractory disease. It is hypothesized that alterations in the function of the AR and its complex signaling pathways are involved in progression of hormone refractory state [125] as mentioned above. Analysis of prostatic tissue from patients revealed that nearly all cancer tissues retain AR expression regardless of patients clinical stage or hormone status [126]. Majority of tissue expresses the androgenresponsive prostate-specific antigen (PSA) gene, indicating that AR signaling pathway remains functional. Moreover, amplification of the AR gene was detected in a subgroup of patients with tumor progression [9, 32, 33]. Mutations within AR were noted, enabling AR to response to residual androgens, non-androgen steroids or even antagonists [26]. In some cases, it is observed that AR can be activated by growth factor and cytokine, independent of its native ligands [65]. All of the above suggests potential causative factors for tumor relapse and progression. Therefore, therapies that solely target androgens ultimately fail in treating advanced prostate cancer. One potentially effective treatment strategy against prostate cancer is by minimizing or eliminating AR. Studies of ribozymes that cleave AR mRNA were performed in evaluating their role in prostate cancer treatment. They are capable of reducing AR protein levels; thereby decreasing androgen related cell growth [127]. Another strategy involves DNA oligonucleotides. Decoy double stranded DNA oligonucleotides are designed to compete with AR for binding on androgen-receptor element (ARE) in the
regulatory region of the target gene, this method has shown promise in inhibiting prostate cancer cell growth [128]. In order to identify natural occurring substances as inhibitors of AR, we conducted studied that involved various compounds, such as tea polyphenols, resveratrol, quercetin, and silymarin [118, 129, 130, 131]. Green tea, one of the most consumed beverages in the world, contains many polyphenolic antioxidants. Epidemiological observations and research in recent years revealed green tea consumption to be inversely associated with cancer rate. The effectiveness of green tea is attributed to it major constituent, polyphenols. Many mechanisms have been proposed for the anti-cancer effects of polyphenols [132]. We were able to demonstrated that (-)-epigallocatechin gallate (ECGC), one of the most potent component of the tea polyphenols, is capable of inhibiting LNCaP cell growth at a relatively low concentration. We found ECGC capable of inhibiting AR expression by reducing its transcriptional activities at its promoter [129]. EGCG also inhibits the expression of the androgen regulated PSA and hK2 genes. Moreover, we found Sp1, an important regulator of AR expression, to be the target of ECGC, i.e., treatments with ECGC decrease the expression, DNA binding and transcriptional activity of SP1 protein. The phytoalexin resveratrol has been extensively studied in its role as a cardio-protective agent. Our study found that resveratrol inhibits LNCaP cell growth and decreases the expression of AR; therefore, decreasing the levels of androgen related proteins. We also noted that treatments with high concentrations of resveratrol caused cell apoptosis and a decrease in p21 levels [118]. Quercetin is an abundant, natural occurring flavonoid that is found in apples, onions, tea, and red wine. In vitro and in vivo studies have shown inhibitory effects of quercetin on different cancer cell lines. Quercetin exhibits anti-neoplastic activities through various mechanisms, including as an antioxidant, its ability to arrest cell cycle, as well as blocking signal transductions within cells [133, 134]. Our experiments shown that quercetin can inhibit androgen action in prostate cancer cells via AR [130]. In addition to inhibiting the expression of PSA and hK2, quercetin also represses the expression of homeodomain transcription factor NKX3.1 and ornithine decarboxylase (ODC), both of which are also androgen-regulated genes. ODC is one of the key regulators in cell differentiation and proliferation. It catalyzes the first and rate-limiting step in polyamine synthesis [135]. It is known that various polyamines putrescine, spermidine and spermine are important for cell differentiation and proliferation. Genistein a major soy isoflavone, has been shown to inhibit prostate cancer cell growth. A recent study (136) showed that genistein represses the expression of the AR in LNCaP cells and consequently inhibit the expression of PSA mRNA and protein. Interestinly, genistein had differential effects on 17-beta-estradiol mediated PSA expressions. Low concentrations of genistein enhanced PSA expression, whereas high levels of Genistein reduce estrogen mediated PSA expression. Silymarin (SM) is a polyphenolic flavonoid found in milk thistle that has been shown to have anti-cancer propert.
