Androgen Receptor in Human Health: A Potential

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Androgen Receptor in Human Health: A Potential Therapeutic Target Hifzur Rahman Siddique1, Sanjeev Nanda1, 2, Aijaz Parray1 and Mohammad Saleem1,3,4,* 1

Molecular Chemoprevention and Therapeutics, The Hormel Institute, University of Minnesota, Austin, MN; 2 Department of Internal Medicine, Mayo Clinic Health Systems, Austin, MN; 3Department of Urology, University of Minnesota, Minneapolis, MN; 4Department of Laboratory Medicine & Pathology, University of Minnesota, Minneapolis, MN Abstract: Androgen is a key for the activation of Androgen Receptor (AR) in most of the disease conditions, however androgen-independent activation of AR is also found in aggressive type human malignancies. An intense search for the inhibitors of AR is underway to cure AR-dependent diseases. In addition to targeting various components of AR signaling pathway, compounds which directly target AR are under preclinical and clinical investigation. Various In vitro and preclinical animal studies suggest that different natural compounds have potential to act against AR. Some natural compounds have been found to be pharmacologically effective against AR irrespective of varying routs of administration viz; oral, intra-peritoneal and intravenous. This mini-review summarizes the studies conducted with different natural agents in determining their pharmacological utility against AR signaling.

Keywords: Androgen Receptor, Cancer, Therapy, Natural Compounds. INTRODUCTION Androgen Receptor: Androgen receptor (AR) is a member of the steroid hormone receptor family that shares sequence homology with other members such as progesterone (PR), glucocorticoid (GR), mineralocorticoid (MR) and estrogen (ER) receptors [1]. Androgens are essential for the development of the reproductive organs and exert their effects through AR. AR modulates androgen activity by regulating the transcription of target genes those are involved in numerous physiological functions and pathological disorders. Aberrant AR expression and activation promoted by mutations, and binding partner misregulation are presented in several clinical manifestations including androgen insensitivity syndrome, acne vulgaris, androgenetic alopecia, benign prostate hyperplasia (BPH), and different type of cancers in humans (Fig. 1A). AR generally resides in the cytoplasm bounds by heat-shock proteins in an inactive state and upon ligand binding, translocates to the nucleus to form homodimers. The homo-dimers bind with the specific DNA sequences known as androgen response elements (AREs) in the promoter or enhancer region of target genes [1, 2]. Despite many decades of investigation, the role of AR in gene regulation of cells and tissues remains only partially characterized. In this current review, we discuss the relevance of AR in the pathogenesis of non-cancerous and cancerous diseases, and utility of AR as a target for therapeutic agents particularly of natural background. Gene and protein structure of AR: The genomic structure of AR is highly conserved throughout mammalian evolution. The AR gene is located on the chromosome X (Xq11*Address correspondence to this author at the Section Leader and Director of Research, Department of Molecular Chemoprevention and Therapeutics, The Hormel Institute, 801, 16th Ave NE, Austin, MN; Tel: 507-437-9662; Fax: 507-437-9606 ; E-mail: msbhat@umn.edu

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12) and spans ~90 kb. The gene contains 8 exons that encode a cDNA approximately 2,757bp length within a 10.6 kb mRNA. The resultant AR protein is composed of 919 amino acids with a calculated molecular mass of 98,845 Dalton. AR is found in many cell types in two isoforms: the predominant isoform B (80%) with 110 kDa mass and the less dominant isoform A (20%) with ~80 kDa [3]. Several AR splice variants have also been reported [1, 4]. AR protein consists of three domains [viz., amino-terminal domain (NTD; 555 aa coded by exon 1), DNA-binding domain (DBD; 68 aa long and coded by exon 2 and 3), ligand-binding domain (LBD; 295 aa coded by exons 4-8)], nuclear localization (628-657 aa) and AF1, AF5 and AF2 transactivation units. AR has been reported to be expressed in neuroendocrine tissues (except spleen), musculoskeletal tissues and the male genitourinary system [5]. Role of AR in non-malignant diseases: AR is reported to play role in several non-cancerous diseases in men and women (Fig. 1A). The most common clinical symptoms of androgen deficiency in humans are the reduction of sex motivation, sex arousal, vaginal vasocongestion, reduction of pubic hair, bone mass, muscle mass, worsening of quality of life (mood, affect, energy), frequent vasomotor symptoms, insomnia, depression and headache [6]. Hyperandrogenemia is the most consistent feature of polycystic ovary syndrome (PCOS) and AR is reported to play an important role in PCOS pathogenesis in women [7]. Studies conducted in transgenic/knockout mouse models showed that aberration in AR signaling impairs critical functions such as follicular maturation, fertility, brain patterning and sexual behavior [8]. Irregular androgen levels have been shown to have a positive correlation with metabolic syndrome such as acne, hirsutism and virilization in humans [9]. Furthermore, antiandrogen therapies are generally recommended to ameliorate hirsutism commonly observed in PCOS patients [10, 11]. © 2012 Bentham Science Publishers

