PUSH Fitness & Rehabiliation
Welcome !! PUSH-as-Rx ®™ is leading the field with laser focus supporting our youth sport programs. The PUSH-as-Rx ®™ System is a sport specific athletic program designed by a strength-agility coach and physiology doctor with a combined 40 years of experience working with extreme athletes. At its core, the program is the multidisciplinary study of reactive agility, body mechanics and extreme motion dynamics. Through continuous and detailed assessments of the athletes in motion and while under direct supervised stress loads, a clear quantitative picture of body dynamics emerges. Exposure to the biomechanical vulnerabilities are presented to our team. Immediately, we adjust our methods for our athletes in order to optimize performance. This highly adaptive system with continual dynamic adjustments has helped many of our athletes come back faster, stronger, and ready post injury while safely minimizing recovery times. Results demonstrate clear improved agility, speed, decreased reaction time with greatly improved postural-torque mechanics. PUSH-as-Rx ®™ offers specialized extreme performance enhancements to our athletes no matter the age.

Prostate Cancer, Nutrition And Dietary Interventions

Prostate Cancer: Abstract

Prostate cancer (PCa) remains a leading cause of mortality in US men and the prevalence continues to rise world-wide especially in countries where men consume a ‘Western-style’ diet. Epidemiologic, preclinical and clinical studies suggest a potential role for dietary intake on the incidence and progression of PCa. ‘This minireview provides an overview of recent published literature with regard to nutrients, dietary factors, dietary patterns and PCa incidence and progression. Low carbohydrates intake, soy protein, omega-3 (w-3) fat, green teas, tomatoes and tomato products and zyflamend showed promise in reducing PCa risk or progression. A higher saturated fat intake and a higher β-carotene status may increase risk. A ‘U’ shape relationship may exist between folate, vitamin C, vitamin D and calcium with PCa risk. Despite the inconsistent and inconclusive findings, the potential for a role of dietary intake for the prevention and treatment of PCa is promising. The combination of all the beneficial factors for PCa risk reduction in a healthy dietary pattern may be the best dietary advice. This pattern includes rich fruits and vegetables, reduced refined carbohydrates, total and saturated fats, and reduced cooked meats. Further carefully designed prospective trials are warranted.

Keywords: Diet, Prostate cancer, Nutrients, Dietary pattern, Lifestyle, Prevention, Treatment, Nutrition, Dietary intervention, Review

Introduction: Prostate Cancer

Prostate cancer (PCa) is the second most common cancer in men, with nearly a million new cases diagnosed worldwide per year [1], with approximately a six-fold higher incidence in Western than in non-Western countries. Diet, lifestyle, environmental and genetic factors are hypothesized to play a role in these differences. This review focuses on the latest evidence of the potential role of dietary factors on PCa and includes epidemiologic and clinical trial evidence for the impact of protein, fat, carbohydrate, fiber, phytochemicals, other food components, whole foods and dietary patterns on PCa incidence, development and/or progression. Data from meta-analyses or well-designed randomized trials and prospective studies are emphasized in this review. It should be noted that studies of dietary intake or nutrition and cancer are often subject to various limitations and thus complicate interpretation of results. For example, when a study is designed to examine the effect of the amount of fat intake, alteration in fat intake inevitably will change intake of protein and/or carbohydrate, and may change the intake of other nutrients as well. As a result, it is difficult to attribute the effect to change in fat intake alone. In addition, the impact of macronutrients potentially involves aspects of both absolute quantity and the type of macronutrients consumed. Both aspects may potentially affect cancer initiation and/or development independently, but they are not always distinguishable in research designs. Though this topic was recently reviewed [2], given the extensive new literature on the topic, an updated review is presented herein and a summary table is provided for a quick reference (Table 1).

prostate cancerNutrients Carbohydrates Given the hypothesis that insulin is a growth factor for PCa, it has been hypothesized that reducing carbohydrates and thus lowering serum insulin may slow PCa growth [3]. Indeed, in animal models, either a no-carbohydrate ketogenic diet (NCKD) [4,5] or a low-carbohydrate diet (20% kcal as carbohydrate) has favorable effects on slowing prostate tumor growth [6,7]. In human studies, one study found that high intake of refined carbohydrates was associated with increased risk of PCa [7]. In addition to the amount of carbohydrates, type of carbohydrates may impact on PCa but research has been inconclusive. The potential to reduce PCa risk and progression via impacting carbohydrate metabolism is actively being investigated with Metformin. Metformin reduced PCa cell proliferation and delayed progression in vitro and in vivo, respectively [8-10] and reduced incident risk and mortality in humans [11-13]. Two single arm clinical trials also showed a positive effect of metformin in affecting markers of PCa proliferation and progression [14,15]. However, other retrospective cohort studies have not supported an effect of metformin on recurrence or incident risk of PCa [16-22]. Despite the potential for reducing either total or simple carbohydrates in benefiting PCa control, evidence is lacking from randomized controlled trials (RCT). Two randomized trials are on-going examining the impact of a low-carbohydrate diet (approximately 5% kcal) on the PSA doubling time among PCa patients post radical prostatectomy (NCT01763944) and on glycemic response among patients initiating androgen deprivation therapy (ADT) (NCT00932672 ). Findings from these trials will shed light on the effect of carbohydrate intake on markers of PCa progression and the role of reduced carbohydrate intake on offsetting the side effects of ADT.

