Molecular Targeted Therapies Using Botanicals for Prostate Cancer Chemoprevention
Translational Medicine

Translational Medicine
Open Access

ISSN: 2161-1025

Review Article - (2012) Volume 0, Issue 0

Molecular Targeted Therapies Using Botanicals for Prostate Cancer Chemoprevention

Nagi B. Kumar1,2* and Ganna Chornokur1
1Department of Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Florida, USA
2University of South Florida College of Medicine, Florida, USA
*Corresponding Author: Nagi B. Kumar, Division of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center & Research Institute at the University of South Florida College of Medicine, 12902 Magnolia Drive, Tampa, Florida, USA, Tel: (813)-745-6885, Fax: (813)-745-7183 Email:


In spite of the large number of botanicals demonstrating promise as potential cancer chemopreventive agents, most have failed to prove effectiveness in clinical trials. Critical requirements for moving botanical agents to recommendation for clinical use include adopting a systematic, molecular-target based approach and utilizing the same ethical and rigorous methods that are used to evaluate other pharmacological agents. Preliminary data on a mechanistic rationale for chemoprevention activity as observed from epidemiological, in vitro and preclinical studies, phase I data of safety in suitable cohorts, duration of intervention based on time to progression of pre-neoplastic disease to cancer and using a valid panel of biomarkers representing the hypothesized carcinogenesis pathway for measuring efficacy must inform the design of clinical trials. Botanicals have been shown to influence multiple biochemical and molecular cascades that inhibit mutagenesis, proliferation, induce apoptosis, suppress the formation
and growth of human cancers, thus modulating several hallmarks of carcinogenesis. These agents appear promising in their potential to make a dramatic impact in cancer prevention and treatment, with a significantly superior safety profile than most agents evaluated to date. The goal of this paper is to provide models of translational research based on the current evidence of promising botanicals with a specific focus on targeted therapies for PCa chemoprevention.

Keywords: Prostate cancer, Chemoprevention, Isoflavones, Green Tea Polyphenols (GTP), Decursin, Curcumin


The disease: prostate cancer

Prostate Cancer (PCa) is the most frequently diagnosed malignancy in men with 241,740 new cases and 28,170 deaths estimated to occur in 2012 [1]. The initiation and progression of PCa may involve a complex array of both exogenous and endogenous factors [2-5]. Although it is clear that clinical PCa incidence and mortality vary greatly between populations, the frequency of latent PCa is evenly distributed among populations, suggesting that external factors such as diet, physical activity and other lifestyle factors are important in the transformation from latent into more aggressive, clinical cancer [2-5]. Although early screening and detection has been used historically as strategies for PCa prevention, recently these recommendations have been a subject of much debate. While screening using serum Prostate Specific Antigen (PSA) has not been shown to significantly reduce either PCa-specific or overall mortality, it has been linked to substantial overtreatment of clinically insignificant, potentially indolent tumors [6,7]. Taking into consideration all the evidence accumulated to date, the U.S. Preventive Services Task Force (USPSTF) recommended against PSA-based PCa screening in asymptomatic men (grade D recommendation) [8]. These features of PCa, namely, high prevalence in specific populations, the uncertainty with regard to effectiveness and value of early screening along with a concerned and eager cohort of men interested in reducing their risk for PCa provides an excellent opportunity and need to develop alternate PCa control strategies targeting these specific populations of men.

The goal of this review is to: 1. establish the rationale for use of botanicals for PCa chemoprevention; 2. provide a practical model using a systematic approach for evaluating botanicals, and; 3. provide examples of several botanicals that we have taken from bench to bedside using this approach, with a specific focus on the molecular pathways that these botanicals target.

Cancer chemoprevention

Chemoprevention refers to the inhibition of pre-invasive and invasive cancer and its progression or treatments of identifiable pre-cancers [9,10]. Chemoprevention efforts require a thorough understanding of the mechanism of carcinogenesis including signaling and metabolic pathways and genetic progression pathways. New technologies in genomics and proteomics have spurred this field of research. The use of this knowledge to develop pharmacologic agents (including botanicals/biologicals) to reverse or halt the process of carcinogenesis is called chemoprevention. Agents for chemoprevention include anti-promotion and anti-progression agents that prevent the growth and survival of cells that are already committed to become malignant [9,10].

Approach to identifying and evaluating safety and effectiveness of Botanicals for PCa chemoprevention

Although several targeted “smart” drugs have emerged over the past decade, it is clear that diseases like cancer have an etiology based on perturbations of multiple signaling pathways. Thus, targeting multiple pathways may represent a more effective approach to cancer control [11,12]. In addition, the mono-targeted “smart” drugs are associated with high cost, and produce numerous side effects. These drawbacks of mono-targeted drugs underscore the importance for the development of multi-targeted, innocuous, inexpensive, and readily available botanicals for the prevention of cancer [13]. Botanicals have been shown to influence multiple biochemical and molecular cascades that inhibit mutagenesis, proliferation, induce apoptosis, suppress the formation and growth of human cancers, thus modulating several hallmarks of carcinogenesis. Additionally, these agents appear promising in their potential to make a dramatic impact in cancer chemoprevention, with a significantly superior safety profile than most agents evaluated to date [14-20]. It is clear that although several botanicals have been characterized and used for hundreds of years in medicine [21,22], there have been several challenges and limitations towards progress in this field. The slow pace of growth of several of these leads could be attributed to regulatory protection of classical formulation, lack of standardization, quality control, and molecular mechanism-based approach in evaluation, population-based normal range of bio-markers, laboratory practices and lack of translational scientists engaged in conducting well designed trials. However, several valuable lessons have been learnt from the chemoprevention trials of the past such as the Selenium and Vitamin E Cancer Prevention Trial (SELECT) [23], Alpha-Tocopherol, Beta Carotene Cancer Prevention trial (ATBC) [24] and the Carotene and Retinol Efficacy Trial (CARET) [25]. Critical requirements for moving botanicals from bench to bedside include adopting a systematic, molecular-mechanism based approach and utilizing the same ethical and rigorous methods such as those used to evaluate other pharmacological agents. Preliminary data on a mechanistic rationale and molecular targets for chemoprevention activity as observed from in vitro and preclinical studies, phase I data of safety in suitable cohorts, duration of intervention based on time to progression of pre-neoplastic disease to cancer and using a valid panel of biomarkers, including safety markers representing the hypothesized carcinogenesis pathway for measuring efficacy must inform the design of phase I-II prior to embarking on phase III clinical trials. Chemoprevention trials using combinations of botanicals such as curcumin with piperine [26] have demonstrated that synergy between agents can lead to lower doses, improved efficacy and fewer or less severe toxicities. An assessment of endpoints in trials resulting in approval of an agent for cancer chemoprevention agent reveals that nearly all have been approved on the basis of intraepithelial neoplasia. Intermediate endpoint biomarkers must be identified, validated and must be conducive to be obtained using non-invasive techniques and without compromising safety to men in chemoprevention trials. To reduce patient burden, these markers must be obtained from accessible organs and during the normal course of clinical surveillance. Randomized, placebo-controlled design and the long-term follow-up and monitoring are critical to meet FDA requirements and promote acceptance in the marketplace [13,27,28]. Multiple botanicals have been identified and appear promising for PCa chemoprevention. Applying the lessons learnt from previous trials with botanicals to the design of future PCa chemoprevention trials should facilitate the translation of novel preventive agents from bench to bedside.

Target populations at high risk for PCa

Most chemoprevention trials of the past have demonstrated that there are significant benefits to targeting germline, familial, or increased-risk cohorts such as those with a family history or other risk based on race and ethnicity [13]. These trials can produce more power over a shorter time frame. In most epithelial tissues, including the prostate, genetic progression and loss of cellular control functions are observed as the cell and tissue phenotype changes from normal to dysplasia (prostatic intraepithelial neoplasia or PIN), then to increasingly severe dysplasia (High Grade PIN or HGPIN), superficial cancers and finally to invasive disease [3-5,29-31]. Recent studies have quantified the risk for invasive PCa in men with HGPIN, and it was suggested that the incidence of PCa was as high as 30% within 1 year after repeated biopsy [32,33]. Several lines of evidence derived from animal models, together with data obtained in epidemiological, morphological, genetic, and molecular studies, support HGPIN as the main premalignant lesion of PCa [3-5,29-33]. Thus, HGPIN is considered a possible pre-invasive precursor of PCa [3-5]. Isolated high-grade prostatic intraepithelial neoplasia has a 3% to 14% incidence and predicts cancer on repeat biopsy in 23% of cases [34-36]. More recently, Atypical Small Acinar Proliferation (ASAP) has emerged as a diagnosis of exclusion but with a greater association to prostatic carcinoma than HGPIN. ASAP is characterized by a focus of glands that do not contain sufficient cytologic or architectural atypia to establish a definitive diagnosis of cancer [34-36]. Atypical small acinar proliferation suspicious for malignancy designates foci that have either qualitative or quantitative limitations in atypia precluding a definite cancer diagnosis. Contemporary studies indicate that ASAP has a 39% predictive value for cancer on repeat biopsy. In studies reviewed in the literature, HGPIN/ASAP had a mean predictive value for cancer of 43.6%, much higher than isolated HGPIN but similar to ASAP [37-39]. Thus, HGPIN and ASAP are associated with progressive abnormalities of phenotype and genotype, which are intermediate between normal prostatic epithelium and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of prostatic carcinogenesis. Due to the uncertainty with PCa screening and early detection strategies, especially in the high-risk populations, alternative cancer control strategies are needed. Importantly, PCa is an ideal malignancy for PCa chemoprevention due to the high prevalence, long latency, significant mortality and morbidity, and the availability of HGPIN and ASAP as intermediate predictive stages of progression. These estimates justify the rationale for selecting these groups of men with HGPIN and ASAP as a target high-risk population for evaluating promising chemopreventive agents for prevention of PCa.