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Silibinin (SB), the major component of SM, can arrest cell cycle at G1 phase by altering cell cycle related proteins [137, 138]. In our study (131), we found that the nuclear level of AR is reduced with addition of SM and SB, although total cellular AR levels were not affected by the treatments. In addition, we noted a decrease in FKBP51, a member of immunophilins family. It has been proposed that FKBP51 might act as a nuclear shuttle protein [139], facilitating nuclear transport of steroid receptors; therefore, a decrease in FKBP51 can potentially lead to a reduction of AR in the nucleus. Herbal supplements like Equiguard and PC-SPES (also see the following section) are also known to repress the expression of PSA and the AR. Although it is not clear what the specific chemicals in the herbal extracts are exactly responsible for inhibiting the function of the AR, it may be inferred from other studies that at least some phytochemicals similar to the above phyto-phenols in the herbal supplements could exhibit anti-AR effects. In fact, it has been reported [140] that a flavonoid, baicalin, found in PCSPES, can inhibit ARs function. 3.1.3 Herbs Herbal treatments as alternative options for patients with malignancies have been known for many years throughout the world. There are at least two herbal dietary supplements such as PC-SPES [141, 142] and Equiguard [143] that have been reported to be used by patients against specifically prostate cancer. These two are propriety products comprised of standardized extracts from herbs. PC-SPES is an extract of eight different herbs: Scutellaria baicalensis, Glycyrrhiza glabra, Ganoderma lucidum, Isatis indigotica, Panax pseudoginseng, Dendranthema morifolium tzvel, Rabdosia rebescens, and Serenoa repens, containing numerous bioactive compounds including include phytoestrogens, flavonoids, alkanoids, triterpenes, polysaccharides, and trace elements [142]. Several studies found the in vitro and in vivo efficacy of PC-SPES against prostate cancer partly through its estrogenic activity [141, 142, 144]. In fact, a recent study showed that phytochemical composition of PCSPES varied by lot, and chemical analyses detected various amounts of the synthetic drugs diethylstilbestrol, indomethacin, and warfarin. Other study seemed to dispute its estrogenic effects [145]. A cDNA microarray analysis of gene expression changes in LNCaP prostate carcinoma cells exposed to PC-SPES showed alterations of the expression of 156 genes after 24 h of exposure including the downregulation of the AR and AR regulated genes. In the same study, a comparison of gene expression profiles from PCSPES treatment with a synthetic estrogen exhibited activities distinct from those attributable to diethylstilbestrol. Side effects from administration of PC-SPES have been noticed. The side-effect profile of PC-SPES [141] suggests some oestrogen-like activity similar to that of diethylstilboestrol. Side-effects of PC-SPES include reduced libido, hot flashes, diarrhoea, dyspepsia, leg cramps, nipple tenderness, and gynaecomastia. More life-threatening are pulmonary emboli in 4-5% and deep-vein thrombosis in 2% of patients who might have exceeded the manufacturer's recommended dose. Nevertheless, it has been suggested that the clinical responses to PC-SPES may compare favorably
with second-line hormonal therapy with agents such as oestrogens and ketoconazole. The Equiguard is an extract from nine herbs consisting of Herba epimedium brevicornum Maxim (stem and leaves), Radix morindae officinalis (root), Fructus rosa laevigatae michx (fruit), Rubus chingii Hu (fruit), Schisandra chinensis (Turz.) Baill (fruit), Ligustrum lucidum Ait (fruit), Cuscuta chinensis Lam (seed), Psoralea corylifolia L. (fruit), and Astragalus membranaceus (Fisch.) Bge (root) [143]. In vitro studies [143] demonstrated that the Equiguard extract significantly reduced cancer cell growth, induced apoptosis, suppressed expression of the AR and lowered intracellular and secreted prostate specific antigen (PSA), and almost completely abolished colony forming abilities of prostate cancer cells. More studies may be required for evaluation of the use of this herbal mixture extract. 