Protein

The ideal level of protein intake for optimal overall health or prostate health is unclear. Despite the popularity of low carbohydrate diets that are high in protein, recent human studies reported that low protein intake was associated with lower risk for cancer and overall mortality among men 65 and younger. Among men older than 65, low protein intake was associated with a higher risk for cancer and overall mortality [23]. In animal models the ratio between protein and carbohydrate impacted on cardiometabolic health, aging and longevity [24]. The role of dietary protein and the protein to carbohydrate ratio on PCa development and progression requires further study.

Animal-Based Proteins

Studying protein intake, like all aspects of nutritional science, can be challenging. For example, animal meat, which is a source of protein in Western diets, is composed not only of protein, but also of fat, cholesterol, minerals and other nutrients. The amount of these nutrients including fatty acids may vary from one animal meat to the other. Previous studies in human have shown that consumption of skinless poultry, which is lower in cholesterol and saturated fat than many red meats, was not associated with the recurrence or progression of PCa [25]. However, consumption of baked poultry was inversely associated with advanced PCa [26,27], while cooked red meat was associated with increased advanced PCa risk [26,27]. Thus, how the food is prepared may modify its impact on PCa risk and progression. Overall, fish consumption may be associated with reduced PCa mortality, but high temperature cooked fish may contribute to PCa carcinogenesis [28]. Thus, it may be advisable to consume fish regularly but cooking temperature should be kept moderate.

Dairy-Based Protein

Another common protein source is dairy products, such as milk, cheese and yogurt. Previous studies have shown that dairy increased overall PCa risk but not with aggressive or lethal PCa [29,30]. In addition, both whole milk and low-fat milk consumption were reported to either promote or delay PCa progression [29,31]. In the Physicians Health follow up cohort with 21,660 men, total dairy consumption was found to be associated with increased PCa incidence [32]. In particular, low fat or skim milk increased low grade PCa, whereas whole milk increased fatal PCa risk. Though the exact component(s) of dairy products driving these associations is unknown, the high concentrations of saturated fat and calcium may be involved. A cross-sectional study of 1798 men showed that dairy protein was positively associated with serum IGF-1 [33] levels which may stimulate initiation or progression of PCa. Thus, further research is needed to clarify the relationship between dairy intake and PCa. There is insufficient data to provide recommendations specifically related to dairy or dairy protein and PCa risk or progression.

Plant-Based Proteins

Soy and soy-based products are rich in protein and phytoestrogens that may facilitate PCa prevention, but its role on PCa is unclear. In a study in mice, intake of soy products was associated with decreased hepatic aromatase, 5α-reductase, expression of androgen receptor and its regulated genes, FOXA1, urogenital tract weight and PCa tumor progression [34]. A recent randomized trial of 177 men with high-risk disease after radical prostatectomy found that soy protein supplementation for two years had no effect on risk of PCa recurrence [35]. Although epidemiological and pre-clinical studies [36,37] support a potential role for soy/soy isoflavones in PCa risk reduction or progression, a meta-analysis did not find significant impact of soy intake in PSA levels, sex hormone-binding globulin, testosterone, free testosterone, estradiol or dihydrotestosterone [38]. Another RCT in patients before prostatectomy also did not find any effect of soy isoflavone supplement up to six weeks on PSA, serum total testosterone, free testosterone, total estrogen, estradiol or total cholesterol [39]. Since most RCTs conducted have been small and of short duration, further examination is needed.