An estimated 35, 110 cases of PCa are expected to occur among African American men in 2011, accounting for 40% of all cancers diagnosed in that population. Between 2003 and 2007, the average annual PCa rate was 60% higher in AA men compared to white men [40]. In addition, AA men have the highest PCa-specific mortality rate of any other racial or ethnic group in the US. Although the overall incidence of and mortality from PCa has been declining in Caucasian men since 1991, possibly due to improved diagnostic techniques, better screening and improved surgical and radiologic treatments, the decline in AA men lags behind Caucasian men. For AA men with a family history of hereditary PCa, the increased risk is even greater [41]. Autopsy studies and clinical findings support the argument that PCa exhibits more aggressive biological behavior in AA men than that observed in other populations. Interestingly, not only the prevalence of HGPIN is higher in the general population of AA men [42-44], but AA men with HGPIN are more likely to develop aggressive PCa [44]. Finally, HGPIN seems to be a risk factor for biochemical recurrence following the definitive treatment specifically in AA, but not in Caucasian, men [45]. These findings help delineate the cohorts of men under exceptionally high CaP risk. Importantly, such cohorts may represent ideal targets to evaluate botanicals for PCa chemoprevention.

Promising Agent for Chemoprevention of PCa


Isoflavones in the diet are primarily derived from soy products, although isoflavones are also found in other legumes, including peas, lentils, or other bean varieties [46]. The primary isoflavones in soybeans are genistein, daidzein, and glycitein. Epidemiological studies have consistently reported lower incidence of clinically evident disease in populations consuming isoflavones. An inverse relationship between dietary intake, plasma [47-52] and prostatic fluid concentrations of isoflavones and the incidence of PCa and Benign Prostatic Hyperplasia (BPH) has been observed in these populations, demonstrating the potential role of isoflavones in mediating epigenetic effects. In vitro data have consistently shown that genistein, the most active and predominant isoflavone, modulates cell proliferation [53-57], angiogenesis [58,59], tumor cell invasion and tumor metastasis [53,60,61], cell cycle regulation [62], antioxidant [60,63] and induction of apoptotic cell death [64]. These data indicate that isoflavones are promising chemopreventive agents, with several cellular effects which are both genomic and non-genomic. Specific anticarcinogenic activity of the isoflavone genistein include inhibition of protein-tyrosine kinase, which results in the alleviation of cancer growth via inhibition of PTK-mediated signaling mechanisms; inhibition of topoisomerases I and II and protein histodine kinase, which have antiproliferative or pro-apoptotic effects; antioxidant effects, through inhibition of the expression of stress-response related genes; inhibition of nuclear factor kappa B (NF-κB) and Akt signaling pathways, both of which are important for cell survival; inhibition of angiogenesis; down-regulation of transforming growth factor-beta; and the inhibition of Epidermal Growth Factor (EGF) [65]. Our computational docking and in vitro and in vivo proteasome activity studies confirmed that the isoflavone genistein is also a proteasome inhibitor [25,26]. In addition, we found that genistein at 1 μM could inhibit ~30% of the chymotrypsin-like activity of purified 20S proteasome. It has been reported that plasma levels of genistein are in a range of 0.5-2.5 μM and the concentrations of genistein vary in different tissues and organs. It is therefore possible that a partial inhibition of the proteasome activity by genistein at a physiological concentration might contribute to its reported cancerpreventative effects. Among different soy compounds, genistein was the most potent inhibitor of the proteasomal chymotrypsin-like activity. This is consistent with the previous reports that genistein is the most potent soy isoflavone. Inhibition of proteasome activity by genistein in PCa cells (LNCaP) was associated with increased levels of p27Kip1, IĸB-α (an important inhibitor of the tumor survival factor NFκB), Bax, and ubiquitinylated proteins, accompanied by induction of apoptotic cell death. We also found that genistein was the most potent of all the tested isoflavones in terms of inducing Bax accumulation and PARP cleavage. However, daidzein and glycetin, in addition to genistein, were able to indice accumulation of the p27Kip1 protein. These results suggest that accumulation of Bax and IĸB-α is associated with apoptosis induction while p27Kip1 accumulation is probably associated with G1 arrest [24].

Based on its structural and functional similarity to estrogen, genistein is considered a phytoestrogen. Although a role for the Estrogen Receptors (ERs), ERα and ERβ, has been implicated in prostate tumorigenesis, their role in mediating the chemo-preventive effect of genistein in prostate is not clear. Research led by Bai et al. [28,66,67] and others [68-70] showed that androgens and estrogens repressed the FOXO1 activity in PCa cells, a process that is independent of the PKB/AKT-mediated FOXO1 phosphorylation. The repression is Androgen Receptor (AR) and ERα-dependent, respectively, and mediated through the formation of receptor-FOXO1 protein complex. These data demonstrate that FOXO1 as a novel target of genistein in PCa cells. The mechanism of action of genistein signaling via the ER/ AR-FOX01 pathway is relevant in specifically studying the effectiveness and safety of genistein in AA men. It has been shown that the AR activity is controlled by the length of poly-glutamine repeat in the N-terminal region and AA men, on an average, have been shown to have shorter poly-glutamine repeat and thus higher AR activity [70]. Based on these results that demonstrated that genistein down regulates AR expression and that the increase in FOX01 activity by genistein is mediated through AR down regulation, we suggest that genistein may have a stronger preventive effect in AA men [66-70].

Attempts to understand the cellular origin of cancer has advanced the theory of Cancer Stem Cells (CSCs). These rare cells have indefinite proliferative potential and are believed to be responsible for tumor invasiveness and heterogeneity [71]. Since Cancer Stem Cells (CSCs) are also involved in tumorigenesis and progression of PCa, Zhang et al. [72] reported that Tumorsphere (T) formation and colony formation of PCa cells were noticeably suppressed in the presence of genistein. Pretreatment of PCa Tumor Cells (TC) with genistein also suppressed tumorigenicity in vivo. Additionally, genistein treatment inhibited growth of PCa TCs. Further studies showed that genistein treatment not only led to the down-regulation of PCa CSC markers CD44 in vitro and in vivo, but also inhibited Hedgehog-Gli1 pathway, which may contribute to the anti-CSC effect of genistein in PCa TCs. Their finding thus demonstrated that genistein may be a dietary phytochemical with the potential to target prostate CSCs.

Phase I trials have demonstrated the clinical characteristics and pharmacokinetics and safety of whole soy and purified isoflavones with single and multiple-dose administration in healthy, early stage or treated cancer patient cohorts [73-75]. While the doses of purified soy isoflavones ranged from 1-16 mgs/kg body weight, some of the doses were higher than those previously administered to humans as whole soy proteins, without significant clinical toxicity. A few pilot phase II clinical trials including our study, have demonstrated a trend towards stabilization or reduction of PSA with short-term isoflavone supplementation in PCa patient populations, without significant clinical toxicity [76-81], with the exception of mild Gastrointestinal (GI) symptoms. In our phase II clinical trial of isoflavone supplementation in men with localized PCa, [78] we administered whole soy isoflavones at a dose of 60 mgs in 60 grams soy protein. Fifty-nine patients completed the 12-week intervention. Serum free testosterone was reduced or showed no change in 61% of subjects in the isoflavone group compared to 33% in the placebo group. Serum total PSA decreased or was unchanged in 69% of the subjects in the isoflavone treated group compared to 55% in the placebo group and nineteen (19) percent of subjects receiving soy isoflavones reduced total PSA by two points or more during the intervention period. Seventeen (17) subjects were unable to complete the study reporting constipation and GI symptoms such as bloating, discomfort, diarrhea and pain which were attributable to the protein content of these supplements and required early exclusion of these subjects from the study. Since the potent agent in these soy compounds are isoflavones and not the protein, and as demonstrated by these earlier trials have few clinical symptoms attributable to them, isoflavones preparations without the protein may be the most promising agent in clinical trials.

