ANTICANCER RESEARCH 33: 4163-4174 (2013)

Review Chemoprevention of Prostate Cancer by Major Dietary Phytochemicals

AJAY BOMMAREDDY, WILLIAM EGGLESTON, STACY PRELEWICZ, ANDREA ANTAL, ZBIGNIEW WITCZAK, DAN F. MCCUNE and ADAM L. VANWERT

Department of Pharmaceutical Sciences, Nesbitt College of Pharmacy and Nursing, Wilkes University, Wilkes-Barre, PA, U.S.A.

Abstract. Prostate cancer continues to be one of the most management of advanced PCa is challenging (5). Androgen commonly diagnosed diseases and the second leading cause of ablation is one of the most frequently suggested treatment cancer-related deaths among men in the United States. Options options for PCa, but this treatment selection is palliative and exist to treat localized disease, including surgery, radiation has a limited scope for hormone-refractory cancer (6). In therapy, and hormonal therapy, but clinical management of addition, chemotherapy and radiation therapy are largely advanced prostate cancer is challenging. In the past few ineffective against advanced PCa (5). decades, chemoprevention involving naturally- occurring A continuous increase in incidence and failure of compounds has emerged as a promising and cost-effective conventional therapies against advanced PCa warrants approach to reduce incidence and morbidity of prostate cancer development of novel agents to treat and prevent this by inhibiting the precancerous events before the occurrence of malignancy. In the past few decades, chemoprevention involving clinical disease. The present review focuses on summarizing naturally occurring compounds has emerged as a promising and the recent advances in studies of major dietary phytochemicals cost-effective approach to reduce incidence and morbidity of and their role in prostate cancer development. PCa by inhibiting the precancerous events even before the occurrence of clinical disease (7). PCa provides a large window Prostate cancer (PCa) is one of the most commonly diagnosed of opportunity for intervention to prevent or slow its progression diseases and is the second leading cause of cancer related and in many ways remains an ideal candidate for deaths among men in the United States (1). It is typically chemoprevention because of its high incidence and long latency. diagnosed in the sixth and seventh decades of life, and hence Therefore, development of agents which offer significant a modest delay in disease progression could have a significant protection against the development of this disease is highly impact on disease-related morbidity, mortality and quality of desirable. Such chemopreventive agents could have a significant life. Molecular mechanisms underlying onset and progression impact on disease-related costs, morbidity, and mortality for a of PCa are not fully understood, but the factors implicated in large segment of the population (8-13). The identification of pathogenesis of this disease include age, race, diet, androgen agents and their molecular targets for PCa chemoprevention is secretion and metabolism, and activated oncogenes (2-4). guided by data derived from a variety of sources including Several options exist to treat localized disease including epidemiological, clinical, and pre-clinical studies (9). As with surgery, radiation therapy, and hormonal therapy, but clinical other types of cancer, PCa is thought to develop via modifications in different molecular events, and hence blocking or inhibiting only one event may not be sufficient to prevent or This article is freely accessible online. delay the disease onset. Therefore, ongoing research to better understand the disease and to develop novel approaches for its Correspondence to: Ajay Bommareddy, Ph.D., Assistant professor, prevention and treatment is critical. Epidemiological evidence Department of Pharmaceutical Sciences, Nesbitt School of suggests lower PCa risk in populations with higher consumption Pharmacy, Wilkes University, 84 W. South Street, Wilkes-Barre, of major phytochemical-containing diets (14). These Pennsylvania 18766, U.S.A. Tel: +1 5704084220, Fax: +1 5704084299, e-mail: [email protected] observations have generated enough curiosity among the scientific world to explore the utility of natural agents for the Key Words: Prostate cancer, lycopene, resveratrol, capsaicin, prevention of PCa. Several naturally occurring agents are curcumin, dietary phytochemicals, review. currently being studied for their chemopreventive potential. This

0250-7005/2013 $2.00+.40 4163 ANTICANCER RESEARCH 33: 4163-4174 (2013)

Figure 1. Structure of lycopene.