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Reports has shown that anti-androgen administration restores ovulation in subsets of women [10, 11]. It has been shown that AR plays a crucial role in Adrenal virilism, characterized by excess production of androgens, cortisol, or mineralocorticoids [12]. AR activation is reported to play a role in endocrine disorders in children such as Precocious puberty [13]. AR has been implicated in several skin-related diseases, such as androgenetic alopecia and acne vulgaris [9]. A recently published comprehensive review by Lai et al. has shown the role of androgen/AR in acne vulgaris (cystic acne or simply acne), androgenetic alopecia/alopecia androgenetica (hair loss), hirsutism (overproduction of androgens or increased sensitivity of hair follicles to androgens in females), and cutaneous wound healing [9]. Role of AR in malignant diseases: AR is reported to play an important role in the pathogenesis of various types of maligancies in humans (Fig. 1A). These are discussed below: AR and prostate cancer: AR plays a crucial role during prostate cancer (CaP) development and has been found to be a principal driver of disease initiation and progression [2, 14]. However, some exceptions have been reported where prostatic tumors are reported to be independent of AR signaling [4, 14]. The initial stage of CaP is dependent on androgen and can be managed by a series of therapies that are antagonist to AR or suppress AR signaling [4 & references therein]. However, the success of these therapies is temporary and after a short remission period, tumors reappear as castration-resistant prostate cancer (CRPC). Recently, it has been observed that overexpression of AR is the most common event associated with CRPC [4, 14]. Emergence of CRPC phenotype depends on different mechanisms such as activation of receptor tyrosine kinase, uncontrolled cell growth, genomic mutation of AR that allows response to nonspecific AR ligands [4 & references therein]. Among different mechanisms, AR plays a crucial role during CRPC emergence. Multiple mechanisms activate AR in CaP cells during CRPC emergence [4]. These include ligandindependent activation of AR in an androgen depleted environment, AR gene amplification and overexpression of AR co-activators [4, 15]. It has been shown that mutation and amplification of AR gene resulted in elevated AR protein level in the majority of metastatic prostatic tissues in CRPC patients [4 & references therein]. There is some consensus that even after androgen ablation therapy a low concentration of androgens released from adrenal gland and biosynthesized within tumors sustains the active AR signaling in CRPC patients [16]. The detection of AR splice variants in CRPC disease has given another important dimension to the significance of AR during this disease [1, 17]. AR splice variants have also been observed in different CaP cell lines [1, 17]. Though LBD is absent in AR splice variants, yet exhibit higher AR transcriptional activity in CaP cells [1, 17]. The molecular mechanisms through which functionally active AR splice variants arise during progression of disease are not well known. It has been reported that splicing of exon within AR intron 2 introduces a stop codon upstream of exon 3 in the AR transcript that would encode an AR protein (lacking the second zinc finger of the DBD and LBD) if translated [1, 17]. Among all identified AR splice variants ARv7 or AR3 has been de-

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tected in several human CaP cell lines xenografts, normal and malignant human prostate-tissue samples [17]. ARv7 levels are generally higher in CRPC tumors, and it expression in early-stage of CaP has been associated with a worse prognosis after radical prostatectomy [17]. It has been reported that AR splice variants activate genes involved in the metabolism of androgens and provide a survival advantage for cells in a low-androgen environment [4 & references therein]. AR and breast cancer: The most common cause of breast cancer disease progression and mortality is evading of ER signaling during development of endocrine resistance disease. Recent study showed that AR is expressed in 6070% of breast tumors, independent of ER status [18]. Androgens are reported to inhibit or stimulate cell proliferation in pre-clinical models of breast cancer [18]. Molecular apocrine is a subtype of ER-negative breast cancer that is characterized by the overexpression of steroid-response genes such as AR [19]. AR is reported to exert growth inhibitory effect on normal breast cells and estrogen receptor (ER)-positive cells where as promote growth of a subset of ER-negative breast cancers cells within the tumor of apocrine phenotype [19]. Chia et al. showed that AR regulates extracellular signal-regulated kinase (ERK) phosphorylation and kinase activity in molecular apocrine breast cancer [20]. Further, AR inhibition results in the down-regulation of ERK target proteins such as phospho-RSK1, phospho-Elk-1, and c-Fos in breast cancer cells [20]. This study also reported that ARmediated induction of ERK requires ErbB2, and AR in turn regulates ErbB2 expression. These findings suggest that a positive feedback loop between AR and ERK-signaling in apocrine subtype of breast cancer [20]. Naderi and Meyer showed that prolactin-induced protein (PIP) is the most regulated molecular apocrine gene by the AR-ERK feedback loop and is overexpressed in ER-/AR+ breast tumors [21]. These observations are explained by the fact that PIP is induced by AR [21]. Ni et al. showed that AR is enriched in ER negative breast tumors that overexpress HER2 [18]. Peters et al. showed that AR expression can be used as an informative biomarker for breast cancer survival [22]. Naderi et al. demonstrated that synergistic action of AR inhibitor (flutamide) and MEK inhibitor (CI-1040) against the growth of apocrine breast cancer cells [23]. Mishra et al. showed that AR is associated with the therapeutic response to neoadjuvant chemotherapy in locally advanced breast cancer patients [24]. AR and salivary duct carcinoma: Salivary duct carcinoma (SDC) is an uncommon and pathologically distinct entity characterized by its morphologic resemblance to ductal carcinoma of the breast [25-27]. Although ER expression in SDC disease is rare, the presence of AR has reported by different studies [25-26]. AR is reported to be expressed in over 90% of SDCs [26]. The immunophenotypic homology that exists between SDC and prostate cancer (CaP) suggests that antiandrogen therapy which is used for the treatment of CaP might also be beneficial in patients of metastatic SDC disease [26]. Williams et al. reported the differential expression of hormonal receptors in SDCs patients [28]. AR is reported to express significantly more often in SDCs of men than in SDCs of women (79% vs. 33%) [28]. Moriki et al. reported that AR expressed in majority of SDC is useful for