Based on our experience and the results of these earlier phase I and II studies, we then hypothesized that supplementation with a constant dose of purified isoflavones (vs. a placebo) will produce an increase in plasma levels of isoflavones which will be correlated with stabilization or reduction in surrogate markers of proliferation (serum total PSA) and thereby contribute to a decrease or stabilization of disease progression in men diagnosed with early stage PCa. To test this hypothesis, we recently completed a pilot Phase II randomized, doubleblinded, placebo-controlled trial [79,81] of men with early stage PCa (Gleason 2-6) to receive purified isoflavones, (Prevastein HC® 80 mgs/ day, IND #61,949 Kumar) vs. a placebo, and observed the effectiveness of the study agent in producing an increase in plasma levels of isoflavones (daidzein, glycitein and genistein) and a corresponding reduction/stabilization in serum total PSA. In addition, our aim was to evaluate compliance and toxicity. In this phase II trial, evaluation of the effectiveness of intervention was based on the magnitude of change in plasma levels of isoflavones in the isoflavone-supplemented group compared to the placebo group and a corresponding stabilization or reduction in surrogate markers of proliferation (total PSA), increase in serum estradiol and reduction in free testosterone. Fifty subjects completed the 12-week intervention. Significant increases in plasma isoflavones (p ≤ 0.001) were observed from baseline to 4 and 12 weeks in the isoflavone-treated group compared to placebo, without significant clinical toxicity. Although greater mean reduction of serum free testosterone was observed in subjects in the isoflavonetreated group compared to the placebo group, these changes were not statistically significant for this duration of intervention (p=0.3). Increasing concentrations of plasma isoflavones diadzein (p=0.02) and genistein (p=0.01) in the isoflavone-treated group were inversely correlated to changes in serum PSA compared to the placebo arm. In a recently completed Phase II randomized-controlled trial [74] to evaluate the safe and effective dose of isoflavones to be used in future clinical trials for PCa prevention; forty-five eligible men were supplemented with 40, 60 and 80 mgs of purified isoflavones or no supplement from biopsy to prostatectomy. Compliance to study agent, toxicity, changes in plasma isoflavones, serum steroid hormones, Prostate Specific Antigen (PSA) and tissue Ki-67 were analyzed from baseline to completion of study. Forty-four subjects completed the study with duration of intervention of 30 (± 3) days. We observed significant increases in plasma isoflavones with treatment for all doses compared to controls without producing any toxicity. A significant increase in serum total estradiol was observed in the 40 mgs and 60 mgs isoflavone-treated arms. However, significant increase in serum free testosterone was observed in the 60 mgs isoflavone-treated arm. Since only post-intervention tissue samples were available for staining, the difference between the treatment arms and control of percentage Ki- 67 staining were estimated in these samples. Compared to the control group and other treatment arms, the 40 mgs isoflavone supplemented arm had a lowest percentage of cells expressing Ki-67, although this was not statistically significant for this sample size and duration of intervention. We concluded that 40 mgs of purified isoflavones may be the best dose to be used in a future definitive, larger phase II clinical trial to evaluate purified isoflavones in prostate carcinogesis. With prolonged consistent administration of purified isoflavones, we could potentially delay onset of the disease by interfering with the later stages of prostate carcinogenesis or growth and progression of pre-neoplastic and histologic cancer.

Based on the finding that genistein down regulates AR expression and produces an increase in FOX01 activity, a pathway that may be more relevant in African American (AA) men, we are now examining the comparative efficacy and safety of 40 mgs of isoflavones in AA and Caucasian men and validating the potential mechanisms by which isoflavones modulate prostate carcinogenesis, specifically in AA men. In this clinical trial, we are testing the hypothesis that the pathway by which isoflavones will suppress prostate tumorigenesis is mediated by the ERβ, which can be suppressed by ERα in PCa cells such that ERβ is decreased. In addition, genistein inhibits androgen signaling through FOXO1 by down regulating AR expression, resulting in apoptosis and leading to the suppression of prostate carcinogenesis. We additionally hypothesize that the effectiveness of isoflavones to modulate prostate carcinogenesis will be significantly higher in AA men compared to Caucasian men. This trial is scheduled for completion in (month and year), and we expect the results to be published by December 2013 [28].

Green Tea Polyphenols (GTP)

Similar to isoflavones, numerous reports have provided the epidemiological evidence suggestive of a protective effect of tea consumption against human cancers including PCa [82-85]. In contrast, a few studies have associated an increased risk potentially attributed to confounding factors that include consumption of salted or very hot tea, geographical location, tobacco and alcohol use, and other dietary differences [82-86]. Of all the tea produced worldwide, about 20% of green tea is consumed in Asian countries such as China, Japan, Korea and India. Interestingly, these populations consistently demonstrate lower risk of PCa [87-90].

Several published preclinical studies using green tea, green tea leaves, green tea extracts, GTP mixtures, Green Tea Catechin (GTC) mixtures, and individual catechins have demonstrated chemopreventive efficacy in PCa [91-95]. Using the TRAMP mice model, Gupta et al. [91] were able to demonstrate that oral infusion of GTP extract at a human achievable dose (equivalent to six cups of green tea per day) significantly delayed primary tumor incidence and tumor burden as assessed sequentially by Magnetic Resonance Imaging (MRI), decreased prostate (64% of baseline) and Genitourinary (GU) (72%) weight, inhibited serum insulin-like growth factor-I (IGF-I) and restoration of insulin-like growth factor binding protein-3 levels (IGFBP-3), and produced marked reduction in the protein expression of Proliferating Cell Nuclear Antigen (PCNA) in the prostate compared with water-fed TRAMP mice. Furthermore, GTP consumption caused significant apoptosis, which possibly resulted in reduced dissemination of cancer cells, thereby causing inhibition of development, progression and metastasis to distant organ sites. However, in another similar animal model, Epigallocatechin Gallate (EGCG) only slightly reduced occurrence of these endpoints [91]. These disparate observations may be attributed to the pharmacokinetic properties of EGCG, which has relatively low oral bioavailability, possibly due to slow absorption as well as high metabolic clearance by the liver [27]. Other potential confounders may include doses, method of infusion, duration of intervention and timing of castration, all of which may influence the markers of progression and the antioxidant property of EGCG. Oral administration of GTPs (vs. pure EGCG) at 500 mg/kg/day in drinking water to TRAMP mice is expected to cause a higher systemic exposure compared to gavage and may explain the protective effects observed by Gupta et al. and other groups [91,93-95] compared with Suttie et al. [92]. In the authors’ opinion, the animal data demonstrating the chemopreventive efficacy of GTP in PCa appear promising, although additional research is needed to resolve the aforementioned concerns before a controlled phase II/III human trial could be initiated.

Tea and tea compounds reduce growth and/or induce apoptosis in several human cancer cell lines in vitro, including the prostate. Among the constituents of Green Tea Extracts (GTE), laboratory studies have identified Epigallocatechin Gallate (EGCG) as the most potent chemopreventive agent which appears to affect a number of molecular processes including induction of apoptosis and inhibition of tumor growth and angiogenesis [96-99]. More recently, EGCG has been found to affect several cancer-related proteins including p27, Bcl-2 or Bcr-Abl oncoproteins, Bax, matrix metalloproteinases (MMP-2 and MMP-9) [100], the androgen receptor, EGF receptor, Activator proteins 1(AP1), and some cell cycle regulators [101-103]. Based on these studies of GTP in cell culture systems, Adhami et al. [100] were able to demonstrate that EGCG in GTP induces apoptosis, cell growth inhibition and cyclin kinase inhibitor WAF-1/p21-mediated cell cycle-dysregulation. Using cDNA microarrays, they also observed the EGCG treatment of LNCaP cells results in induction of genes that exhibit the growth-inhibitory effects and repression of genes that belong to the G-protein signaling network [100]. These data confirm that GTPs exert potent and selective in vitro and in vivo pro-apoptotic activity on PCa cells.