review summarizes the recent advances on four major prostatic carcinoma LNCaP cells with 24-h lycopene phytochemicals, namely lycopene, resveratrol, capsaicin, and treatment (2.5-10 μM) reduced intracellular total cholesterol curcumin and their potential role in PCa prevention and or in a dose-dependent manner. Lycopene inhibited 3-hydroxy- treatment, including details of clinical trials. 3-methyl-glutaryl coenzyme A (HMG-CoA reductase), consequently, inactivating RAS and reducing the RAS- Lycopene dependent activation of nuclear factor-kappaB (NF-κB). PCa cells have abnormal cholesterol biosynthetic pathways that Lycopene (Figure 1) is a member of the carotenoid family are resistant to down-regulation by cholesterol. Thus, by and is commonly synthesized in plants. Lycopene occurs in inhibiting this key step in cholesterol synthesis (HMG-CoA many plant foods including but not limited to watermelon, reductase), lycopene may control tumor cell growth (21). tomatoes, papaya, and apricots. It is the substance that gives The modulation of the nuclear factor erythroid 2-related these fruit and vegetables their characteristic red color (15- factor 2 (NRF2)-mediated oxidative stress response signaling 17). In the United States and other western countries, dietary pathway may be an important mechanism involved in lycopene comes from the consumption of tomatoes and chemoprevention (22). NRF2 is a transcription factor that is tomato-based products, including tomato sauce, tomato juice commonly activated by increased reactive oxygen species and pizza sauce. Lycopene metabolites circulate in serum and (ROS) and often induces the transcription of several accumulate in tissues at concentrations equivalent to those of antioxidant and detoxification enzymes, including several bioactive retinoids (18). Studies from around the world have classes of glutathione S-Transferases (GSTs) (22). demonstrated cancer chemopreventive properties of lycopene Antioxidants function by neutralizing free radicals and and other carotenoids specifically against PCa. Lycopene has reducing oxidative stress, both of which cause significant been noted for its protective effects against PCa, acting as an damage to DNA on generation of ROS (23). This damage can antioxidant and inhibiting cell proliferation (19). lead to the formation of cancer in various tissues (23). PCa Lycopene has demonstrated potential anticancer properties tissues, in particular, have high levels of oxidative damage in multiple human cancer cell lines. Cell lines treated with (23). The risk of prostate damage has been reported to be lycopene (1-5 μM) for 48 and 96 h were analyzed by various lower in patients who regularly consume higher levels of techniques for apoptotic cells [by flow cytometry, Terminal lycopene (23). Patients with localized prostate Deoxynucleotidyl Transferase-Mediated DuTP Nick adenocarcinoma who consumed tomato sauce-based dishes for Labeling (TUNEL) and 4’, 6-diamidino-2-phenylindole three weeks (30 mg of lycopene per day) exhibited a (DAPI assay)]. There was a significant decrease in the statistically significant decrease in oxidative DNA damage in number of viable cells after a 48-h treatment with lycopene the prostate tissues (23). This was concluded through along with changes in the fraction of cells retained in observations of serum prostate-specific antigen (PSA) levels different phases of the cell-cycle. After 96 h, lycopene- as well as DNA oxidative damage to DNA in leukocytes. promoted cell cycle arrest was followed by a decrease in cell Compared with ratios from leukocytes isolated before the viability in the majority of cell lines tested. Additionally, intervention, the average leukocyte DNA [8-OHdG/105 dG] there was an increase in apoptosis compared to the controls. ratio of 31 patients with PCa decreased by 21.3% from 0.61 to A rate-limiting step in the cell cycle that is often seen with 0.48 after the tomato sauce intervention, a statistically the used anticancer agents is inhibition of the progression of significant difference (23). In a randomized trial of transgenic cells through the first gap (G1) phase. In a recent study, it adenoma of mouse prostate (TRAMP) mice, equivalent doses was shown that lycopene induces cell-cycle arrest at the G1 of lycopene from a tomato paste product and from a lycopene phase and thus has chemopreventive properties (20). beadlet were given to mice; after 20 weeks of administration, Lycopene has also shown its antitumor properties through prostate histopathology was compared with mice on a control changes in the mevalonate pathway and in rat sarcoma diet. The lycopene beadlet group had a significant reduction (RAS) activation of PCa cells. Incubation of RAS-activated in the incidence of PCa relative to the control group (60% vs.