3.2 Lipids Dietary intake of essential fatty acids including both long chain omega -3 and omega-6 fatty acids is crucial for many important cellular processes including cell proliferation and differentiation [146] The quantity and composition of the fat intake can affect largely biological consequence in the body. Lipid peroxidation could be one of the major sources to cause DNA damage [146, 147]. Epidemiological studies demonstrated a correlation between consumption of fat and death from prostate cancer [146, 147]. Controlled case studies added support to a positive association with dietary fat, particularly saturated animal fat [148], although some controversy exists {149]. A large prospective study of American men showed a positive association between linoleic acid (omega-6 fatty acid) in the diet and prostate cancer [5]. A nested case-control study on plasma lipid levels and the development of prostate cancer suggested that low plasma levels of -linoleic acid might be associated with a reduced risk of prostate cancer [150]. Wang et al [151] showed that lowering the proportion of fat in the diet decreased the growth rate of human prostate adenocarcinoma cells in nude mice. Animal studies indicate that some fatty acids in the diet might influence the development of cancer [152]. In vitro studies showed that the growth of PC-3 human prostate cancer cells is stimulated in the presence of linoleic acid , whereas long chain omega -3 fatty acids (i.e., docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) inhibit in vitro and in vivo cell growth of prostate cancer cell lines [153]. Diets high in omega -6 polyunsaturated fatty acids can stimulate prostate cancer development [154, 155]. There is some epidemiological support for a protective influence of omega-3 fatty acid against prostate cancer [156-158]. In Japan, fish traditionally provides the major source of animal proteins and fat. Fish oil is generally rich in omega-3 fatty acids. Mishina reported that Japenese with a low consumption of seafood was associated with increased prostate cancer risk [157]. Moreover, Alaskan Eskimo men who eat large quantities of fish are at low risk for prostate cancer, suggesting that external factors such as fish oil may have a role in repressing the development and growth of prostate cancer [158]. Our recent study [159] with LNCaP cells showed that both DHA and EPA inhibited androgen-stimulated cell growth, and the expression of multiple androgen-regulated genes e.g., PSA,
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ornithine decarboxylase, NKX3.1 and Drg-1. In addition, we found that proto-oncoprotein, c-jun, was increased by DHA. Studies have shown that c-jun inhibits the formation of ARARE (androgen-receptor element) complex in androgen regulated genes, which may underlie the effects of DHA and/or EPA on ARs function [160]. It is commonly known that meat consumption is associated with elevated cancer risk [146-148]. A diet composed of high meat intake, in combination with physical inactivity, contributes to obesity and metabolic consequences such as increase levels of IGF-1, insulin, estrogen, and possibly testosterone, all of which can promote cellular growth and increase risk of cancer development. One major component of meat is fat which is rich in arachidonic acid. It has been shown that the human prostate cell lines, both LNCaP and PC3 have the ability to convert arachidonic acid into lipoxygenase (LOX) product, 5-hydroxy- eicosatetraenoic acid (5-HETE) [161]. 5-HETE is associated with cell death, when 5-HETE is eliminated, human prostate cells enter apoptosis, while the addition of exogenous 5-HETE reverses this process. Thus, 5-HETE is probably critical in the development and progression of prostate cancer. In fact, several HETEs can be produced by the corresponding LOX for regulating cell proliferation, differentiation or growth inhibition. The roles of LOXs and HETEs may implicate the development and progression of prostate cancer [161, 162]. In addition, diet, especially one containing animal fat, can influence prostate cancer in part by changing the levels of sex steroid hormones [163]. A lowering of urinary androgens and estrogens has been noted in a group of Caucasian and African American men who was fed a diet where the fat content was reduced from 40% to 30% (164). In a separate study of healthy men, it was noted that a diet composed of lower percentage of fat (18.8% vs. 41.0%) was associated with lower serum and urine free testosterone [165]. Fatty acid synthase (FAS) is a key enzyme catalyzing the terminal steps in the synthesis of long chain saturated fatty acids. Overexpression of FAS has been correlated with malignancy of the prostate [166]. Interestingly, FAS is upregulated by androgens in prostate cancer cells [167]. A recent study [168] showed that Akt/protein kinase B can upregulate FAS expression in PTEN inactivated cells. PTEN inactivation that may enhance the activity of Akt/protein kinase B is common in prostate cancer . Although how Akt/protein kinase B can enhance the expression of FAS remains to be further elucidated, previous reports indicated that Akt/protein kinase B may direct interact with and activate the AR [71], which could at least in part account for the overexpression of FAS. In other in vitro and in vivo systems, it has been shown that EPA and DHA can suppress the expression of FAS [169]. Our study [159] showed that EPA and DHA could inhibit AR mediated gene expression, we speculate that inhibiting ARs function might be one mechanism for EPA and DHA to repress FAS expression. 3.3 Minerals and Vitamins 3.3. 1 Vitamin D and Calcium Studies have shown correlations between vitamins, trace minerals and prostate cancer [170, 171]. An inverse
relationship between vitamin D and risk of prostate cancer has been demonstrated in many, if not all, epidemiological studies [172-174]. Binding of D3 (1,25(OH)2 D3 ), the metabolic active form of vitamin D, promotes cellular differentiation while inhibiting proliferation in prostate cancer cells [175]. Even though, it was somewhat surprised, D 3 can up-regulate AR protien as shown in our study and other (176, 177). It remains to be seen whether this AR upregulation will become concern for cancer progression. More serious problem is that toxicity of hypercalcaemia by vitamin D has hampered the intervention evaluation in humans [178]. This has stimulated the development of vitamin D analogues with low toxicity for anti-cancer purposes. Calcium plays an very important biological role as a second messenger in cell proliferation, differentiation and apoptosis. Calcium seems to be able to reduce colon cancer risk [179]. In vitro studies showed that disturbance of subcellular calcium ion distribution may reduce the expression and function of the AR and cause apoptosis in prostate cancer cells [160, 180]. On the other hand, a few studies have shown that a high intake of calcium may increase prostate cancer risk [181, 182]. Since high serum levels of calcium may reduce the levels of vitamin D, it has been hypothesized that the reduced level of vitamin D may be the secondary factor to increase the risk of prostate cancer. However, not every survey study agrees with the above claims that high uptake of calcium correlate the high risk of prostate cancer [183]. Further, a xenograft study did not support that high intake of calcium could enhance tumor growth [184]. 3.3.2 Lycopene, Vitamin A and Vitamin C Vitamin C and A have also been extensively studied for anti-prostate cancer activities [170, 171]. Results from laboratory and epidemiology studies still remain inconclusive for their anticancer ability. Lycopene, one of carotenoids has drawn a great deal of attention for its potential of lowering prostate cancer risk [185]. Lycopene is a carotenoid without provitamin-A activity found in vegetables and fruits, with highest concentration in tomatoes. Recent studies (185-189) demonstrated an inverse relationship between tissue/serum lycopene levels and cancer risk . Results from these studies prompt additional phase II clinical trials to assess the efficacy of lycopene (190). In vivo studies seemed to indicate that the antioxidant activity of lycopene may be able to lower oxidative DNA damage (187). Lycopene can also enhance the expression of connexin 43 in cancer cells, implying that lycopene may reduce the metastasizing ability of cancer cells (190). Furthermore, lycopene treatments could reduce IGF-1, therefore decrease cancer cell proliferation. Serum PSA levels were also decreased by lycopene (187). Since PSA expression is directly regulated by AR, it is not clear whether the decrease in PSA is due to the negative effect of lycopene on AR. 3.3.3 Selenium and Vitamin E Results from epidemiologic studies, laboratory bioassays, and human clinical intervention trials strongly support a protective role of selenium (Se) against cancer development (191-196). The essential trace mineral, selenium, is of fundamental importance to human health [197]. As early as 1916, Se was recognized as a potentially