By using various proteasome inhibitors, several recent studies have suggested that the ubiquitin/proteasome pathway plays an essential role in the regulation of apoptosis, and activation of the cellular apoptotic program is a current strategy for treatment of human cancers. Although there are several mechanisms by which EGCG may operate in prostate carcinogenesis, our group has demonstrated that EGCG potently and selectively inhibits the proteasome activity in intact human cells leading to the accumulation of IkB-α and p27 proteins, and growth arrest [32-35,40]. This inhibition of proteasome activity by EGCG occurred at or near physiological concentrations similar to that found in the body fluids of green tea drinkers. We have observed that Polyphenon E (a mixture of tea catechins) specifically inhibits the proteasomal chymotrypsin-like activity with an IC50 value of 7 μM [27]. The IC50 value for trypsin-like activity was above 100 μM, demonstrating that Polyphenon E preferentially inhibits the proteasomal chymotrypsin-like activities. Our data strongly suggest that the proteasome is a PCa-related molecular target of EGCG and Polyphenon E, and that inhibition of the proteasome activity by EGCG in Polyphenon E, and subsequent apoptosis, may contribute to the PCa preventative effect of GTP. Several Phase I studies and a single phase II pilot trial have compared the pharmacokinetics and safety of oral green tea, Polyphenon E and EGCG [104-109] demonstrating safety in single and multi dose studies of doses ranging from 200-1200 mgs per day administered for up to 12 months in both healthy men and men at high risk for PCa. A significant increase in plasma catechins was observed in association with all Adverse Events (AEs); however, AEs were related to the caffeine in the Polyphenon E preparation and not to the catechins. Based on the promising results of our studies and those of others as well as the relatively safety, we are currently completing a phase II clinical trial, powered to examine the effects of a standardized green tea preparation (Polyphenon E) in inhibiting the progression to PCa in a cohort diagnosed with HGPIN lesions or ASAP, while validating the molecular targets observed in the laboratory. The results of these studies can inform the design of well powered phase III clinical trials in the coming years.


Lycopene is a red-colored carotene with no recognized vitamin A activity and a potent antioxidant, found in certain red-colored vegetables and fruits, such as tomatoes (the main dietary source for the most people), red peppers and watermelon [110]. Epidemiological studies have demonstrated that populations with high intake of dietary lycopene have lower risk of PCa [111-116]. While prospective and case control studies have shown lycopene to be significantly lower in serum and tissue of cancer patients than in controls [111,117-120], results of a large nested case-control study, found no association between serum lycopene and PCa [121]. This variability in the experimental data obtained in these epidemiological studies may be related to lycopene source, exposure misclassification, lack of a dose response and other confounding lifestyle factors such as obesity, use of tobacco and alcohol, other dietary differences, varying standardization of quantities and compositions of lycopene, geographical location and genetic risk factors. Given these caveats, result based on epidemiological evidence should be interpreted with caution [122].

Biological PCa protective mechanisms of lycopene appear to be related either to the antioxidative and anti-inflammatory or apoptosisinducing properties, such as ability to induce G0/G1 cycle arrest, apoptosis and delayed in vivo growth in different PCa cell lines. Other mechanisms mediated by steroid hormones may also be involved. In vitro data have consistently shown that lycopene modulates cell cycle progression, proliferation [123], has an inhibitory effect on DNA synthesis [124], initiating up-regulation of gap-junction proteins and a reduction of local androgen signaling [125], impacts IGIF-1 signaling [126], Antioxidant [127] and induction of apoptotic cell death [128]. These data indicate that lycopene is a promising chemopreventive agent, with several cellular effects. On the other hand, lycopene has also been observed to up-regulate the expression of urokinase plasminogen activator that is known to facilitate metastasis to the bone [129]. Several laboratories have examined the effects of lycopene in prostate carcinogenesis in rodent models, [129,130-133] suggesting that lycopene metabolism was modulated by androgens [130,133], as castrated rats accumulated twice the liver lycopene as compared to intact controls, [130] interfering with local testosterone activation. Prostatic IGF-I and IL-6 expression was also found to be down-regulated by lycopene [131]. A few clinical trials have reported reduction of tumor volume, [134,135] and lower prostate specific antigen [136,137] with lycopene supplementation. To date, the results of the initial early clinical trials appear promising, although they have included various lycopene preparations and relatively short and varying duration of interventions (ranged from 12 mg/day for 8 weeks to 150 mg/day for 7 days) and men at various stages of PCa, utilizing both intermediate and surrogate biomarkers to evaluate chemoprevention efficacy. In a Phase II randomized-controlled trial [74] to evaluate the safety and effect of administering several doses of lycopene to men with clinically localized PCa, on intermediate endpoint biomarkers implicated in prostate carcinogenesis, forty-five eligible men with clinically localized PCa were supplemented with 15, 30 or 45 mg of lycopene or no supplement from biopsy to prostatectomy. Compliance to study agent, toxicity, changes in plasma lycopene, serum steroid hormones, PSA and tissue Ki-67 were analyzed from baseline to completion of intervention. Forty-two of forty-five subjects completed the intervention in approximately 30 days from the time of biopsy until prostatectomy. Plasma lycopene increased from baseline to post treatment in all treatment groups with greatest increase observed in the 45 mg lycopenesupplemented arm compared to the control arm without producing any toxicity. Overall, subjects with PCa had lower baseline levels of plasma lycopene similar to those observed in previous studies in men with PCa. Serum free testosterone decreased with 30 mg lycopene supplementation and total estradiol increased significantly with 30 mg and 45 mg supplementation from baseline to end of treatment, with no significant increases in serum PSA or tissue Ki-67. These changes were not significant compared to the control arm for this sample size and duration of intervention. Although antioxidant properties of lycopene have been hypothesized to be primarily responsible for its beneficial effects, our study suggests that other mechanisms mediated by steroid hormones may also be involved [74]. Because PCa in AA men may demonstrate decreased apoptosis [138,139], lycopene may be more potent in that population. Unfortunately, the number of AA participants in the major lycopene studies was small thus precluding a separate sub-analysis for that racial group. Smaller studies have shown that blood lycopene levels are generally lower in AA men compared to White men [138], and that lycopene administration leads to increased plasma lycopene concentrations in AA men [139]; however, the value of the aforementioned observations for PCa prevention remains to be established. Lycopene is generally well tolerated and is considered safe in either its natural or synthetic form [140,141]. Collectively, these earlier findings support a hypothesis that lycopene may play a role in the modulation of prostate carcinogenesis, warranting further well powered and well-designed phase II clinical trials.

Other Promising Botanicals in the Pipeline

Other than isoflavones green tea catechins and lycopne, other botanicals that appear promising for PCa chemoprevention include curcumin and Dercusin.


Decursin is a novel coumarin compound, which inhibits the growth of human PCa cells. A coumarin compound decursin (C19H20O5; molecular weight 328) was isolated from angelica (Angelica gigas) root. Singh et al. [142,143] observed that decursin (25-100 μmol/L) treatment strongly inhibits growth and induces death in human prostate carcinoma DU145, PC-3, and LNCaP cells. Decursinol, in which (CH3)2-C=CH-COO- side chain of decursin is substituted with –OH, shows lesser effects as compared to decursin, suggesting for a possible structure-activity relationship. Decursin induced a strong G1 arrest in DU145 and LNCaP cells, and G1 as well as G2-M arrest in PC-3 cells. Further, decursin was nontoxic to human prostate epithelial PWR-1E cells and exhibited only moderate growth inhibition and G1 arrest [142,143]. With cell cycle effect on G1 phase, decursin strongly increased Cip1/p21 but showed a moderate increase in Kip1/p27 with a decrease in cyclin-dependent kinases CDK2, CDK4, CDK6, and cyclin D1, and inhibited CDK and cyclin-associated kinase activity. Decursin-caused cell death was associated with an increase in apoptosis and cleaved caspase-9, caspase-3, and poly(ADP-ribose) polymerase. Pan-caspases inhibitor only partially reverses decursininduced apoptosis, suggesting the involvement of both caspasedependent and caspase-independent pathways [142]. Furthermore, decursin significantly decreased human umbilical vein endothelial cell (HUVEC) proliferation concomitant with G1 phase cell cycle arrest in biologically relevant growth (with serum) conditions. Decursin also inhibited HUVEC-capillary tube formation and invasion/migration in which was associated with the suppression of matrix metalloproteinase (MMP) -2 and -9 activities. Decursin suppressed angiogenesis in ex vivo rat aortic ring angiogenesis model where it inhibited blood capillary-network sprouting from rat aortic sections [144]. These findings suggested anti-angiogenic activity of decursin in biologically relevant condition, and warrants further pre-clinical studies for its potential clinical usefulness. Taken together, these findings revealed the novel anticancer efficacy of decursin mediated via induction of cell cycle arrest and apoptosis selectively in human prostate carcinoma cells. Anti-angiogenic activity of decursin could also contribute to its in vivo anticancer efficacy. Further studies are needed to explore the pan-efficacy and mechanisms of decursin or angelica root extract in different stages of PCa.