AR: A Potential Therapeutic Target

the diagnosis of SDC disease [25]. Jaspers et al. demonstrated the clinical benefit of androgen deprivation therapy in SDC patient with brain metastases [27]. AR and hepatocellular carcinoma (HCC): Recent studies showed the contribution of AR in pathogenesis of HCC disease in humans. Ao et al. reported that AR is expressed at high levels in HCC cell lines exhibiting high metastatic potential [29]. AR activation was observed to promote the cell migration and invasion potential of HCC cells [29]. AR activation was shown to enhance the expression of metastasispromoting gene, ID1, which leads to the increased invasiveness of HCC cells [29]. Recently, Ma et al. showed that mice lacking AR develop more undifferentiated hepatic tumors with larger tumor size at the metastatic stage [30]. This study showed that hepatic AR enhances the anoikis of HCC cells [30]. Hepatitis B viruses (HBV)-induced hepatitis and carcinogen-induced HCC have been shown to have a positive association with serum androgen levels in human patients. Recently, Wu et al. showed that AR plays a crucial role in HBV-induced hepatocarcinogenesis in HBV transgenic mice [lacking AR only in the liver hepatocytes HBV-L-AR(-/y)] [31]. Mutant HBV-L-AR(-/y) mice exhibit lower incidence of HCC, smaller size of tumors, fewer number of foci, and less HCC markers such as alpha-fetoprotein than wild-type HBV-AR(+/y) littermates. AR is reported to increase the HBV viral titer by enhancing HBV RNA transcription [31]. This study suggests that AR could be developed as target for therapy to combat HBV-induced HCC [31]. Zhu et al. showed a positive correlation between hepatitis B virus X protein (HBx) and AR in HCC [32]. HBx is reported to activate DNA methyl-transferase (DNMT) in hepatocarcinogenesis. Notably, HBx was found to be correlated with high levels of AR in HCC cases [32]. This study showed that AR expression is induced by HBx in liver cell lines [32]. This study also showed that HBx-induced AR plays a role in hepatocarcinogenesis (independent of promoter methylation or DNMTs [32]. AR and lung cancer: According to American Cancer Society, lung cancer is the leading cause of cancer-related death in humans. Previous clinical study in no-small cell lung cancer patients showed that androgen levels in women responding to Gefitinib were significantly lower during treatment than in women who did not responds to treatment [33]. Recchia et al. showed that a cross talk between AR and mTOR results in the growth of human lung cancer cells [34]. This study suggested that serum androgen levels might be playing a role in lung cancer disease development [34]. Mikkonen et al. showed that androgen induces AR levels in lung cells [35]. This study showed that different lung cancer types are AR positive in humans [35]. Recently, Jeong et al. showed that AR has a potential to be used as a theragnostic marker for predicting lung cancer and suggested its potential as a target for individualized treatment [36]. This study showed that nuclear receptor signature was 79% accurate in diagnosing lung cancer incidence in smokers [36]. Rades et al. opined that AR was not associated with outcome of radiotherapy in non small cell lung cancer [37], however, suggested further investigations warrant in this field.