4164 Bommareddy et al: Chemoprevention of Prostate Cancer (Review)

95%). The difference in PCa incidence between the tomato a reduction in androgen signaling in prostate. Out of the four paste and control group, however, was not statistically phytochemicals reviewed here, lycopene has been studied in significant (80% vs. 95%, p=0.34). One speculative the largest number of human trials which are either explanation for these results is that the tomato paste used in completed or in progress. These trials highlight the the study did not contain the skin and seeds of the tomato. chemopreventive and therapeutic properties of lycopene as There may be anticarcinogenic properties associated with the well as its effects on cancer development. A web search skin and seeds, therefore explaining the variation in results using the terms “lycopene” and “cancer” on the accredited (24). In another study using the MatLyLu orthotopic Dunning site clinicaltrials.gov revealed 21 studies out of which 18 are tumor model, a rat model for aggressive PCa, rats were related to the role of lycopene in PCa prevention and grouped and fed a diet supplemented with 200 ppm lycopene treatment, either alone or in combination with other or 540 ppm vitamin E for four weeks. Both compounds therapeutic regimens. According to several clinical trials, accumulated in tumor tissue and the levels achieved were varying degrees of evidence exist in the ability of dietary comparable with those of humans. After four weeks of lycopene and tomato products to reduce the risk of PCa. This feeding, a highly aggressive and metastatic cell line, MatLyLu, evidence is measured clinically by the observation of was injected into the ventral lobes of the prostate and the increasing apoptotic cell proteins and also observations of prostate tumors were monitored for necrosis by magnetic various biological markers such as the level of PSA. In resonance imaging (MRI). There were no differences in tumor patients diagnosed with PCa who were given tomato sauce volume among all groups. However, a significant increase in pasta entrees (30 mg lycopene/day) for three weeks, an the necrotic area of tumor was reported in both lycopene- and increase in apoptotic cell death in comparison to placebo vitamin E-supplemented groups compared to the control. showed that tomato sauce consumption may suppress the Moreover, mechanistic details revealed that lycopene progression of PCa. Apoptotic cell death and associated B- interfered with local testosterone activation by down- cell lymphoma-2 (BCL-2) and BCL2-associated X protein regulating 5-α-reductase and consequently reduced steroid (BAX) proteins were markers in this case and showed a target gene expression (25). In a nude mouse model, orally- comparable increase (29). The inverse relationship between gavaged lycopene alone (5 or 50 mg/kg body weight) did not lycopene/tomato intake and the risk of PCa has been noted affect androgen-independent human PC-346C PCa xenograft through observation of PSA response. This response is an growth, however, combination of low-dose lycopene and outcome that is associated with risk of PCa and overall vitamin E significantly reduced tumor growth (26). In a disease progression. The majority of clinical trials with a different study, it was shown that consumption of tomato small number of enrolled patients have found an improved powder and not lycopene is associated with reduced prostate PSA response with intake of lycopene or tomato carcinogenesis. Male rats (n=194) treated with the carcinogen consumption indicating that consumption of lycopene and or N-methyl-N-nitrosourea and testosterone to induce PCa were tomato products can reduce the burden of PCa (26). fed diets containing whole tomato powder (13 mg lycopene/kg However, a large multicenter trial, termed the Prostate, Lung, diet), lycopene beadlets (161 mg lycopene/kg diet), or control Colorectal and Ovarian Cancer Screening Trial, examined the beadlets (27). The authors concluded that consumption of relationship between tomato or lycopene intake and PCa risk tomato phytochemicals and diet restriction may independently among participants and concluded that greater act to reduce the risk of PCa development (27). As noted, there lycopene/tomato product consumption does not protect from are varying degrees of evidence that show that tomato PCa development (30). Similar results were observed in a products containing lycopene reduce oxidative damage and recent PCa prevention trial examining whether serum tumor growth through multiple mechanisms. lycopene concentration was associated with PCa risk (31, Epidemiological evidence suggests that increased 32). The results of several pre-clinical and clinical trials consumption of tomatoes or its major carotenoid lycopene is reveal tomato products and lycopene may have a role in associated with a decreased risk for PCa (28). Tomato prostate cancer prevention and treatment, however, further products and lycopene have been shown to reduce the studies are warranted to specify the beneficial properties of proliferation of cancer cells, induce apoptosis, enhance gap lycopene and tomato products and their role in disease junction communication between cells, alter normal cell- prevention and treatment. cycle progression, and modulate androgen signaling pathways (19, 28). It has been noted that a reduction in Resveratrol testosterone levels is a key goal when treating PCa. In mouse models, it was shown that the expression of key testosterone Resveratrol (3, 5, 4’-trihydroxystilbene; Figure 2), a metabolism genes or receptors is significantly reduced in naturally-occurring phytoalexin, is produced in plants by the response to a diet containing 248 nmol lycopene per gram of enzyme stilbene in response to infection or other stress diet. This decrease in the expression of these genes suggests conditions. It is found in various dietary sources, including