Curcumin is a naturally occurring plant-derived phenol that is a component of a popular Indian spice turmeric and a powerful antioxidant, that has been extensively studied because of its beneficial health effects including antimicrobial/antifungal [145,146], hepatoprotective [147], neuro-protective [148], cardio-protective [149], antiinflammatory [150] and anticancer properties [151]. Mechanistic effects of curcumin on PCa in vitro and in vivo have been extensively studied and are both antiproliferative (down regulated AR, EGFR and cyclin D expression, inactivated NFkB) and proapoptotic (down regulated bclxl, bcl-2 and surviving expression) [152]. Importantly, curcumin was shown to inhibit PCa growth (50% inhibition) and induce the caspasedependent apoptosis and reduce lung metastases by 89% in vivo [153]. Taken together, this evidence indicates that curcumin exhibits robust multi targeted anticancer activity against PCa, [154-156]. Curcumin is generally considered safe even at the very high doses of up to 12 grams per day [157]. Despite convincing and very encouraging preclinical data and established safety, prostate chemoprevention clinical trials of curcumin are lacking.


Based on the promising trends observed preclinical and early clinical trials by our group and others, including the relatively safety compared to currently available agents for PCa chemoprevention [47-49] the current research using a systematic approach to identify molecular targets of botanicals and translating the findings to design and implement clinical trials for chemoprevention provides an alternate to strategies other than screening. Although, currently there are no chemopreventive strategies that are standard of care in medical practice that have resulted from over 2 decades of research, it is clear that several valuable lessons have been learnt from earlier studies that continue to inform the design and approach of current chemoprevention trials using botanicals. With a better understanding of the promiscuous targeting of botanicals and a clear understanding of the synergistic effects of these agents present as whole mixtures or compounds based on evidence from in vitro, cutting-edge pre-clinical informing design of clinical studies and selection of intermediate endpoint biomarkers, the path has been paved to move several botanicals from bench to bedside.


The research study was funded by the National Institute of Health - National Cancer Institute R01 CA12060-01A1 and National Institute of Health - 1 P20 MD003375-01 and GC by the Department of Defense CaP Research Program (W81XWH-11-1-0376).