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AR and bladder cancer: Emerging evidences support the view that bladder cancer is a member of the endocrinerelated tumors. Males are reported to have higher incidence of bladder cancer than females [38, 39]. Recent studies suggest that AR plays a crucial role in the pathogenesis of bladder cancer [38]. Blockage of AR has been shown to decrease growth, colony formation and viability in bladder cancer cells [39]. Castration slightly suppressed UMUC3 tumor growth In vivo, although this did not attain statistical significance [39]. Miyamoto et al. showed that more than 92% of AR wild-type male and 42% of AR wild-type female mice treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) eventually developed bladder cancer, whereas none of the male or female in AR knockout (ARKO) mice did develop tumor [40]. This study showed that BBN treatment supplemented with DHT induced bladder cancer in ARKO mice and castrated wild-type male mice [40]. This study established AR as a target for treatment of bladder cancer [40]. Zhai et al. showed that AR agonist R1881 strengthens the AR specific oncolytic virus (Ad/PSCAE/UPII/E1A-AR) in bladder cancer cells [41]. This study showed that AR could play a crucial role in bladder cancer development [41]. UDP-glucuronosyltransferases (UGTs), major phase II drug metabolism enzymes, play an important role in urinary bladder cancer initiation by detoxifying carcinogens. A recent study showed that AR promotes bladder carcinogenesis by down-regulating UGTs in the bladder [42]. Epidermal growth factor receptor (EGFR) family (EGFR and ERBB2) is known to play role in bladder cancer cell growth [43]. EGFR also correlates with poor prognosis of bladder cancer patients [43]. Notably, AR activation was observed to cause the upregulation of EGFR, ERBB2, and contributed to the progression of bladder cancer [43]. JMJD2A and LSD1 are AR co-regulator proteins which mediate AR-dependent transcription via histone lysine-demethylation (KDM). Recently, it has been shown that AR-KDM complex is involved in initiation of bladder cancer and its progression [44]. Silencing of AR is reported to inhibit proliferation, apoptosis, and migration of human bladder carcinoma cell lines T24 and 253-J [45]. Further, silencing of AR expression was observed to significantly suppress bladder tumor growth In vivo [45]. Boorjian et al. showed that AR and its associated coactivators play important roles in bladder cancer and showed the differences (in the regulation of AR) between bladder and CaP cells [46]. On the contrary, Mir et al. suggested that neither loss of AR expression is gender-related nor is it associated with invasive bladder cancer [47]. Tuygun et al. showed that loss of AR expression is associated with high grade invasive bladder cancer but had no prognostic effect on survival and suggested that sex-specific hormone receptors alone cannot be responsible for gender differences in bladder cancer rates [48]. Keeping view these reports further investigations are warrants in this field. AR and thyroid tumors: Gender bias in the incidence of thyroid cancer is well known, however, the underlying mechanism is largely unknown. AR is reported to be expressed in thyroid tumors, however, its prognostic role is still controversial. Recently, it has been shown that AR expression is associated with a more aggressive phenotype of small thyroid cancer [49]. This study suggested that AR expression along with ER may be used to decide whether to perform


radioiodine ablation in these tumors [49]. Stanley et al. showed that the varying patterns of testosterone level and AR status in thyroid tissues may predispose to the gender specific incidence of thyroid tumors and androgen mediated thyroid tumor growth [50]. AR as a target for therapeutic agents: AR has emerged as a promising therapeutic target for the treatment of both cancerous and non-cancerous diseases in humans (Fig. 1B; Table 1). Agents targeting the AR axis are considered as critical for chemoprevention and treatment of cancer at all stages of the disease. An approach used to develop synthetic as well as natural compounds and their derivatives to reverse or halt the process of one of the progressive stages of tumor development is called chemoprevention. Chemoprevention also refers to the inhibition of preinvasive and invasive cancer and its progression or treatments of identifiable precancers [51]. Several natural compounds have demonstrated promise as potential chemopreventive agents in the prevention of cancer [52]. Epidemiological and laboratory studies have demonstrated that several natural compounds could suppress the growth of human cancers including those which involve androgen and AR [53]. Phase II clinical trials have demonstrated a trend towards reduction of AR-target gene PSA with short-term isoflavone (diadzein and genistein) supplementation in CaP patient population [51]. A phase II clinical trial showed that lycopene supplements reduce tumor size and PSA levels in localized CaP [54]. A clinical trial with oral administration of green tea catechins (GTC) showed that GTC decreased PSA levels in men [55, 56]. Numerous studies have shown the anticancer efficacy of natural agents, however very few of these compounds have been shown to be AR-specific [2, 4, 51]. The antitumor efficacy of these agents is being attributed to their effect on other signaling pathways (Akt, NF-B, Wnt, Hedgehog, and Notch), but not exclusively through AR [51, 57]. A limited number of natural compounds have been shown to inhibit tumor growth exclusively or partially through blocking AR [2, 58, 59]. Several synthetic agents targeting AR have been developed and some of which are being tested at clinical level (Fig. 1B). The most commonly known anti-AR agent is bicalutamide (also known as Casodex). Bicalitumaide is a competitive inhibitor to dihydrotesterone and testosterone [2]. MDV3100 is another synthetic AR antagonist that blocks androgens from binding to the AR and prevents nuclear translocation of the ligand-receptor complex [60]. Phase I and II clinical trials with MDV3100 showed that 43% CaP patients showed >50% decline in serum concentrations of PSA [60]. Following this phase I–II trial, two placebo- controlled phase III trials evaluating MDV3100 in the pre and post docetaxel setting were initiated. If confirmed in phase III trials, MDV3100 will be an important additional tool for the clinician, providing more options for patients [61]. Recently, several more synthetic agents those target AR have been reported. These include ARN-509, 6-(3,4-dihydro1H-isoquinolin-2-yl)-N-(6-methylpyridin-2-yl)nicotinamide (DIMN); Cycloalkane[d]isoxazole and Adenosine dialdehyde [62-64]. However, further extensive preclinical and clinical studies warrant to declare these compounds as a promising AR-antagonist.