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The effect of resveratrol on the phosphatase and tensin homolog (PTEN)/Protein Kinase B (AKT) pathway, one of the most commonly dysregulated pathways in PCa, has been studied extensively. PTEN is a tumor suppressor protein and a negative regulator of the cell survival phosphoinositide 3- kinase [(PI3K)/AKT] pathway whose function is often lost in PCa and other types of cancer. It was shown that resveratrol stimulates PTEN in C4-2 cells, a sub-clone of Figure 2. Structure of resveratrol. LNCaP cells (42). Further investigation comparing PTEN- transfected C4-2 cells and DU145 cells resulted in activation of PTEN promoter constructs in the former but not in the latter (42). The direct effect of resveratrol on phosphorylation of AKT, a protein kinase involved in cellular red grapes, red wine, peanuts, and mulberries. Two isoforms proliferation and survival, was determined by Western blot of resveratrol have been isolated, trans- and cis-resveratrol analysis and the results demonstrated a reduction in (33). Numerous studies have demonstrated the ability of phosphorylation. Resveratrol was also shown to inhibit the resveratrol to function as an antioxidant and a phosphorylation of mammalian target of rapamycin (mTOR) cardioprotective agent but recent research has focused on its and forkhead box O (FOXO), downstream proteins in the potential to function as a chemopreventive agent after it was PI3K/AKT pathway. Furthermore, dephosphorylation of demonstrated to inhibit the carcinogenic process at multiple FOXO results in its translocation to the nucleus and stages (34). These properties may play an important role in activation (43). These alterations serve as potential preventing or delaying the progression of PCa. components of the compound’s overall mechanism of action Studies employing PCa cell culture models have focused on within PCa cells. Resveratrol has demonstrated a high- elucidating the poorly understood mechanisms by which affinity for quinone reductase-2 (NQO2), a phase II resveratrol inhibits the development or progression of PCa. The detoxification enzyme that may contribute to gene control in focal points of these studies have included the compound’s PCa cells. NQO2 was shown to reduce the stability of cyclin- effect on cellular signal transduction pathways, specifically D1, as compared to NQO2-knockdown cells, in the presence intracellular regulatory proteins, cellular metabolism, and of cylclohexamide, indicating that NQO2 may play a crucial androgen receptors. In addition, induction of apoptosis and role in down-regulating the proliferation pathway. management of the cell cycle have also been investigated. Additionally, it was demonstrated that 10 μM of resveratrol Studies in different PCa cell lines revealed that resveratrol was sufficient to down-regulate cyclin-D1 in NQO2- effectively inhibits cell growth in general, causes disruption of containing cells, but 50 μM of resveratrol were required to transition between G1/S in DU145 and PC-3 cell lines, and achieve an equivalent reduction in NQO2-knockdown cells induces apoptosis in androgen-responsive LNCaP human PCa (44). The effects of resveratrol on cyclin-D1 levels are of cells. Resveratrol caused cell-cycle arrest and increased particular interest due to the commonality of cyclin-D1 apoptotic cell death in DU145 and PC-3 cells by sensitizing overexpression in malignant cells and the resulting them to ionizing radiation (35-38). Moreover, resveratrol dysregulation of the G1 to S phase transition. sensitized various human cancer cell lines, including PCa, to Cellular metabolism, frequently altered in cancer cells, such chemotherapeutic agents as doxorubicin, cytarabine may also serve as a target for induction of cell death by (AraC), actinomycin D, taxol, and methotrexate by down- resveratrol. Glutamine expression is usually up-regulated in regulating survivin expression and increasing apoptosis (39, cancer cells to enhance production of citrate via α- 40). An additional study that demonstrated reduction of ketoglutarate supplementation. The up-regulation of proliferation rates and increased apoptosis in PCa cells in a glutamine was demonstrated by treating C4-2 cells with dose-and time-dependent manner showed variability in cell U0126, a mitogen-activated protein kinase (MEK) 1 and 2 cycle proteins in LNCaP and PC-3 cells. For example, inhibitor, prior to treatment with resveratrol. Cells treated expressions of cyclin-D1, -E, and cyclin-dependent kinase-4 with U0126 were resistant to resveratrol-induced cell death. (CDK4), as well as cyclin-D1/CDK4 kinase activity were Additionally, U0126 demonstrated an ability to reduce reduced by resveratrol only in LNCaP cells. In contrast, cyclin- mitochondrial membrane potential and ATP levels. Depletion B and CDK1 expression and cyclin B/CDK1 kinase activity of glutamine from the cell media provided a protective effect were decreased in both cell lines in the presence of resveratrol. for the C4-2 cells for 60 h after the addition of resveratrol; Moreover, the induction of apoptosis in LNCaP and PC-3 cells cells observed in glutamine-free media did not display any was mediated by activation of caspases-3 and -9 and a change morphological changes indicative of distress (45). These in the ratio of BAX/BCL2 (41). results demonstrate that the effects of resveratrol may, like

4166 Bommareddy et al: Chemoprevention of Prostate Cancer (Review)

Figure 3. Structure of capsaicin.