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significant trace element for human and animals. However, until 1957 it was firmly demonstrated that it is an essential nutrient constituent. Liver necrosis induced by feeding rats a vitamin E deficient diet could be prevented by adding Se [197]. Se has been shown to protect against human diseases such as Keshan disease (an endemic cardiomyopathy) and Kaschin-Beck disease (an osteoarthropathy) and other various disorders involving growth and fertility [197]. One of major roles of Se for anti-carcinogenesis has been suggested due to Se as an essential component of glutathione peroxidase (192, 196). Glutathione as the product of glutathione peroxidase can act as an antioxidant to protect cells from damage by oxygen reactive species. On the other hand, many studies showed that the anti-cancer activities could also be due to non-antioxidant properties of Se [197-201]. Sodium selenite, sodium selenate and organic forms of SE (e.g., seleocystine and selenomethionine are conventional Se compounds as successfully dietary supplements for suppression of rodent carcinogenesis. It has been suggested that methylated Se compounds in plasma derived from the above Se compounds may be the predominant forms responsible for anticarcinogenic effects [197, 198]. Inorganic selenite, inorganic selenate and organic Se compounds can undergo reduction to form hydrogen selenite and become methylated Se compounds. Vitamin E is one of fat-soluble vitamins and has at least eight members in the family including -, -, - and tocopherol and -, -, - and --, tocotrienol. Vitamin E supplements contain mainly -tocopherol. Very recently, -tocopherol is called for attention because it is also a major form of vitamin E in diets as well as in human blood. -tocopherol appears to be a more effective trap for lipophilic electrophiles than is -tocopherol (202, 203). Vitamin E seems to exert many different biological activities that can not be explained simply by its antioxidant property. Vitamin E involves in gene regulation and function in cell growth, differentiation and apoptosis [204]. Intriguingly, a new study [205] showed that vitmin E succinate can reduce the androgen mediated expression of PSA. Further, the expression of the AR was inhibited by vitamin E at the transcriptional and post transcriptional levels. This inhibitory effect was specific to AR not to other nuclear receptors. In multi-institutional, double blind, randomized, placebo-controlled cancer prevention trials, administration of these two antioxidants has resulted in a decline in incidence of prostate cancer, although prostate cancer incidence was only a secondary endpoint in both these trials. First, Clark and others examined 1312 patients with a prior history of skin cancer and randomly assigned them to one of two treatment arms: selenium 200 micrograms/day versus placebo [206]. With 13 cases of prostate cancer in the selenium-treated group, and 35 in the placebo group, this finding suggested that selenium supplementation may play some role in preventing prostate cancer. Second, the Finnish study examined 29,133 male smokers and found that alpha tocopherol at a dose of 50 mg/day appeared to reduce the incidence of prostate cancer with 99 cases in the alphatocopherol-treated group and 151 cases in the group that did not receive this vitamin [208]. These provocative findings
have prompted further investigation into this mineral and vitamin in the ongoing Selenium and Vitamin E Chemoprevention Trial. (SELECT), a study that includes 32,400 men in one of the largest chemoprevention trials ever undertaken. Note, the study of SELECT is only focusing on one form of each kind of supplements (i.e., selenomethionine and -tocopherol). The limitation of this study is that other forms of Se and/or vitamin E are not considered in this study. 3.3.4 Zinc and Cadmium The prostate is one of few tissues/organs to possess the highest Zn content [209]. For normal human prostate, the epithelial cells contain 158-474 ppm Zn and the stroma have 101-180 ppm Zn, wherease in the cancerous tissues, the adenocarcinoma have 89-221 ppm Zn and the stroma with 44-713 ppm Zn. It is not very clear how prostate cells can concentrate high levels of zinc. However, the role of zinc in the prostate just began to be revealed. It was found that prostatic mitochondria can accumulate high zinc levels which in turn inhibit mitochondrial (m-)aconitase activity and subsequent citrate oxidation [210]. This event disrupts the Krebs cycle and markedly decreases the cellular energy (ATP) production normally coupled to citrate oxidation. The study showed clearly that zinc accumulation in citrateproducing prostate epithelial cells is regulated by androgens and prolactin [210, 211]. On the other