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AR as a target for natural agents: As summarized in Table 1, there is enormous amount of literature regarding the efficacy of natural agents to inhibit AR expression or activity [2, 65-68]. The systemic toxicity, non-achievable pharmacological doses and less bioavailability do not permit most of the reported natural agents to be pursued beyond the laboratory stage, though some of these agents seem very promising [2]. However, few of these agents have translational potential and require additional preclinical studies, with tailored doses and enhanced bioavailability. These potential anti-AR agents are briefly discussed as following: i. Lupeol: Lupeol, a small triterpene molecule exhibiting a structural similarity to cholesterol, is found in different cereals, fruits and vegetables. It has been reported that Lupeol has different pharmacological properties that include anti-cancer, anti-inflammation, anti-oxidative, anti-arthritis, anti-microbial, hepatoprotective and cardioprotective activities [69]. In vitro and In vivo studies have identified Lupeol as a potentially effective agent against a wide variety of disease conditions [69]. We recently showed that Lupeol significantly inhibits the activity of AR in both androgendependent as well as CRPC cells and tumor xenografts [2]. It is noteworthy that Lupeol was observed to be highly stable under physiological conditions and exhibited high bioavailability in mice [2]. Lupeol significantly inhibited R1881 (androgen analog) induced transcriptional activity of AR. Lupeol was found to (i) compete antagonistically with androgen for AR and (ii) block the binding of AR to AR-responsive genes such as PSA, TIPARP, SGK, and IL-6 [2]. Further, Lupeol was observed to inhibit the recruitment of RNA Pol II to AR target genes. Lupeol also was reported to sensitized CRPC cells to anti-hormone therapy [2]. Lupeol was found to inhibit the tumorigenicity of both androgen dependent and CRPC cells in animals [2]. Serum and tumor tissues exhibited reduced PSA levels. These studies suggest that Lupeol, an effective AR inhibitor, could be developed as a potential agent to treat human CaP. ii. Diadzein and genistein: Isoflavones are the most abundant phytoestrogens in soybeans and are structurally similar to 17--estradiol. The beneficial property of the soy isoflavones, especially, genistein and daidzein is well established in different experimental models in both clinical and preclinical studies. The Isoflavones, genistin and daidzin, are hydrolyzed by gut microflora after ingestion to form genistein and daidzein, which have the potential to bind ER and AR [70, 71]. Beck et al. reported the beneficial properties of daidzein and genistein-rich plant extracts (from soy and red clover) and suggested these as an alternative to conventional hormone replacement therapy [70]. Red clover and soy extracts contain daidzein and genistein and have been shown to exhibit a high affinity to ER, ER, PR and AR [70]. Using a computerized docking approach, Wang et al. showed that genistein and daidzein strongly bind to AR [67]. Genistein and daidzein rich-isoflavones have been reported to cause a decline in the PSA levels in men with recurrent CaP in a Phase II trials study [52]. This study is encouraging, however, needs further clinical and preclinical testing. Tepper et al. showed that Genistein combined polysaccharide (GCP) inhibits the growth and proliferation of CaP cells through AR down regulation [72].