malignancies, depend on altering cellular metabolism to tumor development, but further exposure resulted in the enhance or achieve cellular death. Androgens also play a promotion of angiogenesis and inhibition of apoptosis (50). A critical role in prostatic carcinogenesis, and therefore the recent study employing LAPC-4- and LNCaP-xenografted effects of resveratrol on the steroid hormones and their SCID mice which were on a diet supplemented with 50 mg/kg receptors are of interest. Resveratrol in the presence of an of resveratrol showed significantly worse survival of mice with androgen receptor (AR) promoter induced a reduction in PSA LAPC-4 tumors, but unchanged survival for those with LNCaP mRNA levels and attenuation in AR transcription (46). tumors (51). In a different study which compared the Resveratrol also demonstrated an ability to inhibit the chemopreventive effects of oral resveratrol and two of its translocation of AR to the nucleus. By using wild-type AR analogs, trimethoxy-resveratrol (3M-Res) and piceatannol and a ligand binding domain (LBD)-deleted mutant it was (PIC), in LNCaP-Luc-xenografts, it was found that two weeks demonstrated that, unlike in estrogen receptors, the LBD of pre-treatment with the compounds diminished cell binding site of AR does not play a role in the mechanism of colonization, reduced tumor volume, and reduced tumor action of resveratrol. Inhibition of AR transcriptional activity growth in the xenografts. The analogs 3M-Res and PIC indicates that resveratrol impacts the receptor’s actions at a demonstrated higher potency in inhibiting tumor progression post-translational level (47). compared to resveratrol alone (52). Many studies employing in vivo models have attempted to Numerous clinical trials have demonstrated the safety of reproduce the in vitro activities of resveratrol. The transgenic resveratrol in humans (53, 54). Although there are currently rat for adenocarcinoma of prostate (TRAP) model was used to 17 human trials that have been completed or are in progress assess the effects of resveratrol in vivo. Treatment with drinking investigating the chemopreventive or therapeutic potential of water containing 50 μg/ml, 100 μg/ml, and 200 μg/ml of resveratrol, no trial to date has examined specifically the resveratrol, compared to normal drinking water resulted in a effects of resveratrol on prostate cancer in humans. modest reduction in responses, including reduced prostatic neoplastic lesions in TRAP rats (48). While the in vitro Capsaicin reduction in AR protein expression was reproduced in TRAP rats, no significant difference in the incidence of Capsaicin (Figure 3), a member of the vanilloid family is adenocarcinoma or prostatic intraepithelial neoplasia (PIN) was naturally present in a variety of foods of the human diet and demonstrated. The TRAP rat model revealed the translational is the element that is responsible for the hot burning effects of resveratrol from in vitro to in vivo; however, it failed sensation experienced upon physical contact with red and to produce a clinically significant reduction in adenocarcinoma chili peppers (55, 56). Its structure is related to endogenous or PIN. In a PC-3M-MM2 xenografted severe combined lipophillic agents such as N-arachidonoyl dopamine (NADA) immunodeficiency (SCID) mouse model of PCa, oral (3). Capsaicin is known for its anti-inflammatory and administration of resveratrol not only inhibited tumor growth analgesic effects and is a common ingredient in several but also reduced the incidence and number of metastatic lung creams and lotions used to treat arthritis and muscle pain lesions. The antitumor effects which were also observed in (55, 56). Studies have found that capsaicin also has anti- LNCaP and DU145 cells were attributed to reduced expression proliferative and apoptotic effects on PCa cells. Its of miR-21 (only in xenograft tumors) and pAKT, and elevated mechanism of action appears to be mediated via both programmed cell death protein 4 (PDCD4) (49). In a different transient receptor potential vanilloid-1 (TRPV-1) receptor- study, Wang et al. reported that resveratrol exerts differential dependent and -independent means (56). effects on in vivo and in vitro PCa models (50). It was shown Capsaicin demonstrated in vitro growth inhibition and that resveratrol exhibits growth-inhibitory effects on LNCaP induction of apoptosis of androgen-independent PCa cells, cells through multiple mechanisms including steroid-dependent PC3 and DU-145, through many receptor-independent hormone pathways. However, in vivo studies employing actions. A study found that capsaicin (≥10 μM) reduced LNCaP xenografts showed that resveratrol initially delayed proliferation of PC3 and DU-145 cells. It induced apoptosis