hand, prostate cancer cells can not accumulate high zinc levels that result in increased citrate oxidation and the coupled ATP production, which could be critical leading to progression of malignancy. If it is true, the concept might offer new approaches to the treatment of the cancer. It has been shown that occupational cadmium exposure is associated with lung cancer [212]. Cadmium was considered as a human carcinogen in 1993. Some evidence also indicate that cadmium exposure may be linked to human prostate cancer [213, 214], Cadmium inhalation in rats caused pulmonary adenocarcinomas, supporting a role in human lung cancer. Prostate tumors and preneoplastic proliferative lesions can be induced in rats after cadmium ingestion. Prostatic carcinogenesis in rats occurs only at cadmium doses below those that induce chronic degeneration and dysfunction of the testes, a well-known effect of cadmium. Intriguingly, it has recently been demonstrated that cadmium can replace androgens to bind the ligand binding domain of and activate the AR [214]. This study seemed to imply the potential role of the AR in cadmium induced prostatic carcinogenesis. Cadmium mediated carcinogenesis seems to be attenuated by supplemental zinc or selenium [215]. Cadmium is a relatively poor mutagen and probably acts through indirect mechanisms [212, 216], although the precise mechanisms remain unknown. Cadmium does not easily form in vivo stable DNA adducts [216] and, since cadmium is not a redox active metal, indirect oxidative DNA damage is unlikely as a primary carcinogenic mechanism. Thus, epigenetic non-genotoxic or indirect genotoxic mechanisms are more plausible for its carcinogenesis. Such mechanisms could include aberrant gene expression resulting in stimulation of cell proliferation or blockage of apoptosis. Both these potential mechanisms could result in carcinogenic transformation in the absence of cadmium-induced genetic damage. Alternatively, cadmium
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might inhibit DNA repairing which could be an indirect source of mutational events. Together, upregulation of mitogenic signaling, perturbed DNA repair and the resulting indirect genotoxicity could be key events in cadmium mediated carcinogenesis. A study reported malignant transformation of the nontumorigenic human prostatic epithelial cell line RWPE-1 by in vitro cadmium exposure [217]. The cadmium-transformed cells exhibited a loss of contact inhibition in vitro and rapidly formed highly invasive and occasionally metastatic adenocarcinomas upon inoculation into mice. The transformed cells also showed increased secretion of MMP-2 and MMP-9, a phenomenon observed in human prostate tumors and linked to aggressive behavior. This cadmium-induced malignant transformation of human prostate epithelial cells seems to strengthen the potential role of cadmium in prostate cancer 4. DIETARY FACTORS AND MANAGEMENT OF METASTATIC AND HORMONE REFRACTORY PROSTATE CANCER Approximately a third of the patients diagnosed with prostate cancer (PCA) will develop advanced disease in the regional lymph nodes and/or the bony skeleton. Once this event has occurred, loco-regional therapies (prostatectomy, radiation therapy) are ineffective. Gonadal steroid deprivation by means of castration, antiandrogens or gonadatropinreleasing hormone (GnRH) analogs remains the only widely accepted standard of care for these patients. Unfortunately, responses to this form of therapy are short-lived in most patients and progression to disease refractory to hormonal alterations is the inevitable course over 2 to 3 years. Once this event has occurred, additional conventional treatments are either investigational or have low clinical response rates. The lack of effective therapies has driven many patients and their families to implement alternative medical therapies [218]. Proper diet, exercise and estrogen-like supplementation have all been suggested to lessen the incidence and progression of PCA [219], however, evidence supporting the effectiveness of these measures on preventing the progression of established metastatic disease or hormone refractory PCA is sparse. In addition, despite the numerous suggested mechanisms of action for the dietary supplements, it is possible that all may operate via one central mechanism of partial androgen suppression and/or enhanced estrogen stimulation. If this is the case, these measurers may be very ineffective for the problematic group of men with metastatic or hormone refractory PCA. PC-SPES, despite