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Fig. (1). A) The chart represents role of androgen receptor in human malignant and non-maligant diseases. B) The flow-diagram shows the intervention points at which natural and synthetic agents can block/inhibit the androgen receptor pathway. AR: Androgen Receptor; ARE: Androgen Response Element; HSP:Heat Shock Proteins.

iii. Quercetin: Quercetin is a phytoestrogen, abundantly present in soybeans. Yuan et al. demonstrated that quercetin increases c-Jun expression as well as its phosphorylation form [73]. Notably, c-Jun is shown to represse PSA and AR promoter activity [73]. This study showed that quercetin inhibits the AR activity and decreases PSA secretion through inducing c-Jun [73]. Furthermore, quercetin was shown to

decrease the mRNA levels of PSA, the AR target gene in CaP cells [74]. Yuan et al. showed that quercetin suppresses AR activity by reducing the interaction between Sp1, c-Jun and AR [73]. This study showed that overexpression of c-Jun by quercetin had inhibitory effect on the function of AR and this inhibition is not reversed by CBP overexpression. This study showed that quercetin-mediated inhibition on the AR


Table 1.

Siddique et al.

Natural Agents Targeting Androgen Receptor

S.N.

Diseases/ conditions

Model/Disease Model

Agents

Reference number

1

Prostate Cancer

LAPC4, LNCaP, 22R1, C42b, and LNCaP and C42b-tumor xenograft in nude mice

Lupeol

[2]

2

Prostate cancer

Phase II clinical trials in Men

Genistein and daidzein

[52]

3

Prostate cancer

LNCaP and 22R1

poly[3-(3, 4-dihydroxyphenyl) glyceric acid] (p-DGA)

[58]

4

Prostate cancer

LNCaP, LNCaP-p53(GOF) and 22R1

Genistein

[72]

5

Prostate cancer

LNCaP

Quercetin

[73,74]

6

Testicular Sertoli-germ cells

Rat Sertoli-germ cells (SGCs)

Quercetin

[76]

7

Prostate cancer

LNCaP

Epigallocatechin-3-gallate (EGCG)

[77,78]

8

Prostate cancer

LNCaP and 22R1

EGCG

[80]

9

Prostate cancer

LNCaP

Curcumin

[81, 83]

10

Prostate cancer

LNCaP

Decursin

[66,84,85]

11

Prostate cancer

LNCaP

Lycopene

[86]

12

Normal Prostate

Normal prostate stromal and Normal human prostate epithelial cells

Lycopene

[87]

13

Prostate cancer

LNCaP

Silibinin

[65,88]

14

Prostate cancer

LNCaP

Resveratrol

[89,91,92]

15

Prostate cancer

LNCaP and 22R1

Resveratrol

[90]

16

Prostate cancer

Transgenic rat for adenocarcinoma of prostate (TRAP) model

Resveratrol

[93]

17

Prostate cancer

LNCaP and 22R1

Cryptotanshinone

[94]

18

Prostate cancer

22R1

Cryptotanshinone

[95]

19

Prostate cancer

LNCaP

Piperlongumine

[96]

20

Prostate cancer

LNCaP and LNCaP xenograft in SCID mice.

Luteolin

[97]

21

Prostate cancer

22R1 and 22R1 xenograft in nude mice.

Fisetin

[98]

22

Prostate cancer

LNCaP and LNCaP xenograft in nude mice.

Tanshinones

[99]

23

Prostate cancer

22R1 and C42B

Physalins

[100]

24

Prostate cancer

LNCaP

Niphatenone

[101]

function is not by competition with limited amount of CBP in the cell, but through a direct association of c-Jun and the AR [75]. Recently, it has been shown that quercetin normalizes the expression levels of atrazine induced AR and androgen-binding protein (ABP) in Sertoli-germ cells [76]. iv. Epigallocatechin-3-gallate (EGCG): Green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG) has been reported to inhibit the development and progression of CaP in TRAMP mice and in men [77]. The anti-androgen action of EGCG was first described by Ren et al. who showed that EGCG inhibited LNCaP cell growth and the expression of AR and PSA [78]. Further, Lee et al. showed that EGCG inhibits the translocation of AR to nucleus from the cytoplasmic compartment [79]. Recently, Siddiqui et al. showed that EGCG physically interacts with the ligand-binding domain of AR by replacing a high-affinity labeled ligand in silico modeling and FRET-based competition assay [80]. Further, this study showed that EGCG inhibits AR nuclear translocation and expression in a xenograft model [80].

v. Curcumin: Curcumin (diferuloylmethane), a dietary natural yellow pigment from the root of Curcuma longa (turmeric), has emerged as a potent chemopreventive agent. It has been shown that curcumin exhibits anti-inflammatory, anticarcinogenic, antiproliferative, antiangiogenic, and antioxidant properties in various cancers [68]. It has been shown that curcumin treatments blocked androgen-stimulated PSA expression in CaP cells [81]. The effects of curcumin appeared to be mediated via the androgen response element of PSA gene [81]. Further, curcumin has been shown to modulate the AR binding activity on androgen response element of PSA gene [81]. The major concern with curcumin is poor bioavailability and thereby limiting its clinical use. Ohtsu et al. synthesized a number of curcumin analogs and evaluated their anti-androgen activity [82]. These include, 4 [5hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3one], 20 [5-hydroxy-1,7-bis[3-methoxy-4-(methoxycarbonylmethoxy) phenyl]-1,4,6-heptatrien-3-one], 22 [7-(4hydroxy-3-methoxyphenyl)-4-[3-(4-hydroxy-3-methoxy-