Many studies have continued to examine the primary isoflavone in soy, genistein, and its effect on PCa. The potential for genistein to inihibit PCa cell detachment, invasion and metastasis is reported [40]. Genistein may modify glucose update and glucose transporter (GLUT) expression in PCa cells [41], or exert its anti-tumor effect by down regulating several microRNAs [42]. Studies using tumor cells and animal models suggest genistein may compete with and block endogenous estrogens from binding to the estrogen receptor, thereby inhibiting cellular proliferation, growth, and inducing differentiation and, specifically, genistein may inhibit cell detachment, protease production, cell invasion and thus prevent metastasis [36,40,43]. However, neither plasma nor urinary genistein levels were associated with PCa risk in case control studies [44,45]. In a phase 2 placebo-controlled RCT with 47 men, supplementation of 30 mg genistein for three to six weeks significantly reduced androgen-related markers of PCa progression [46]. In addition, genistein may be beneficial in improving cabazitaxel chemotherapy in metastatic castration-resistant PCa [37]. Clinical studies are warranted to further examine the role of soy and soy isoflavones for PCa prevention or treatment. A definitive recommendation regarding protein intake for PCa prevention or treatment is not available yet.

Fat

Research findings examining fat consumption with PCa risk or progression are conflicting. Both the total absolute intake [47] of dietary fat and the relative fatty acid composition may independently relate to PCa initiation and/or progression. While animal studies repeatedly show that reducing dietary fat intake slows tumor growth [48-50] and high fat diets, especially animal fat and corn oil increase PCa progression [51], human data are less consistent. Case–control studies and cohort studies have shown either no association between total fat consumption and PCa risk [52-55] or an inverse association between fat intake and PCa survival, particularly among men with localized PCa [47]. In addition, a cross-sectional study showed that fat intake expressed as percent of total calorie intake was positively associated with PSA levels in 13,594 men without PCa [56]. Given these conflicting data, it is possible that the type of fatty acid [56] rather than total amount may play an important role in PCa development and progression. A study found plasma saturated fatty acids to be positively associated with PCa risk in a prospective cohort of 14,514 men of the Melbourne Collaborative Cohort Study [57]. In addition, another study found that eating more plant-based fat was associated with reduced PCa risk [58]. These studies support the current dietary guideline of eating less animal-based fat and more plant-based fat.

The data regarding omega-6 (w-6) and omega-3 (w-3) polyunsaturated fatty acid (PUFA) consumption and PCa risk are also conflicting. While there are data to support a link between increased w-6 PUFA intake (mainly derived from corn oil) and risk of overall and high-grade PCa [57,59], not all data support such a link [60]. In fact, a greater polyunsaturated fat intake was associated with a lower all cause mortality among men with nonmetastatic PCa in the Health Professionals Follow-up study [58]. The postulated mechanism linking w-6 PUFAs and PCa risk is the conversion of arachidonic acid (w-6 PUFA) to eicosanoids (prostaglandin E-2, hydroxyeicosatetraenoic acids and epoxyeicosatrienoic acids) leading to inflammation and cellular growth [61]. Conversely, w-3 PUFAs, which are found primarily in cold water oily fish, may slow growth of PCa through a number of mechanisms [61-63]. In a study of 48 men with low risk PCa under active surveillance, repeat biopsy in six months showed that prostate tissue w-3 fatty acids, especially eicosapentaenoic acid (EPA), may protect against PCa progression [64]. In vitro and animal studies suggest that w-3 PUFAs induce anti-inflammatory, pro-apoptotic, antiproliferative and anti-angiogenic pathways [65,66]. Moreover, a mouse study comparing various types of fat found that only the fish oil diet (that is, omega-3 based diet) slowed PCa growth relative to other dietary fats [67]. In regards to human data, a phase II randomized trial showed that a low-fat diet with w-3 supplementation four to six weeks prior to radical prostatectomy decreased PCa proliferation and cell cycle progression (CCP) score [62,68]. A low-fat fish oil diet resulted in decreased 15(S)- hydroxyeicosatetraenoic acid levels and lowered CCP score relative to a Western diet [69]. The potential benefits of omega-3 fatty acids from fish are supported by epidemiological literature showing that w-3 fatty acid intake was inversely associated with fatal PCa risk [70,71]. Despite the promise of omega-3 fatty acids, not all studies agree. Supplementing 2 g alpha-linolenic acid (ALA) per day for 40 months in 1,622 men with PSA <4 ng/ml did not change their PSA [72]. However, another study found that a high blood serum n-3 PUFA and docosapentaenoic acid (DPA) was associated with reduced total PCa risk while high serum EPA and docosahexaenoic acid (DHA) was possibly associated with increased high-grade PCa risk [73]. Further research is required to understand better the role of omega-3 PUFAs in PCa prevention or treatment.