4167 ANTICANCER RESEARCH 33: 4163-4174 (2013) by increasing production of ROS, dissipating the inner tumor cell transformation. TRPV1 expression has also been mitochondrial transmembrane potential, and activating correlated with increasing malignancy, suggesting that caspase-3 (55). The increase induced in ROS is due to the TRPV1 may serve as a prognostic factor (55). When inhibition of nicotinamide adenine dinucleotide hydrogen capsaicin binds to TRPV1 intracellularly, it induces the entry (NADH)-oxidoreductase, a key enzyme of the electron of calcium and other cations, leading to apoptosis (56). A transport chain which interacts with caspase-3 during the S study found that capsaicin induces a biphasic effect phase and possibly the G0/G1 phase of the cell cycle. promoting growth at low doses and inducing apoptosis at Capsaicin may also be considered a coenzyme Q antagonist doses greater than 100 μM. Therefore, low doses of (56). All of these properties contribute to alterations in cell capsaicin increase AR expression, whereas high doses inhibit permeability, stability and viability. It is important to note androgen-dependent PSA activation (55). In one study, that capsaicin specifically targets tumors due to their capsaicin was found to increase the viability of the LNCaP increased energy requirements and activity (56). Researchers cells TRPV1 receptor-dependently and the proliferative have also found that capsaicin works by generating and action of capsaicin was concomitant with a reduction in accumulating ceramide from sphingomyelin hydrolysis. The intracellular ceramide levels which was mediated by the molecular target involved for this specific action has not been PI3K/AKT and ERK pathways (61). Researchers have also determined yet but tNOX, a cancer specific cell surface examined the effects of capsaicin on TRPV6, which is NADH oxidase, is a candidate (57). In addition, capsaicin involved in the proliferation of LNCaP cells. They found that has been found to induce endoplasmic reticulum (ER) stress it is not involved in the apoptotic process but is also not in PC3 cells by inducing eukaryotic initiation factor 2α (eIF- regulated in advanced PCa cells (55). Its expression 2α) phosphorylation, activating transcription factor 4 (ATF4) correlates with Gleason scores and metastasis, so this may expression, and Growth arrest- and DNA damage-inducible be a marker to look at in more detail. Conversely, other gene 153 (GADD153)/C/EBP homologous protein (CHOP) studies found that capsaicin has a profound anti-proliferative expression (55, 58). Researchers completed a microarray effect on prostate cancer cells, inducing the apoptosis of both analysis on different genes involved in ER stress and AR-positive (LNCaP) and -negative (PC-3, DU145) PCa cell apoptosis. PC3 cells were treated with 20 μM capsaicin for lines associated with an increase of p53, p21, and BAX. 72 h and then total mRNA was extracted. It was found that Capsaicin reduced expression of PSA and AR, and activation capsaicin induces phosphorylation of eIF-2α, which then of NF-κB (59). Another in vitro study examined the growth activates GADD153/CHOP, an ER stress-regulated gene. of LNCaP cells in monoculture and co-culture with This triggers a signal transduction network to induce cellular osteoblasts and the response to tNOX inhibitors. They found apoptosis. Blockade of GADD153/CHOP activity that capsaicin preferentially inhibits growth and tNOX significantly reduced capsaicin-induced anti-proliferative activity of a number of carcinoma cell lines. They also actions (58). Additional studies indicate that capsaicin also examined the effect of capsaicin on LNCaP cells when reduces transcription of the AR and impairs activation of the combined with a green tea mixture, Capsibiol T. Capsibiol PSA promoter/enhancer. The same study also demonstrated T, at a concentration of 50 μM, was more potent at inhibiting that capsaicin inhibits the nuclear translocation and the viability of LNCaP cells grown in co-culture with activation of NF-κB (59). Another study examined the effects osteoblasts compared to LNCaP cells grown in monoculture. of capsaicin on interleukin-6 (IL-6) production by PC3 cells. This suggests that the combination of tea catechins with Capsaicin induced a time-dependent increase in the synthesis capsaicin has the potential to inhibit the growth of PCa cells and secretion of IL-6 and tumor necrosis factor-α (TNFα). in the bone environment, making it appropriate for further Investigators determined that capsaicin worked via TRPV1- study in this particularly common metastatic site (62). and AKT-independent pathways to promote cell death, but Studies have also demonstrated the in vivo effect of induction of IL-6 was mediated via receptor- and Akt- capsaicin on PC-3 xenografts in nude mice. Oral dependent pathways. It has been shown that in LNCaP and administration of capsaicin (5 mg/kg) three days a week PC-3 cells, TNFα has anti-proliferative and proapoptotic resulted in tumors which were significantly smaller in size effects, while in other cancer types, TNFα is an indicator of and volume compared to the control group (63). In a a poor prognosis (55). different study, capsaicin at 10 mM concentration was used As outlined above, some of the effects of capsaicin appear to induce prostatitis in a rat model (64). This difference in to be TRPV1 receptor-dependent. Expression of functional concentration of capsaicin used suggests that there is a TRPV1 receptors was confirmed in both PC3 and LNCaP clinical therapeutic window which must be determined to lines, as well as in human prostate tissue, via western blot achieve beneficial effects (65). analysis and reverse transcription polymerase chain reaction A literature search yielded only one epidemiological (RT-PCR) (60). In humans, TRPV1 is found in the epithelial study, thus far, with capsaicin. Chili peppers are native to and interstitial cells of the prostate and is regulated following Nigeria and sub-Saharan Africa where the incidence of PCa