phenyl)acryloyl]-5-oxohepta-4,6-dienoic acid ethyl ester], 23 [7-(4-hydroxy-3-methoxyphenyl)-4-[3-(4-hydroxy-3-methoxyphenyl)acryloyl]5-oxohepta-4,6-dienoic acid], and 39 [bis(3,4-dimethoxyphenyl)-1,3-propanedione] which showed potent antiandrogenic activities and were observed to perform better than hydroxyflutamide (currently available antiandrogen for the treatment of CaP) [82]. The reduced expression of AR by curcumin has also been related to enhance AR degradation [83]. vi. Decursin: Decursin is found in the roots of Angelica gigas Nakai (which has been traditionally used to treat various diseases). Recently, it has been reported that decursin possesses potent anti-AR activities [66, 84]. Decursin was shown to suppress PSA expression, inhibit androgenstimulated AR translocation to the nucleus and downregulate AR protein without affecting its transcription [84]. Guo et al. reported that decursin and its isomer decursinol angelate decrease PSA expression inhibit the androgenstimulated AR nuclear translocation and increase AR proteasomal degradation [66]. Furthermore, decursin and it structural isomer decursinol angelate are reported to exert a longlasting inhibition of both ligand-dependent and ligandindependent AR signaling [66]. Zhang et al. showed that synthetic analog of decursin has high In vivo stability, decreases AR/PSA and inhibited AR nuclear translocation [85]. vii. Lycopene: lycopene is a carotenoid (without provitamin A activity). Zang et al. reported that lycopene inhibits the AR activity and its expression in a dose dependent manner in CaP cells [86]. A clinical study showed that lycopene decreases the PSA levels in the CaP patients [86]. Lycopene consumption is also inversely related to androgen signaling in a rat prostate cancer model [87]. Liu et al. showed that lycopene reverses the androgen-stimulated gene expression by reducing AR translocation to the nucleus [87]. viii. Silibinin: Silibinin is flavolignan derived from the fruits of Silybum marianum (milk thistle). Growing evidence suggests that silibinin is a potential agent for cancer chemoprevention and chemotherapy. Silibinin is reported to inhibit cell growth by targeting AR [88]. Silibinin is reported to down-regulate AR target gene PSA under androgen stimulated conditions [65]. ix. Resveratrol: Resveratrol (3,4',5-trihydroxystilbene), a phytoalexin enriched in red grapes, strawberries and peanuts is known to inhibit the function of AR [89, 90]. Harada et al. reported that the inhibitory effect of resveratrol on AR function is partly attributable to a decrease in the posttranslational AR level in CaP cells [89]. Recently, it has been shown that resveratrol analog, 4'-O-methylresveratrol (3,5dihydroxy-4'-methoxystilbene) inhibits AR transcriptional activity in CaP cells. This analog is reported to have better anti-androgenic activity than parent compound [91]. This study suggested that hydroxyl groups of resveratrol play a key role in its anti-androgenic effect [91]. A recent study showed that resveratrol inhibits AR transcriptional activity in both androgen-dependent and -independent CaP cells [90]. This study reported that resveratrol enhanced PTEN expression through AR inhibition [90]. The combination of resveratrol with known antiandrogen compound such as flutamide has been shown to be an attractive pharmacological combination to treat CaP [92]. Resveratrol is reported to inhibit the