Cholesterol

Many pre-clinical studies have shown that the accumulation of cholesterol contributes to the progression of PCa [74-76]. It was suggested that a high cholesterol in Lin et al. BMC Medicine (2015) 13:3 Page 5 of 15 circulation may be a risk factor for solid tumors, primarily through the upregulation of cholesterol synthesis, inflammatory pathways [77] and intratumoral steroidogenesis [78]. According to a recent study with 2,408 men scheduled for biopsy, serum cholesterol was independently associated with prediction of PCa risk [79]. Consistent with the cholesterol findings, usage of the cholesterol lowering drug statin post radical prostatectomy (RP) was significantly associated with reduced risk of biochemical recurrence in 1,146 radical prostatectomy patients [80]. Another study also showed that statins may reduce PCa risk by lowering progression [81]. Although the mechanism has not been established, more recent studies also showed that a low high-density lipoprotein (HDL) cholesterol level was associated with a higher risk for PCa and, thus, a higher HDL was protective [81-84]. These findings support the notion that a heart-healthy dietary intervention that lowers cholesterol may benefit prostate health also.

Vitamins & Minerals

Herein we will review the recent data on vitamins A, B complex, C, D, E, and K and selenium. In the two large clinical trials: the Carotene and Retinol Efficacy Trial (CARET; PCa was a secondary outcome) and the National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health prospective cohort study, excessive multivitamin supplementation was associated with a higher risk of developing aggressive PCa, particularly among those taking individual β-carotene supplements [85,86]. Similarly, high serum β-carotene levels were associated with a higher risk for PCa among 997 Finnish men in the Kuopio Ischaemic Heart Disease Risk Factor cohort [87]. However, β-carotene supplement was not found to affect risk for lethal PCa during therapy [88], or in the Danish prospective cohort study of 26,856 men [89]. Circulating retinol also was not associated with PCa risk in a large case–control study [90]. Thus, the association between vitamin A and PCa is still unclear.

Preclinical evidence suggests folate depletion may slow tumor growth, while supplementation has no effect on growth or progression, but may directly lead to epigenetic changes via increases in DNA methylation [91]. Two meta-analyses also showed that circulating folate levels were positively associated with an increased risk of PCa [92,93], while dietary or supplemental folate had no effect on PCa risk [94] in a cohort study with 58,279 men in the Netherlands [95] and a case–control study in Italy and Switzerland [96]. In fact, one study of a cohort of men undergoing radical prostatectomy at several Veterans Administration facilities across the US even showed that higher serum folate levels were associated with lower PSA and, thus, lower risk for biochemical failure [97]. Another study using data from the 2007 to 2010 National Health and Nutrition Examination Survey showed that a higher folate status may be protective against elevated PSA levels among 3,293 men, 40-years old and older, without diagnosed PCa [98]. It was suggested that folate may play a dual role in prostate carcinogenesis and, thus, the complex relationship between folate and PCa awaits further investigation [99].

Despite the potential role of vitamin C (ascorbic acid) as an antioxidant in anticancer therapy, trials examining dietary intake or supplementation of vitamin C are few. A RCT showed no effect of vitamin C intake on PCa risk [89]. Furthermore, vitamin C at high doses may act more as a pro-oxidant than antioxidant, complicating the research design and interpretation.

The primary active form of vitamin D, 1,25 dihydroxyvitamin D3 (calcitriol) aids in proper bone formation, induces differentiation of some immune cells, and inhibits pro-tumor pathways, such as proliferation and angiogenesis, and has been suggested to benefit PCa risk [100]; however, findings continue to be inconclusive. More recent studies found that increased serum vitamin D levels were associated with decreased PCa risk [101,102]. Further, supplementing vitamin D may slow PCa progression or induce apoptosis in PCa cells [103-105]. Other studies, however, reported either no impact of vitamin D supplement on PSA [106] or no effect of vitamin D status on PCa risk [107,108]. Some studies contrarily reported that a lower vitamin D status was associated with a lower PCa risk in older men [109], or a higher serum vitamin D was associated with a higher PCa risk [110,111]. A study even suggested that a ‘U’ shaped relationship may exist between vitamin D status and PCa and the optimal range of circulating vitamin D for PCa prevention may be narrow [112]. This is consistent with the findings for other nutrients that a greater intake of a favorable nutrient may not always be better.

A recent study showed that the association between vitamin D and PCa was modulated by vitamin D-binding protein [113] which may have partially explained the previous inconsistent findings. Further, a meta-analysis investigating the association between Vitamin D receptor (VDR) polymorphisms (BsmI and FokI) and PCa risk reported no relationship with PCa risk [114]. Thus, the role of vitamin D in PCa remains unclear.