4168 Bommareddy et al: Chemoprevention of Prostate Cancer (Review) is very prevalent (constituting 24% of all cancer cases). It is believed that if Nigerians begin a proper diet (diet comprised with foods such as tomatoes, citrus fruits, soy beans, capsicum species and tea which have important phytochemicals) early in life that the incidence could be reduced, and the time-to-onset delayed (66). No human trials have been reported on efficacy or safety of capsaicin in the clinical setting. There is one case report of a 66-year-old man Figure 4. Structure of curcumin. with a PSA relapse after radiotherapy for a T2b, Gleason score 7 adenocarcinoma of the prostate. He had a continual rise in PSA and discontinued medication therapy due to intolerable side-effects. Prior to initiation of capsaicin, the PSA level was doubling every four weeks. The patient yellow color to foods. Turmeric also has a long history of started taking 2 ml of habaneras chili sauce, containing medicinal use and has been used for centuries throughout 454 μg/ml capsaicin, one or two times per week. Upon Asia, especially in the Hindu, Ayurvedic and Chinese testing the level of PSA (five consecutive time points), it was cultures, where it is used to treat a variety of inflammatory found that the doubling time increased from 4 to 7.3 weeks, conditions and chronic diseases (68). Many of its traditional with PSA calculated to be 13.26 ng/ml six months later. At properties, including its anti-carcinogenic activity, have been this time, he began taking 2 ml of the sauce daily and within validated in various cellular and animal models of diseases. three months, the PSA level dropped to 11.3 ng/ml. The Curcumin and its active metabolites, such as patient decided to stop taking the habanera sauce, and the tetrahydrocurcumin, have been widely studied for their anti- PSA level rose to 13.57 ng/ml in a month and a half. He inflammatory and anti-carcinogenic effects (69, 70). restarted the treatment increasing the amount of sauce to Several in vitro studies employing different PCa cell lines 15 ml daily, his PSA level was stable for nine more months have provided evidence that curcumin may inhibit the before deciding to discontinue the treatment again. Within development of PCa at different stages (71-76). Early studies two months, his PSA level had reached 22.3 ng/ml. The involving LNCaP and PC-3 cells showed that curcumin is a patient never reported any side-effects from the intake of potent inhibitor of epidermal growth factor receptor (EGFR) capsaicin. Based on this case, one may conclude that signaling (77). Treatment of cells with curcumin suppressed capsaicin has the potential to reduce and stabilize the PSA both constitutive (DU145) and inducible (LNCaP) NF-κB level in humans, and further clinical studies are needed to activation, and potentiated TNF-induced apoptosis. These substantiate the role of capsaicin on PSA level (67). effects appeared to be mediated via down-regulation of In conclusion, capsaicin appears to have a role in the BCL2 and BCL-XL and the activation of procaspase-3 and prevention and management of PCa. It is inexpensive and procaspase-8 (78). Curcumin arrests cell movements and appears harmless when administered at appropriate alters cell shape more potently in PC-3 cells compared to concentrations, although there is still some controversy LNCaP cells (79). Chendel et al. also demonstrated the concerning its clinical use, some studies showing that it can ability of curcumin to inhibit TNF-α-mediated NF-κB induce pain and inflammation at higher concentrations (64). activity, resulting in BCL2 protein down-regulation in PC-3 Some investigators even believe that capsaicin has the cells. This enhanced radiation-induced apoptosis by releasing potential to be carcinogenic at certain concentrations (64, cytochrome c and activating caspases (80). Studies also 67). Nonetheless, capsaicin may potentially be used for those demonstrated the ability of curcumin to trigger DNA damage patients who are refractory to hormonal therapy (59). This and cell death of PCa cells. Curcumin induced the expression would be helpful as there is currently no successful therapy of various pro-apoptotic factors, including the p53 tumor for this population group (67). There is much work to be suppressor protein, p53 up-regulated modulator of apoptosis done in understanding the role of capsaicin in PCa (PUMA) and BIM (75, 76). The latter study (76) reported a prevention and treatment and hence it is essential to conduct reduced expression and activity of CC motif ligand-2 more preclinical and clinical studies to determine its safety (CCL2) and matrix metalloproteinase-9 (MMP-9) proteolytic and efficacy. activity, causing reduced PC-3 cell adhesion, motility and invasion. In a recent study, it was shown that curcumin Curcumin suppressed EGF-stimulated and heregulin-stimulated PC-3 cell invasion, as well as androgen-induced LNCaP cell Curcumin (diferuloylmethane; Figure 4), a major yellow invasion (81). Curcumin treatment also reduced MMP-9 pigment of turmeric (Curcuma longa Linn.) is the most activity and down-regulation of cellular matriptase, a common spice in the Indian subcontinent, adding flavor and membrane-anchored serine protease with oncogenic roles in