  1. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012.
  2. Mohamed MA, Greif PA, Diamond J (2007) Epigenetic events, remodeling enzymes and their relationship to chromatin organization in prostatic intraepithelial neoplasia and prostatic adenocarcinoma. BJU Int 99: 908.
  3. Bostwick DG, Qian J (2004) High-grade prostatic intraepithelial neoplasia. Mod Pathol 17: 360-379.
  4. Epstein JI, Herawi M (2006) Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. J Urol 175: 820-834.
  5. Burzon D, Kahnoski RJ, Bennett JK (2005) Men with high-grade prostatic intraepithelial neoplasia (HGPIN) remain at high risk for prostate cancer regardless of whether HGPIN is detected on subsequent biopsies. J Urol 173: 673.
  6. Ilic D, O'Connor D, Green S, Wilt TJ (2011) Screening for prostate cancer: an updated Cochrane systematic review. BJU Int 107: 882-891.
  7. Andriole GL, Crawford ED, Grubb RL 3rd, Buys SS, Chia D, et al. (2009) Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 360: 1310-1319.
  8. Moyer VA (2012) Screening for Prostate Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 157:120-134.
  9. Kelloff GJ, Lieberman R, Steele VE, Boone CW, Lubet RA, et al. (1999) Chemoprevention of prostate cancer: concepts and strategies. Eur Urol 35: 342-350.
  10. Kelloff GJ, Lippman SM, Dannenberg AJ, Sigman CC, Pearce HL, et al. (2006) Progress in chemoprevention drug development: the promise of molecular biomarkers for prevention of intraepithelial neoplasia and cancer--a plan to move forward. Clin Cancer Res 12: 3661-3697.
  11. Sung B, Prasad S, Yadav VR, Aggarwal BB (2012) Cancer cell signaling pathways targeted by spice-derived nutraceuticals. Nutr Cancer 64: 173-197.
  12. Gupta SC, Prasad S, Kim JH, Patchva S, Webb LJ, et al. (2011) Multitargeting by curcumin as revealed by molecular interaction studies. Nat Prod Rep 28: 1937-1955.
  13. Kannappan R, Gupta SC, Kim JH, Aggarwal BB (2012) Tocotrienols fight cancer by targeting multiple cell signaling pathways. Genes Nutr 7: 43-52.
  14. Jia L (2012) Cancer complementary and alternative medicine research at the US National Cancer Institute. Chin J Integr Med 18: 325-332.
  15. Gogtay NJ, Bhatt HA, Dalvi SS, Kshirsagar NA (2002) The use and safety of non-allopathic Indian medicines. Drug Saf 25: 1005-1019.
  16. Amin AR, Kucuk O, Khuri FR, Shin DM (2009) Perspectives for cancer prevention with natural compounds. J Clin Oncol 27: 2712-2725.
  17. Reddy BS (1996) Chemoprevention of colon cancer by minor dietary constituents and their synthetic analogues. Prev Med 25: 48-50.
  18. Aravindaram K, Yang NS (2010) Anti-inflammatory plant natural products for cancer therapy. Planta Med. 76: 1103-1117.
  19. Aggarwal BB, Prasad S, Reuter S, Kannappan R, Yadev VR, et al. (2011) Identification of novel anti-inflammatory agents from Ayurvedic medicine for prevention of chronic diseases: "reverse pharmacology" and "bedside to bench" approach. Curr Drug Targets 12: 1595-1653.
  20. Wargovich MJ, Jimenez A, McKee K, Steele VE, Velasco M, Woods J, et al. (2000) Efficacy of potential chemopreventive agents on rat colon aberrant crypt formation and progression. Carcinogenesis. 21: 1149-1155.
  21. Minich DM, Bland JS (2007) A review of the clinical efficacy and safety of cruciferous vegetable phytochemicals. Nutr Rev 65: 259-267.
  22. Scott EN, Gescher AJ, Steward WP, Brown K (2009) Development of dietary phytochemical chemopreventive agents: biomarkers and choice of dose for early clinical trials. Cancer Prev Res (Phila) 2: 525-530.
  23. Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, et al. (2009) Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 301: 39-51.
  24. (1994) The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 14; 330: 1029-1035.
  25. Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, et al. (1996) Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J Natl Cancer Inst 88: 1550-1559.
  26. Kakarala M, Brenner DE, Korkaya H, Cheng C, Tazi K (2010) Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat 122: 777-785.
  27. Kumar NB, Crocker T, Smith T, Connors S, Pow-Sang J, et al. (2012) Prostate Cancer Chemoprevention Targeting Men with High-Grade Prostatic Intraepithelial Neoplasia (HGPIN) and Atypical Small Acinar Proliferation (ASAP): Model for Trial Design and Outcome Measures J Clinic Trials 2:1.
  28. Kumar N, Crocker T, Smith T, Pow-Sang J, Spiess PE (2012) Prostate Cancer Chemoprevention Targeting High Risk Populations: Model for Trial Design and Outcome Measures. J Cancer Sci Ther
  29. Kelloff GJ, Lieberman R, Steele VE, Boone CW, Lubet RA, et al. (2001) Agents, biomarkers, and cohorts for chemopreventive agent development in prostate cancer. Urology 57: 46-51.
  30. Lieberman R (2001) Prostate cancer chemoprevention: Strategies for designing efficient clinical trials. Urology 57: 224-229.
  31. Gokden N, Roehl KA, Catalona WJ, Humphrey PA (2005) High-grade prostatic intraepithelial neoplasia in needle biopsy as risk factor for detection of adenocarcinoma: current level of risk in screening population. Urology 65: 538-542.
  32. Kronz JD, Allan CH, Shaikh AA, Epstein JI (2001) Predicting cancer following a diagnosis of high-grade prostatic intraepithelial neoplasia on needle biopsy: data on men with more than one follow-up biopsy. Am J Surg Pathol 25: 1079-1085.
  33. Naya Y, Ayala AG, Tamboli P, Babaian RJ (2004) Can the number of cores with high-grade prostate intraepithelial neoplasia predict cancer in men who undergo repeat biopsy? Urology 63: 503-508.
  34. San Francisco IF, Olumi AF, Kao J, Rosen S, DeWolf WC (2003) Clinical management of prostatic intraepithelial neoplasia as diagnosed by extended needle biopsies. BJU Int 91: 350-354.
  35. Iczkowski KA (2006) Current prostate biopsy interpretation: criteria for cancer, atypical small acinar proliferation, high-grade prostatic intraepithelial neoplasia, and use of immunostains. Arch Pathol Lab Med 130: 835-843.
  36. Ayala AG, Ro JY. (2007) Prostatic intraepithelial neoplasia: recent advances.Arch Pathol Lab Med. 131:1257-66.
  37. Merrimen JL, Jones G, Hussein SA, Leung CS, Kapusta LR, et al. (2011) A model to predict prostate cancer after atypical findings in initial prostate needle biopsy. J Urol 185: 1240-1245.
  38. Ploussard G, Plennevaux G, Allory Y, Salomon L, Azoulay S, et al. (2009) High-grade prostatic intraepithelial neoplasia and atypical small acinar proliferation on initial 21-core extended biopsy scheme: incidence and implications for patient care and surveillance. World J Urol. 27: 587-92.
  39. Schoenfield L, Jones JS, Zippe CD, Reuther AM, Klein E, et al. (2007) The incidence of high-grade prostatic intraepithelial neoplasia and atypical glands suspicious for carcinoma on first-time saturation needle biopsy, and the subsequent risk of cancer. BJU Int 99: 770-774.
  40. Cancer Facts & Figures for African Americans 2011-2012. Atlanta, GA: American Cancer Society 2011.
  41. Sakr WA, Grignon DJ, Haas GP, Schomer KL, Heilbrun LK, et al. (1995) Epidemology of High Grade Prostatic Intraepithelial Neoplasia, Pathology - Research and Practice 191: 838–841.
  42. Fowler Jr. JE, Bigler SA, Lynch C, Wilson SS, Farabaugh PB (2001) Prospective study of correlations between biopsy-detected high grade prostatic intraepithelial neoplasia, serum prostate specific antigen concentration, and race, Cancer 91: 1291–1296.
  43. Powell IJ, Bock CH, Ruterbusch JJ, Sakr W (2010) Evidence supports a faster growth rate and/or earlier transformation to clinically significant prostate cancer in black than in white American men, and influences racial progression and mortality disparity. J Urol 183: 1792-1796.
  44. Potts JM, Lutz M, Walker E, Modlin C, Klein E (2010) Trends in PSA, age and prostate cancer detection among black and white men from 1990-2006 at a tertiary care center. Cancer 116: 3910-3915.
  45. Sakr WA (1999) Prostatic intraepithelial neoplasia: A marker for high-risk groups and a potential target for chemoprevention. Eur Urol 35: 474-478.
  46. Perabo FG, Von Löw EC, Ellinger J, von Rücker A, Müller SC, et al. (2008) Soy isoflavone genistein in prevention and treatment of prostate cancer. Prostate Cancer Prostatic Dis 11: 6-12.
  47. Adlercreutz H, Honjo H, Higashi A, Fotsis T, Hämäläinen E, et al. (1991) Urinary excretion of lignans and isoflavonoid phytoestrogens in Japanese men and women consuming a traditional Japanese diet. Am J Clin Nutr 54: 1093-1100.
  48. Blumenfeld AJ, Fleshner N, Casselman B, Trachtenberg J (2000) Nutritional aspects of prostate cancer: a review. Can J Urol 7: 927-935.
  49. Brössner C, Petritsch K, Fink K, Auprich M, Madersbacher S, et al. (2004) Phytoestrogen tissue levels in benign prostatic hyperplasia and prostate cancer and their association with prostatic diseases. Urology 64: 707-711.
  50. Chan JM, Gann PH, Giovannucci EL (2005) Role of diet in prostate cancer development and progression. J Clin Oncol 23: 8152-8160.
  51. Morton MS, Chan PS, Cheng C, Blacklock N, Matos-Ferreira A, et al. (1997) Lignans and isoflavonoids in plasma and prostatic fluid in men: samples from Portugal, Hong Kong, and the United Kingdom. Prostate 32: 122-128.
  52. Shimizu H, Ross RK, Bernstein L, Yatani R, Henderson BE, et al. (1991) Cancers of the prostate and breast among Japanese and white immigrants in Los Angeles County. Br J Cancer 63: 963-966.
  53. Bemis DL, Capodice JL, Desai M, Buttyan R, Katz AE (2004) A concentrated aglycone isoflavone preparation (GCP) that demonstrates potent anti-prostate cancer activity in vitro and in vivo. Clin Cancer Res 10: 5282-5292.
  54. Fotsis T, Pepper M, Adlercreutz H, Hase T, Montesano R, et al. (1995) Genistein, a dietary ingested isoflavonoid, inhibits cell proliferation and in vitro angiogenesis. J Nutr 125: 790S-797S.