In a large randomized trial with a total of 14,641 US male physicians ≥50-years old, participants randomly received 400 IU of vitamin E every other day for an overall mean of 10.3 (13.8) years. Vitamin E supplementation had no immediate or long-term effects on the risk of total cancers or PCa [115]. However, a moderate dose of vitamin E supplement (50 mg or about 75 IU) resulted in lower PCa risk among 29,133 Finnish male smokers [116]. Multiple preclinical studies suggest vitamin E slows tumor growth, partly due to inhibiting DNA synthesis and inducing apoptotic pathways [117]. Unfortunately, human studies have been less than supportive. Two observational studies (the Cancer Prevention Study II Nutrition Cohort and the NIH-AARP Diet and Health Study) both showed no association between vitamin E supplementation and PCa risk [118,119]. However, a higher serum α-tocopherol but not the γ-tocopherol level was associated with decreased risk of PCa [120,121] and the association may be modified by genetic variations in vitamin E related genes [122]. On the contrary, a prospective randomized trial, the Selenium and Vitamin E Cancer Prevention Trial (SELECT), showed vitamin E supplementation significantly increased PCa risk [123] and that a higher plasma α-tocopherol level may interact with selenium supplements to increase high grade PCa risk [124]. This finding is consistent with a case-cohort study of 1,739 cases and 3,117 controls that showed vitamin E increased PCa risk among those with low selenium status but not those with high selenium status [125]. Thus, more research is needed to examine the association between vitamin E and PCa and the dose effect and interaction with other nutrients should be considered.

Vitamin K has been hypothesized to help prevent PCa by reducing bioavailable calcium. Preclinical studies show the combination of vitamins C and K have potent antitumor activity in vitro and act as chemo- and radiosensitizers in vivo [126]. To date, few studies have investigated this, although one study using the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg cohort found an inverse relationship between vitamin K (as menaquinones) intake and PCa incidence [127]. Little to no preclinical studies have been conducted to examine the role of calcium with PCa. Retrospective and meta-analyses suggest increased or reduced PCa risk with increased calcium intake, while others suggest no association [128,129]. Another study suggests a ‘U’-shaped association, where very low calcium levels or supplementation are both associated with PCa [130].

Selenium, on the other hand, has been hypothesized to prevent PCa. While in vitro studies suggested that selenium inhibited angiogenesis and proliferation while inducing apoptosis [131], results from SELECT showed no benefit of selenium alone or in combination with vitamin E for PCa chemoprevention [123]. Further, selenium supplementation did not benefit men with low selenium status but increased the risk of high-grade PCa among men with high selenium status in a randomly selected cohort of 1,739 cases with high-grade (Gleason 7–10) PCa and 3,117 controls [125]. A prospective Netherlands Cohort Study, which included 58,279 men, 55- to 69-years old, also showed that toenail selenium was associated with a reduced risk of advanced PCa [132]. Further research is needed to clarify the role of selenium with PCa.

Phytochemicals

Along with vitamins and minerals [2], plants contain phytochemicals with potential anti-cancer effects. Typically not considered essential compounds, phytochemicals have antioxidant and anti-inflammatory properties.

Silibinin is a polyphenolic flavonoid found in the seeds of milk thistle. It has been shown in vitro and in vivo to inhihit PCa growth by targeting epidermal growth factor receptor (EGFR), IGF-1 receptor (IGF-1R), and nuclear factor-kappa B (NF-kB) pathways [133,134]. A recent study showed that silibinin may be useful in PCa prevention by inhibiting TGFβ2 expression and cancerassociated fibroblast (CAF)-like biomarkers in the human prostate stromal cells [135]. Thus, silibinin is a promising candidate as a PCa chemopreventive agent that awaits further research.

Curcumin is used as food additive in Asia and as an herbal medicine for inflammation [136]. In vitro, curcumin inhibits the pro-inflammatory protein NF-κB while inducing apoptosis through increased expression of proapoptotic genes [137]. In vivo, curcumin slows PCa growth in mice while sensitizing tumors to chemo- and radiotherapies [136]; however, no human trial has examined its impact on PCa.

Pomegranate

The peel and fruit of pomegranates and walnuts are rich in ellagitannins (punicalagins). These phytochemicals are readily metabolized to the active form ellagic acid by gut flora [138]. Preclinical experiments show ellagitannins inhibit PCa proliferation and angiogenesis under hypoxic conditions and induce apoptosis [137,138]. In prospective trials in men with a rising PSA after primary treatment, pomegranate juice or POMx, a commercially available pomegranate extract, increased the PSA doubling time relative to baseline [139,140], although no trials included a placebo group. Results are pending from a prospective placebo RCT using pomegranate extract in men with a rising PSA. However, in a placebo controlled trial, two pills of POMx daily for up to four weeks prior to radical prostatectomy had no impact on tumor pathology or oxidative stress or any other tumor measures [141].