4169 ANTICANCER RESEARCH 33: 4163-4174 (2013) tumor formation and invasion (81). Another study different study, it was shown that curcumin may inhibit or demonstrated that curcumin up-regulated the mitogen- delay the onset of PCa via the activation of protein kinase activated protein kinase phosphatase-5 (MAPK-5), D1 (PKD1) and synergize conventional chemotherapy by subsequently reducing cytokine-induced p38-dependent pro- activating PKD1 and inhibiting β-catenin transcriptional inflammatory changes in normal prostatic epithelial cells. In activity both in cell culture and xenograft models (86). In a contrast, PCa cells (DU145, PC-3, LNCaP and LAPC-4) recent study employing an orthotopic mouse model of retained the ability to up-regulate MAPK-5 following hematogenous metastasis, it was shown that treatment with curcumin treatment (82). A study of the oncoprotein murine curcumin yielded statistically significant inhibition of the double minute (MDM2), a major ubiquitin E3 ligase of formation of lung metastases by disrupting the prometastatic tumor suppressor p53, identified that curcumin down- feedback loop between NF-κB and CXCL1/-2 (90). The regulates MDM2 independently of p53, especially in PC3 anticancer properties and ability of curcumin to inhibit the (p53null) cells. Curcumin reduced both protein and mRNA proliferation of various tumor cells in culture, and its role in levels of MDM2 in a dose- and time-dependent manner, preventing carcinogen-induced cancer in rodents, the growth while enhancing the expression of the tumor suppressor of human tumors in xenografts or orthotransplanted animal p21WAF1/CIP1 (83). Along with other dietary agents, models, either alone or in combination with curcumin was shown to inhibit Hedgehog signaling and chemotherapeutic agents or radiation, has been well expression of the glioblastoma (GLI) protein in PCa cells documented [reviewed (91)]. (84). The role of curcumin on the wingless integration Results from preclinical models have shown that curcumin (WNT)/β-catenin signaling pathway also revealed a marked is rapidly metabolized, conjugated in the liver, and excreted suppression of β-catenin and its targets implicated in cell- in the feces, therefore having limited systemic bioavailability cycle regulation only in androgen-dependent cell lines; [reviewed (92)]. Several phase I and phase II clinical trials further analysis showed that levels of cyclin-D1 and cellular indicate that curcumin is quite safe and may exhibit homolog of retroviral v-mycooncogene (c-MYC), the target therapeutic efficacy (91, 93). A phase I clinical trial which gene of the β-catenin/T-cell factor transcriptional complex, attempted to determine the toxicity of curcumin were also decreased (85-87). demonstrated that curcumin was well tolerated at dose levels Pre-clinical studies employing various animal models up to 3600 mg for up to four months in patients with provided evidence regarding the role of curcumin in advanced colorectal cancer (94) and up to 8000 mg for up to preventing or reducing the development of prostate cancer. three months in 25 patients with various precancerous lesions A curcumin-supplemented diet has been shown to inhibit (95). These results hold promise, and interest in curcumin as tumor growth of DU145 xenografts in addition to reducing a preventive and therapeutic agent continues to grow. A the number of metastatic nodules in lungs by inhibiting the number of human trials investigating the chemopreventive or activity of MMP-2 and MMP-9 (73). Curcumin also therapeutic potential of curcumin in various pre-malignant inhibited growth of LNCaP xenografts in nude mice by and cancer conditions have been completed or are underway, inducing apoptosis and inhibiting cell proliferation, and also however, none of those trials specifically target PCa sensitized these tumors to tumor necrosis factor-related prevention or treatment. The data from all the pre-clinical apoptosis-inducing ligand (TRAIL)-induced apoptosis. studies clearly provide evidence for curcumin as a potential Moreover, in xenografted tumors, curcumin up-regulated the anticancer therapy; however, more studies are required to expression of TRAIL-R1, TRAIL-R2, BAX, BAK, identify the mechanism(s) through which its bioavailability p21/WAF1, and p27/KIP1, and inhibited the activation of may be enhanced and explore possible combination regimens NF-κB and its gene products such as cyclin-D1, vascular for prevention and treatment of PCa. endothelial growth factor (VEGF), urokinase plasminogen activator (uPA), MMP-2, MMP-9, BCL2 and BCl-XL (88). Conclusion Intaperitoneal administration of a combination of curcumin (3 μM) and phenethyl isothiocyanate (PEITC, 2.5 μM) The main focus of this article was to review recent advances inhibited well-established PC-3 tumor xenografts in nude in studies of the chemopreventive properties of four major mice more effectively than administration of PEITC or phytochemicals against PCa development and summarize the curcumin alone at higher doses (72). A further study in vitro and in vivo findings, including results of available conducted by the same group in the TRAMP model revealed and or completed clinical trials. A PubMed search was that a diet supplemented with 2% curcumin or 0.05% PEITC, carried out with the search terms “lycopene and prostate or a combination of 1% curcumin and 0.025% PEITC for a cancer” and likewise with other phytochemicals. Based on period of 10 or 16 weeks significantly reduced the incidence the results from pre-clinical and epidemiological studies, it of the development of high-grade PIN and PCa, at least in is evident that administration of naturally-occurring part, by down-regulating the AKT pathway (89). In a phytochemicals may have a protective effect against the

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