  55. Jonnalagadda SS, Mitchell DC, Smiciklas-Wright H, Meaker KB, Van Heel N, et al. (2000) Accuracy of energy intake data estimated by a multiple-pass, 24-hour dietary recall technique. J Am Diet Assoc 100: 303-308.
  56. Messina M, Barnes S (1991) The role of soy products in reducing risk of cancer. Journal of the National Cancer Institute 83(8): 541-6.
  57. Ouchi H, Ishiguro H, Ikeda N, Hori M, Kubota Y, et al (2005) Genistein induces cell growth inhibition in prostate cancer through the suppression of telomerase activity. International journal of urology : official journal of the Japanese Urological Association 121: 73-80.
  58. Adlercreutz H, Mousavi Y, Clark J, Höckerstedt K, Hämäläinen E, et al. (1992) Dietary phytoestrogens and cancer: in vitro and in vivo studies. J Steroid Biochem Mol Biol 41: 331-337.
  59. Skogseth H, Larsson E, Halgunset J (2006) The invasive behaviour of prostatic cancer cells is suppressed by inhibitors of tyrosine kinase. APMIS 114: 61-66.
  60. Huang X, Chen S, Xu L, Liu Y, Deb DK, et al. (2005) Genistein inhibits p38 map kinase activation, matrix metalloproteinase type 2, and cell invasion in human prostate epithelial cells. Cancer Res 65: 3470-3478.
  61. Li Y, Kucuk O, Hussain M, Abrams J, Cher ML, et al. (2006) Antitumor and antimetastatic activities of docetaxel are enhanced by genistein through regulation of osteoprotegerin/receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/MMP-9 signaling in prostate cancer. Cancer Res 66: 4816-4825.
  62. Handayani R, Rice L, Cui Y, Medrano TA, Samedi VG, et al. (2006) Soy isoflavones alter expression of genes associated with cancer progression, including interleukin-8, in androgen-independent PC-3 human prostate cancer cells. J Nutr 136: 75-82.
  63. Raschke M, Rowland IR, Magee PJ, Pool-Zobel BL (2006) Genistein protects prostate cells against hydrogen peroxide-induced DNA damage and induces expression of genes involved in the defence against oxidative stress. Carcinogenesis 27: 2322-2330.
  64. Kazi A, Daniel KG, Smith DM, Kumar NB, Dou QP (2003) Inhibition of the proteasome activity, a novel mechanism associated with the tumor cell apoptosis-inducing ability of genistein. Biochem Pharmacol 66: 965-976.
  65. Jagadeesh S, Kyo S, Banerjee PP (2006) Genistein represses telomerase activity via both transcriptional and posttranslational mechanisms in human prostate cancer cells. Cancer Res 66: 2107-2115.
  66. Ma Q, Fu W, Li P, Nicosia SV, Jenster G, et al. (2009) FoxO1 mediates PTEN suppression of androgen receptor N- and C-terminal interactions and coactivator recruitment. Mol Endocrinol 2: 213-225.
  67. Katoh M, Katoh M (2004) Human FOX gene family (Review). Int J Oncol 25: 1495-1500.
  68. Li P, Lee H, Guo S, Unterman TG, Jenster G, et al. (2003) AKT-independent protection of prostate cancer cells from apoptosis mediated through complex formation between the androgen receptor and FKHR. Mol Cell Biol 23: 104-118.
  69. Huang H, Muddiman DC, Tindall DJ (2004) Androgens negatively regulate forkhead transcription factor FKHR (FOXO1) through a proteolytic mechanism in prostate cancer cells. J Biol Chem 279: 13866-13877.
  70. Nelson KA, Witte JS (2002) Androgen receptor CAG repeats and prostate cancer. Am J Epidemiol 155: 883-890.
  71. Subramaniam D, Ramalingam S, Houchen CW, Anant S (2010) Cancer stem cells: a novel paradigm for cancer prevention and treatment. Mini Rev Med Chem 5: 359-371.
  72. Zhang L, Li L, Jiao M, Wu D, Wu K, et al. (2012) Genistein inhibits the stemness properties of prostate cancer cells through targeting Hedgehog-Gli1 pathway. Cancer Lett 323: 48-57.
  73. Fischer L, Mahoney C, Jeffcoat AR, Koch MA, Thomas BE, et al. (2004) Clinical characteristics and pharmacokinetics of purified soy isoflavones: multiple-dose administration to men with prostate neoplasia. Nutr Cancer 48: 160-170.
  74. Kumar NB, Besterman-Dahan K, Kang L, Pow-Sang J, Xu P, et al (2008) Results of a Randomized Clinical Trial of the Action of Several Doses of Lycopene in Localized Prostate Cancer: Administration Prior to Radical Prostatectomy. Clin med. Urol 1: 1-14.
  75. Dalais FS, Meliala A, Wattanapenpaiboon N, Frydenberg M, Suter DA, et al. (2004) Effects of a diet rich in phytoestrogens on prostate-specific antigen and sex hormones in men diagnosed with prostate cancer. Urology 64: 510-515.
  76. deVere White RW, Hackman RM, Soares SE, Beckett LA, Li Y, et al. (2004) Effects of a genistein-rich extract on PSA levels in men with a history of prostate cancer. Urology 63: 259-263.
  77. Kranse R, Dagnelie PC, van Kemenade MC, de Jong FH, Blom JH, et al (2005) Dietary intervention in prostate cancer patients: PSA response in a randomized double-blind placebo-controlled study. International journal of cancer. Journal international du cancer 5: 835-40.
  78. Kumar NB, Cantor A, Allen K, Riccardi D, Besterman-Dahan K, et al. (2004) The specific role of isoflavones in reducing prostate cancer risk. Prostate 59: 141-147.
  79. Kumar NB, Krischer JP, Allen K, Riccardi D, Besterman-Dahan K, et al. (2007) Safety of purified isoflavones in men with clinically localized prostate cancer. Nutr Cancer 59: 169-175.
  80. Schröder FH, van der Cruijsen-Koeter I, de Koning HJ, Vis AN, Hoedemaeker RF, et al. (2000) Prostate cancer detection at low prostate specific antigen. J Urol 163: 806-812.
  81. Kumar NB, Krischer JP, Allen K, Riccardi D, Besterman-Dahan K, et al. (2007) A Phase II randomized, placebo-controlled clinical trial of purified isoflavones in modulating steroid hormones in men diagnosed with localized prostate cancer. Nutr Cancer 59: 163-168.
  82. (1996) Clinical development plan: tea extracts. Green tea polyphenols. Epigallocatechin gallate. J Cell Biochem Suppl 26: 236-257.
  83. Bushman JL (1998) Green tea and cancer in humans: a review of the literature. Nutr Cancer 31: 151-159.
  84. Higdon JV, Frei B (2003) Tea catechins and polyphenols: health effects, metabolism, and antioxidant functions. Crit Rev Food Sci Nutr 43: 89-143.
  85. Ahn WS, Yoo J, Huh SW, Kim CK, Lee JM, et al. (2003) Protective effects of green tea extracts (polyphenon E and EGCG) on human cervical lesions. Eur J Cancer Prev 12: 383-390.
  86. Montague JA, Butler LM, Wu AH, Genkinger JM, Koh WP, et al. (2012) Green and black tea intake in relation to prostate cancer risk among Singapore Chinese. Cancer Causes Control 23: 1635-1641.
  87. Nelson WG (2004) Agents in development for prostate cancer prevention. Expert Opin Investig Drugs 13: 1541-1554.
  88. Jian L, Xie LP, Lee AH, Binns CW (2004) Protective effect of green tea against prostate cancer: a case-control study in southeast China. Int J Cancer 108: 130-135
  89. Wu AH, Yu MC, Tseng CC, Hankin J, Pike MC (2003) Green tea and risk of breast cancer in Asian Americans. Int J Cancer 106: 574-579.
  90. Kumar N, Titus-Ernstoff L, Newcomb PA, Trentham-Dietz A, Anic G, et al. (2009) Tea consumption and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 1: 341-345.
  91. Gupta S, Hastak K, Ahmad N, Lewin JS, Mukhtar H (2001) Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols. Proc Natl Acad Sci U S A 98: 10350-10355.
  92. Suttie A, Nyska A, Haseman JK, Moser GJ, Hackett TR, et al. (2003) A grading scheme for the assessment of proliferative lesions of the mouse prostate in the TRAMP model. Toxicol Pathol 31: 31-38.
  93. Khan N, Mukhtar H (2010) Cancer and metastasis: prevention and treatment by green tea. Cancer Metastasis Rev 29: 435-445.
  94. Khan N, Adhami VM, Mukhtar H (2009) Review: green tea polyphenols in chemoprevention of prostate cancer: preclinical and clinical studies. Nutr Cancer 61: 836-841.
  95. Adhami VM, Siddiqui IA, Sarfaraz S, Khwaja SI, Hafeez BB, et al. (2009) Effective prostate cancer chemopreventive intervention with green tea polyphenols in the TRAMP model depends on the stage of the disease. Clin Cancer Res 15: 1947-1953.
  96. Caporali A, Davalli P, Astancolle S, D'Arca D, Brausi M, et al. (2004) The chemopreventive action of catechins in the TRAMP mouse model of prostate carcinogenesis is accompanied by clusterin over-expression. Carcinogenesis 25: 2217-2224.
  97. Nam S, Smith DM, Dou QP (2001) Ester bond-containing tea polyphenols potently inhibit proteasome activity in vitro and in vivo. J Biol Chem 276: 13322-13330.
  98. Kazi A, Wang Z, Kumar N, Falsetti SC, Chan TH, et al. (2004) Structure-activity relationships of synthetic analogs of (-)-epigallocatechin-3-gallate as proteasome inhibitors. Anticancer Res 24: 943-954.
  99. Smith DM, Wang Z, Kazi A, Li LH, Chan TH, et al. (2002) Synthetic analogs of green tea polyphenols as proteasome inhibitors. Mol Med 8: 382-392.
  100. Adhami VM, Ahmad N, Mukhtar H (2003) Molecular targets for green tea in prostate cancer prevention. J Nutr 133: 2417S-2424S.
  101. Liang YC, Lin-Shiau SY, Chen CF, Lin JK (1997) Suppression of extracellular signals and cell proliferation through EGF receptor binding by (–)-epigallocatechin gallate in human A431 epidermoid carcinoma cells. J Cell Biochem 67: 55-65.
  102. Chung JY, Huang C, Meng X, Dong Z, Yang CS (1999) Inhibition of activator protein 1 activity and cell growth by purified green tea and black tea polyphenols in H-ras-transformed cells: structure-activity relationship and mechanisms involved. Cancer Res 59: 4610-4617.
  103. Liang YC, Lin-Shiau SY, Chen CF, Lin JK (1999) Inhibition of cyclin-dependent kinases 2 and 4 activities as well as induction of Cdk inhibitors p21 and p27 during growth arrest of human breast carcinoma cells by (-)-epigallocatechin-3-gallate. J Cell Biochem 75: 1-12.
  104. Chow HH, Cai Y, Alberts DS, Hakim I, Dorr R, et al. (2001) Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and Polyphenon E. Cancer Epidemiol Biomarkers Prev 10: 53-58