Green Tea

Green tea contains a number of antioxidant polyphenols including catechins, such as epigallocatechin gallate (EGCG), epigallocatechin (EGC), (−)-epicatechin-3-gallate (ECG) and (−)-epicatechin. Preclinical studies suggest EGCG inhibits PCa growth, induces intrinsic and extrinsic apoptotic pathways and decreases inflammation by inhibiting NFkB [137]. Furthermore, the antioxidant properties of EGCG are 25 to 100 times more potent than vitamins C and E [131]. In a prospective randomized preprostatectomy trial, men consuming brewed green tea Lin et al. BMC Medicine (2015) 13:3 Page 7 of 15 prior to surgery had increased levels of green tea polyphenols in their prostate tissue [142]. In a small proof-ofprinciple trial with 60 men, daily supplementation of 600 mg green tea catechin extract reduced PCa incidence by 90% (3% versus 30% in the placebo group) [143]. Another small trial also showed that EGCG supplement resulted in a significant reduction in PSA, hepatocyte growth factor and vascular endothelial growth factor in men with PCa [144]. These studies suggest green tea polyphenols may lower PCa incidence and reduce PCa progression but more research is needed to confirm and clarify its mechanism [137,143,145].

Resveratrol

While most in vitro studies suggest resveratrol inhibits PCa growth [146-148], resveratrol suppresses tumor growth in some [137] but not all animal models [149], possibly due to limited bioavailability [150,151]. To date, there are no clinical trials investigating the preventive or therapeutic effects of resveratrol on PCa.

Zyflamend

Zyflamend is an anti-inflammatory mixture of herbs that has been shown to reduce PCa progression by lowering the expression of markers including pAKT, PSA, histone deacetylases and androgen receptor in animal models and PCa cell line [152-154]. Despite its anti-cancer potential [155], very few studies have been conducted in humans [156,157]. In an open-label Phase I trial of 23 patients with high-grade prostatic intraepithelial neoplasia, Zyflamend alone or in conjunction with other dietary supplements for 18 months reduced the risk for developing PCa [156]. More RCTs in humans are needed to confirm the efficacy and clinical application of this herbal supplement.

Other Whole Foods Fruits & Vegetables

Fruits and vegetables are rich sources of vitamins, minerals and phytochemicals. Several epidemiologic studies found inverse relationships between total fruit and vegetable intake [158], and cruciferous vegetable intake and PCa risk [159,160]. Allium vegetables, such as garlic, leeks, chives, and shallots, contain multiple sulfurous phytochemicals that were suggested to enhance the immune system, inhibit cell growth, modulate expression of androgen-responsive genes and induce apoptosis [161]. Although the number of published studies is limited, both preclinical and epidemiologic data suggest allium vegetable intake may be protective against PCa, particularly localized disease [162]. A randomized trial with 199 men also found that a blend supplement of pomegranate, green tea, broccoli and turmeric significantly reduced the rate of rise in PSA in men with PCa [163].

Tomatoes & Tomato Products

A number of studies have examined the association between tomatoes and tomato products with PCa but the findings are inconclusive. The antioxidant lycopene, which is rich in tomatoes, has also been studied specifically for its impact on PCa. In vitro, lycopene halts the cell cycle in several PCa cell lines and decreases IGF-1 signaling by inducing IGF-1 binding proteins [131]. While some animal studies found lycopene specifically slows PCa growth [164] or reduces PCa epithelial cells at stages of initiation, promotion and progression [165], two studies found conflicting findings between tomato paste and lycopene [166,167]. Prospective human studies found higher lycopene consumption [168,169] or higher serum levels were associated with lower PCa risk [170], but others have not [171,172]. Prostatic lycopene concentration below a 1 ng/mg threshold was associated with PCa at six-month follow-up biopsy (P = 0.003) [173]. Two short-term preprostatectomy trials using tomato sauce or lycopene supplementation demonstrated lycopene uptake in prostate tissue and antioxidant and potential anticancer effects [174,175]. While several clinical trials suggested an inverse relationship between lycopene supplementation, PSA levels and decreases in cancerrelated symptoms [171,176], no large-scale randomized trials have tested the role of lycopene or tomato products on PCa prevention or treatment.

Coffee

Coffee contains caffeine and several unidentified phenolic compounds that may serve as antioxidants. Epidemiological studies suggest an inverse relationship between coffee consumption and PCa risk, mainly for advanced or lethal stage disease, and the findings were independent of caffeine content [177,178]. Although several epidemiological studies [179-182] found no association between coffee consumption and PCa risk, a recent meta-analysis of prospective studies concluded that coffee consumption may reduce PCa risk [183]. The potential mechanism(s) and pathway(s) involved are unknown but may include antioxidant, anti-inflammatory effects, glucose and insulin metabolism, and potential impact on IGF-I and circulating sex hormones.