the majority of its activity being reported in hormone-naive PCA patients, has also shown activity in androgen-independent PCA. It is not known whether PC-SPES has anti-tumor activity independent from its estrogenic effects, however in a pilot study of 16 men with androgen-independent metastatic PCA, PC-SPES resulted in significant prostate-specific antigen (PSA) decreases [220, 221]. Still, estrogens, including diethylstilbestrol (DES), have a similar high response rate in androgen-independent PCA [222, 223]. Green tea from the leaves of the plant Camellia sinensis contain a variety of polyphenols which have inhibited androgen independent PCA cell growth and induced apotosis
in vitro [103, 224]. However, a recent phase II trial of 42 men with androgen independent PCA who received 6 grams of green tea daily had an isolated patient with a 50% PSA decrease not sustained beyond two months [225]. Additionally, 69% of patients experienced grade 1 or 2 toxicity, and 17% a grade 3 or 4 toxicity during this study. Dietary and lifestyle alterations in the management of advanced PCA may have a greater role in controlling the many side effects of gonadal steroid deprivation [226]. Extracts of Hypericum perforatum (St. John's wort) H. perforatum have been more effective than placebo for the short-term treatment of mild to moderately severe depression, though the current data is unable to establish it effectiveness when compared to conventional antidepressants [227, 228]. Treatment with H. perforatum is well tolerated with only mild side effects of photosensitivity, constipation, gastrointestinal distress, restlessness, and sedation. The mechanism of action for H. perforatum is undefined, but there is the potential for drug interactions similar to prescription monoamine oxidase inhibitors. Prospective studies suggest that gonadal steroid deprivation for PCA results in 4% to 13% annual decrease in bone mineral density contributing to the skeletal morbidity of advanced PCA [229, 230]. Vitamin D deficiency and inadequate intake of dietary calcium are common in older men and may contribute to additional bone loss in men with metastatic PCA. Supplemental vitamin D (400 IU by mouth daily) and calcium supplementation to maintain a total calcium intake of 1200 to 1500 mg daily may decrease the rate of treatment-related bone loss. However, the possible association between calcium intake and increased PCA incidence attributed to a decrease in conversion of 25hydroxyvitamin D to 1,25-dihydroxyvitamin D makes recommendations for calcium supplementation controversy [231, 232]. The skeletal benefits of calcium and vitamin D supplementation may outweigh any theoretic risks especially in patients with gonadal steroid blockade and established metastatic foci. Episodic inappropriate stimulation of the thermoregulatory centers located in the hypothalamus results in one of the most common symptoms of gonadal steroid deprivation. This vasomotor flushing can persist long after the effective life of the administered GnRH agonist. Controlling vasomotor flushing can be challenging. Soy phytoestrogens have not been evaluated as a treatment for vasomotor flushing in men with PCA. In breast cancer survivors with hot flashes, soy phytoestrogens have no more effective than placebo in reducing hot flashes in a randomized double-blind study of 161 women [233]. Similarly, Cimicifuga racemosa (black cohosh) rootstock extract may contain phytoestrogens. This extract has no more than anecdotal reports of effectively reducing vasomotor flushing in men with PCA, however in studies of menopausal women, treatment with C. racemosa extract appeared to be a safe and effective alternative to hormone replacement [234]. 5. CONCLUSION The AR gene plays a role in the etiology of prostate cancer. AR stimulates prostate cancer growth by binding
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910 Current Medicinal Chemistry, 2004, Vol. 11, No. 7

Effects of Dietary Factors on the Androgen Receptor

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912 Current Medicinal Chemistry, 2004, Vol. 11, No. 7

Effects of Dietary Factors on the Androgen Receptor

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914 Current Medicinal Chemistry, 2004, Vol. 11, No. 7

Effects of Dietary Factors on the Androgen Receptor

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916 Current Medicinal Chemistry, 2004, Vol. 11, No. 7

Effects of Dietary Factors on the Androgen Receptor

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