  105. Chow HH, Hakim IA, Vining DR, Crowell JA, Ranger-Moore J, et al. (2005) Effects of dosing condition on the oral bioavailability of green tea catechins after single-dose administration of Polyphenon E in healthy individuals. Clin Cancer Res 11: 4627-4633.
  106. Ullmann U, Haller J, Decourt JD, Girault J, Spitzer V, et al. (2004) Plasma-kinetic characteristics of purified and isolated green tea catechin epigallocatechin gallate (EGCG) after 10 days repeated dosing in healthy volunteers. Int J Vitam Nutr Res 74: 269-278.
  107. Ullmann U, Haller J, Decourt JP, Girault N, Girault J, et al. (2003) A single ascending dose study of epigallocatechin gallate in healthy volunteers. J Int Med Res 31: 88-101.
  108. Pisters KM, Newman RA, Coldman B, Shin DM, Khuri FR, et al. (2001) Phase I trial of oral green tea extract in adult patients with solid tumors. J Clin Oncol 19: 1830-1838.
  109. Chow HH, Cai Y, Hakim IA, Crowell JA, Shahi F, et al. (2003) Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals. Clin Cancer Res 9: 3312-3319.
  110. Clinton SK (1998) Lycopene: chemistry, biology, and implications for human health and disease. Nutr Rev 56: 35-51.
  111. Giovannucci E (2005) Tomato products, lycopene, and prostate cancer: a review of the epidemiological literature. J Nutr 135: 2030S-2031S.
  112. Giovannuci E (1999) Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature. J Natl Cancer Inst 4: 317-331.
  113. Giovannucci E, Rimm EB, Liu Y, Stampfer MJ, Willett WC (2002) A prospective study of tomato products, lycopene, and prostate cancer risk. J Natl Cancer Inst 5: 391-398.
  114. Wu K, Erdman JW Jr, Schwartz SJ, Platz EA, Leitzmann M, et al. (2004) Plasma and dietary carotenoids, and the risk of prostate cancer: a nested case-control study. Cancer Epidemiol Biomarkers Prev 13: 260-269.
  115. Etminan M, Takkouche B, Caamaño-Isorna F (2004) The role of tomato products and lycopene in the prevention of prostate cancer: a meta-analysis of observational studies. Cancer Epidemiol Biomarkers Prev 13: 340-345.
  116. Jian L, Du CJ, Lee AH, Binns CW (2005) Do dietary lycopene and other carotenoids protect against prostate cancer? Int J Cancer 113: 1010-1014.
  117. Rao AV, Fleshner N, Agarwal S (1999) Serum and tissue lycopene and biomarkers of oxidation in prostate cancer patients: a case-control study. Nutr Cancer 2: 159-164.
  118. Lu QY, Hung JC, Heber D, Go VL, Reuter VE, et al. (2001) Inverse associations between plasma lycopene and other carotenoids and prostate cancer. Cancer Epidemiol Biomarkers Prev 7: 749-756.
  119. Kirsh VA, Mayne ST, Peters U, Chatterjee N, Leitzmann MF, et al. (2006) A Prospective Study of Lycopene and Tomato Product Intake and Risk of Prostate Cancer. Cancer Epidemiol Biomarkers Prev 15: 92-98.
  120. Gann PH, Ma J, Giovannucci E, Willett W, Sacks FM, et al. (1999) Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis. Cancer Res 59: 1225-1230.
  121. Peters U, Leitzmann MF, Chatterjee N, Wang Y, Albanes D, et al. (2007) Serum lycopene, other carotenoids, and prostate cancer risk: a nested case-control study in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol Biomarkers Prev 16: 962-968.
  122. Obermüller-Jevic UC, Olano-Martin E, Corbacho AM, Eiserich JP, van der Vliet A, et al. (2003) Lycopene inhibits the growth of normal human prostate epithelial cells in vitro. J Nutr 133: 3356-3360.
  123. Barber NJ, Zhang X, Zhu G, Pramanik R, Barber JA, et al. (2006) Lycopene inhibits DNA synthesis in primary prostate epithelial cells in vitro and its administration is associated with a reduced prostate-specific antigen velocity in a phase II clinical study. Prostate Cancer Prostatic Dis 9: 407-413.
  124. Goyal A, Delves GH, Chopra M, Lwaleed BA, Cooper AJ (2006) Prostate cells exposed to lycopene in vitro liberate lycopene-enriched exosomes. BJU Int 98: 907-911.
  125. Chan JM, Stampfer MJ, Giovannucci E, Ma J, Pollak M (2000) Insulin-like growth factor I (IGF-I), IGF-binding protein-3 and prostate cancer risk: epidemiological studies. Growth Horm IGF Res. 10(Suppl A): S32-S33.
  126. Cohen LA (2002) Nutrition and prostate cancer: a review. Ann N Y Acad Sci 963: 148-155.
  127. Tang L, Jin T, Zeng X, Wang JS (2005) Lycopene inhibits the growth of human androgen-independent prostate cancer cells in vitro and in BALB/c nude mice. J Nutr 135: 287-290.
  128. Forbes K, Gillette K, Sehgal I (2003) Lycopene increases urokinase receptor and fails to inhibit growth or connexin expression in a metastatically passaged prostate cancer cell line: a brief communication. Exp Biol Med (Maywood) 228: 967-971.
  129. Ilic D, Forbes KM, Hassed C (2011) Lycopene for the prevention of prostate cancer. Cochrane Database Syst Rev CD008007.
  130. Boileau TW, Clinton SK, Zaripheh S, Monaco MH, Donovan SM, et al. (2001) Testosterone and food restriction modulate hepatic lycopene isomer concentrations in male F344 rats. J Nutr 131: 1746-1752.
  131. Siler U, Barella L, Spitzer V, Schnorr J, Lein M, et al. (2004) Lycopene and vitamin E interfere with autocrine/paracrine loops in the Dunning prostate cancer model. FASEB J 18: 1019-1021.
  132. Herzog A, Siler U, Spitzer V, Seifert N, Denelavas A, et al. (2005) Lycopene reduced gene expression of steroid targets and inflammatory markers in normal rat prostate. FASEB J 19: 272-274.
  133. Campbell JK, Stroud CK, Nakamura MT, Lila MA, Erdman JW Jr (2006) Serum testosterone is reduced following short-term phytofluene, lycopene, or tomato powder consumption in F344 rats. J Nutr 136: 2813-2819.
  134. Kucuk O, Sarkar FH, Djuric Z, Sakr W, Pollak MN, et al. (2002) Effects of lycopene supplementation in patients with localized prostate cancer. Exp Biol Med (Maywood) 10: 881-885.
  135. Kucuk O, Sarkar FH, Sakr W, Djuric Z, Pollak MN, et al. (2001) Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy. Cancer Epidemiol Biomarkers Prev. 10: 861-888.
  136. Ansari MS, Sgupta NP (2005) A comparison of lycopene and orchidectomy vs orchidectomy alone in the management of advanced prostate cancer. BJU Int 95: 453
  137. Ansari MS, Gupta NP (2004) Lycopene: a novel drug therapy in hormone refractory metastatic prostate cancer. Urol Oncol 22: 415-420.
  138. Vogt TM, Mayne ST, Graubard BI, Swanson CA, Sowell AL, et al. (2002) Serum lycopene, other serum carotenoids, and risk of prostate cancer in US Blacks and Whites. Am J Epidemiol 155: 1023-1032.
  139. van Breemen RB, Sharifi R, Viana M, Pajkovic N, Zhu D, et al. (2011) Antioxidant effects of lycopene in African American men with prostate cancer or benign prostate hyperplasia: a randomized, controlled trial. Cancer Prev Res (Phila) 4: 711-718.
  140. Trumbo PR (2005) Are there adverse effects of lycopene exposure? J Nutr 135: 2060S-2061S.
  141. Michael McClain R, Bausch J (2003) Summary of safety studies conducted with synthetic lycopene. Regul Toxicol Pharmacol 2: 274-285.
  142. Yim D, Singh RP, Agarwal C, Lee S, Chi H, et al. (2005) A novel anticancer agent, decursin, induces G1 arrest and apoptosis in human prostate carcinoma cells. Cancer Res 65: 1035-1044.
  143. Singh RP, Agarwal R (2006) Mechanisms of action of novel agents for prostate cancer chemoprevention. Endocr Relat Cancer 13: 751-778.
  144. Bhat TA, Moon JS, Lee S, Yim D, Singh RP (2011) Inhibition of angiogenic attributes by decursin in endothelial cells and ex vivo rat aortic ring angiogenesis model. Indian J Exp Biol 49: 848-856.
  145. De R, Kundu P, Swarnakar S, Ramamurthy T, Chowdhury A, et al. (2009) Antimicrobial activity of curcumin against Helicobacter pylori isolates from India and during infections in mice. Antimicrob Agents Chemother 53: 1592-1597.
  146. Martins CV, da Silva DL, Neres AT, Magalhães TF, Watanabe GA, et al. (2009) Curcumin as a promising antifungal of clinical interest. J Antimicrob Chemother 63: 337-339.
  147. O'Connell MA, Rushworth SA (2008) Curcumin: potential for hepatic fibrosis therapy? Br J Pharmacol 153: 403-405.
  148. Ringman JM, Frautschy SA, Cole GM, Masterman DL, Cummings JL (2005) A potential role of the curry spice curcumin in Alzheimer's disease. Curr Alzheimer Res 2: 131-136.
  149. Srivastava G, Mehta JL (2009) Currying the heart: curcumin and cardioprotection. J Cardiovasc Pharmacol Ther 14: 22-27.
  150. Chainani-Wu N (2003) Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa). J Altern Complement Med 9: 161-168.
  151. Bar-Sela G, Epelbaum R, Schaffer M (2010) Curcumin as an anti-cancer agent: review of the gap between basic and clinical applications. Curr Med Chem 17: 190-197.
  152. Aggarwal BB (2008) Prostate cancer and curcumin: add spice to your life. Cancer Biol Ther 7: 1436-1440.
  153. Hong JH, Ahn KS, Bae E, Jeon SS, Choi HY (2006) The effects of curcumin on the invasiveness of prostate cancer in vitro and in vivo. Prostate Cancer Prostatic Dis 9: 147-152.
  154. Maheshwari RK, Singh AK, Gaddipati J, Srimal RC (2006) Multiple biological activities of curcumin: a short review. Life Sci 78: 2081-2087.
  155. Shenouda NS, Zhou C, Browning JD, Ansell PJ, Sakla MS, et al. (2004) Phytoestrogens in common herbs regulate prostate cancer cell growth in vitro. Nutr Cancer 49: 200-208.
  156. Teiten MH, Gaascht F, Eifes S, Dicato M, Diederich M (2010) Chemopreventive potential of curcumin in prostate cancer. Genes Nutr 5: 61-74.
  157. Dadhaniya P, Patel C, Muchhara J, Bhadja N, Mathuria N, et al. (2011) Safety assessment of a solid lipid curcumin particle preparation: acute and subchronic toxicity studies. Food Chem Toxicol 49: 1834-1842.
Citation: Nagi Kumar, Chornokur G (2012) Molecular Targeted Therapies Using Botanicals for Prostate Cancer Chemoprevention. Transl Med S2:005.

Copyright: © 2012 Nagi Kumar, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.