Dietary Patterns

Even though many single nutrients or food factors have been examined for their impact or association with PCa risk or progression, the results have largely been inconclusive. A potential reason for the inconsistency is the fact that the impact of single nutrient or food factor may be too small to be detected. In addition, nutrients naturally existing in foods often are highly correlated and may interact with each other and, thus, affect the impact on PCa. Thus, dietary pattern analysis has received an increasing Lin et al. BMC Medicine (2015) 13:3 Page 8 of 15 interest but research has been limited and the existing results have been inconclusive. In a cohort of 293,464 men, a high dietary quality, as indicated by the Healthy Eating Index (HEI) score, was associated with a lower risk of total PCa risk [70]. The Mediterranean diet, which is high in vegetables, olive oil, complex carbohydrates, lean meats and antioxidants, is consistently recommended to patients for prevention of cardiovascular disease and obesity [184], and may show promise in PCa prevention [185]. Fish and omega-3 fatty acid consumption in the Mediterranean pattern were significantly and inversely associated with fatal PCa risk. In addition, adherence to the Mediterranean diet after diagnosis of non-metastatic PCa was associated with lower overall mortality [186]. Whereas, a Western pattern with high intakes of red meats, processed meats, fried fish, chips, high-fat milk and white bread, was associated with a higher risk for PCa [187].

Furthermore, Asian countries with high consumption of omega-3 PUFAs, soy and green tea-based phytochemicals, have lower PCa incidences versus countries consuming a ‘Western-style’ diet [188]. However, not all studies [189-191] supported an association between certain dietary pattern and risk of PCa. It is possible that the methodology used in identifying dietary patterns may not have captured all the dietary factors associated with PCa risk. Alternatively, each dietary pattern may contain both beneficial and harmful components resulting in an overall null association. More research is needed to continue searching for dietary patterns that combine most of the beneficial nutrients/food factors for PCa and limit most of the negative nutrients/ food factors.

Future Direction For Clinical Trials

Based on the multitude of epidemiologic, preclinical and clinical trials described in this review, dietary interventions for the prevention and treatment of PCa hold great promise. In addition, several dietary factors and vitamins/supplements may be associated with PCa risk and/ or progression of disease. Prospective randomized trials are clearly indicated to identify specific nutrients or combination therapies for the prevention and treatment of PCa.

Recently, active surveillance (AS) has emerged as a viable option for men with lower risk PCa. Men on AS are motivated to adhere to diet and lifestyle modifications [192], making this subset a good target for dietary intervention and quality of life trials [193]. PCa survivors who are more active and report ‘healthy’ eating habits (that is, consuming low-fat, low-refined carbohydrate diets rich in fruits and vegetables) have better overall quality of life versus their inactive, unhealthy counterparts [194]. Thus, more randomized trials are warranted to determine the overall long-term effects of dietary intervention in this population. Specifically, key questions to address in future trials are: 1) Can dietary interventions delay the need for treatment in men on AS; 2) Can dietary interventions prevent recurrence for men after treatment; 3) Can dietary interventions delay progression among men with recurrent disease and, thus, delay the need for hormonal therapy; 4) Can dietary interventions reduce the side effects of PCa treatments including hormonal therapy and newer targeted therapies; and 5) Is there any role for dietary interventions alone or combined with targeted therapies in men on hormonal therapy to prevent castrate-resistance or after the emergence of castrate resistance disease? Because increasing evidence shows that metabolic abnormalities increase risk for PCa, lifestyle intervention that improves metabolic profile is a win-win option for PCa prevention and treatment [195,196].

Conclusions: Prostate Cancer

Future research is required to determine the ideal diet for PCa prevention or treatment. However, several dietary factors and some dietary patterns hold promise in reducing PCa risk or progression and are consistent with current dietary guidelines for Americans [197]. For counseling patients on diet for primary and secondary PCa prevention, many believe ‘heart healthy equals prostate healthy.’ Thus, given the current inconclusive results, the best dietary advice for PCa prevention or management seems to include: increasing fruits and vegetables, replacing refined carbohydrates with whole grains, reducing total and saturated fat, reducing overcooked meats and consuming a moderate amount of calories or reducing carbohydrates with a primary goal of obtaining and maintaining a healthy body weight.

Competing interests The authors declare that they have no competing interests.

Authors’ contributions P-HL and SF conducted the review, P-HL drafted the manuscript and SF and WA edited and provided critical input. All authors read and approved the final manuscript.