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AR transcriptional activity, and decreases both AR and PSA through degradation pathways [92]. Seeni et al. showed that resveratrol feeding inhibits the CaP development in the transgenic rat for adenocarcinoma of prostate (TRAP) model [93]. The inhibiting effect of resveratrol was shown to be associated with decrease in AR activity [93]. x. Cryptotanshinone: Cryptotanshinone is a natural product/Chinese herbal medicine, with a structure similar to dihydrotestosterone (DHT). Cryptotanshinone inhibits the transcriptional activity of AR and suppressed the expression of several AR-target genes at both transcriptional and translational levels [94]. It has been shown that sodium derivative of cryptotanshinone, PTS33 inhibits AR transactivation, block AR regulated gene expression, and reduce cell growth by inhibiting AR in androgen dependent CaP cells [95]. This study showed that PTS33 inhibits AR function by downregulating AR expression, suppression of the AR N-C interaction and AR-coregulator interaction [95]. Wu et al. reported that cryptotanshinone down-regulates AR signaling by modulating lysine-specific demethylase-1 function (LSD1) [94]. LSD1 is a protein that promotes AR-dependent transcriptional activity of genes. This study reported that cryptotanshinone down-regulates AR signaling via functional inhibition of LSD1-mediated demethylation of H3K9 (Histone H3 lysine 9) and represses the transcriptional activity of AR [94]. Recently, Xu et al. reported that cryptotanshinone repress AR in both androgen dependent and CRPC cells [95]. This study showed that cryptotanshinone inhibits CaP cell growth via AR, suppress PSA expression, block AR dimerisation and AR-coregulator complex formation [95]. Furthermore, this study reported that cryptotanshinone inhibits growth of 22R1 cell derived tumor and expressions of AR target genes in the xenograft animal model. xi. Miscellaneous: Piperlongumine (PL), is a naturally occurring alkaloid present in the Long pepper (Piper longum). Golovine et al. showed that PL reduces the levels of both wild and splice variants of AR in CaP cells [96]. Luteolin, 3,4,5,7-tetrahydroxy flavone, is a common natural flavonoid that occurs in its glycosylated form in parsley, green pepper, peppermint, thyme, perilla leaf, celery, and chamomile tea [97]. Luteolin is reported to reduce the both intracellular as well as secreted PSA levels in CaP cells [97]. Luteolin has been shown to reduce the association between AR and heat-shock protein 90 and causing AR degradation through a proteasome-mediated pathway [97]. Fisetin is a novel dietary flavonoid. Khan et al. reported that Fisetin physically interact with AR and acts as an antagonistic competitive inhibitor [98]. Zhang et al. reported that tanshinones (isolated from Chinese medicinal herb Danshen; Salvia miltiorrhiza Bunge) suppress CaP cell growth via suppressing of AR signaling [99]. This study showed that tanshinones inhibits AR nuclear translocation, decreases AR/PSA levels and stimulates proteosomal degradation of AR [99]. Oral administration of tanshinones retarded growth of LNCaP xenografts and down-regulate AR levels In vivo [99]. Han et al. reported that Physalins A and B (secosteriods from Physalisalkekengi var. franchetii) inhibit cell growth through downregulation of AR expression [100]. This study showed that physalins A and B also down-regulate the PSA expression [100]. Recently, Meimetis et al. reported that Niphatenones, glycerol ethers from the sponge Niphates digitalis


inhibit AR transcriptional activity in CaP cells [101]. Niphatenone was shown to bind covalently to the N-terminus domain of AR [101]. Recently, Shrotriya et al. identified a novel phytochemical poly[3-(3, 4-dihydroxyphenyl)glyceric acid] (p-DGA) from Caucasian species of comfrey (Symphytum caucasicum) and its synthetic derivative syn-2, 3dihydroxy-3-(3, 4-dihydroxyphenyl) propionic acid (mDGA). P-GDA and m-DGA were observed to decrease AR and PSA expression In vitro and In vivo [58]. CONCLUSIONS Many natural agents linked to the prevention of different diseases especially cancer were reported to function at least in part through AR signaling. Accumulating data obtained from numerous In vitro and In vivo studies is promising. Further evaluation of natural agents as candidate against development of different AR-induced diseases therapeutic agents appear warranted. Numbers of preclinical compounds are in pipeline (with improved biological profiles) compared with the first-generation anti-androgens. Although different agents inhibit AR through transcriptional suppression or protein degradation or by competitive binding, it is not clear whether these agents inhibit AR splice variants (Fig. 1B). Our laboratory has made some strides in this direction and identified a few natural compounds that harbor potential to inhibit activities of AR-splice variants (Siddique and Saleem, unpublished data). It has been reported that anti-androgen compounds equally inhibit AR in both androgenic (prostate, breast, ovary, skin) and anabolic tissues (muscle, bone). The ability of natural agents to inhibit the AR selectively in androgenic tissues but not anabolic tissues would expand the scope of anti-androgen use beyond oncology. Caution is also needed in extrapolating the information obtained from animal studies to humans due to the inter-species differences. Further, factors such as effective dose and the duration of treatment should be taken into account when these agents are investigated for their therapeutic purposes (for different diseases) under varied conditions. However, the potential of different agents as pharmaceutical agents as AR inhibitor against different human diseases is high because of their wide availability in edible foods, and apparent non-toxicity.

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The authors confirm that this article content has no conflicts of interest.

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ACKNOWLEDGEMENTS The data from our laboratory cited in this manuscript was funded in part by United States PHS grants (CA133807; CA130064) and grant from CDMRP-Department of Defence (W81XWH-08-1-0605) to the corresponding author. REFERENCES [1] [2] [3]

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Revised: October 30, 2012

Accepted: November 18, 2012

DISCLAIMER: The above article has been published in Epub (ahead of print) on the basis of the materials provided by the author. The Editorial Department reserves the right to make minor modifications for further improvement of the manuscript.

PMID: 23140299