Acknowledgements Funding was provided by grants 1K24CA160653 (Freedland), NIH P50CA92131 (W. Aronson). This manuscript is the result of work supported with resources and the use of facilities at the Veterans Administration Medical Center, West Los Angeles (W. Aronson).

Author details 1 Department of Medicine, Division of Nephrology, Duke University Medical Center, Box 3487, Durham, NC 27710, USA. 2 Urology Section, Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA. 3 Department of Urology, UCLA School of Medicine, Los Angeles, CA, USA. 4 Urology Section, Department of Surgery, Durham Veterans Affairs Medical Center, Division of Urology, Durham, NC, USA. 5 Duke Prostate Center, Departments of Surgery and Pathology, Duke University Medical Center, Durham, NC, USA.

References

1. Center MM, Jemal A, Lortet-Tieulent J, Ward E, Ferlay J, Brawley O, Bray F:
International variation in prostate cancer incidence and mortality rates.
Eur Urol 2012, 61:1079–1092.
2. Masko EM, Allott EH, Freedland SJ: The relationship between nutrition and
prostate cancer: is more always better? Eur Urol 2013, 63:810–820.
3. Mavropoulos JC, Isaacs WB, Pizzo SV, Freedland SJ: Is there a role for a
low-carbohydrate ketogenic diet in the management of prostate cancer?
Urology 2006, 68:15–18.
4. Freedland SJ, Mavropoulos J, Wang A, Darshan M, Demark-Wahnefried W,
Aronson WJ, Cohen P, Hwang D, Peterson B, Fields T, Pizzo SV, Isaacs WB:
Carbohydrate restriction, prostate cancer growth, and the insulin-like
growth factor axis. Prostate 2008, 68:11–19.
5. Mavropoulos JC: Buschemeyer WC 3rd, Tewari AK, Rokhfeld D, Pollak M,
Zhao Y, Febbo PG, Cohen P, Hwang D, Devi G, Demark-Wahnefried W,
Westman EC, Peterson BL, Pizzo SV, Freedland SJ: The effects of varying
dietary carbohydrate and fat content on survival in a murine LNCaP
prostate cancer xenograft model. Cancer Prev Res (Phila Pa) 2009,
2:557–565.
6. Masko EM, Thomas JA 2nd, Antonelli JA, Lloyd JC, Phillips TE, Poulton SH,
Dewhirst MW, Pizzo SV, Freedland SJ: Low-carbohydrate diets and
prostate cancer: how low is “low enough”? Cancer Prev Res (Phila) 2010,
3:1124–1131.
7. Drake I, Sonestedt E, Gullberg B, Ahlgren G, Bjartell A, Wallstrom P, Wirfält E:
Dietary intakes of carbohydrates in relation to prostate cancer risk: a
prospective study in the Malmo Diet and Cancer cohort. Am J Clin Nutr
2012, 96:1409–1418.
8. Zhang J, Shen C, Wang L, Ma Q, Xia P, Qi M, Yang M, Han B: Metformin
inhibits epithelial-mesenchymal transition in prostate cancer cells:
Involvement of the tumor suppressor miR30a and its target gene SOX4.
Biochem Biophys Res Commun 2014, 452:746–752.
9. Lee SY, Song CH, Xie YB, Jung C, Choi HS, Lee K: SMILE upregulated by
metformin inhibits the function of androgen receptor in prostate cancer
cells. Cancer Lett 2014, 354:390–397.
10. Demir U, Koehler A, Schneider R, Schweiger S, Klocker H: Metformin antitumor
effect via disruption of the MID1 translational regulator complex
and AR downregulation in prostate cancer cells. BMC Cancer 2014, 14:52.
11. Margel D: Metformin to prevent prostate cancer: a call to unite. Eur Urol
2014. doi:10.1016/j.eururo.2014.05.012. [Epub ahead of time]
12. Margel D, Urbach DR, Lipscombe LL, Bell CM, Kulkarni G, Austin PC, Fleshner
N: Metformin use and all-cause and prostate cancer-specific mortality
among men with diabetes. J Clin Oncol 2013, 31:3069–3075.
13. Tseng CH: Metformin significantly reduces incident prostate cancer risk
in Taiwanese men with type 2 diabetes mellitus. Eur J Cancer 2014,
50:2831–2837.
14. Joshua AM, Zannella VE, Downes MR, Bowes B, Hersey K, Koritzinsky M,
Schwab M, Hofmann U, Evans A, van der Kwast T, Trachtenberg J, Finelli A,
Fleshner N, Sweet J, Pollak M: A pilot ‘window of opportunity’
neoadjuvant study of metformin in localised prostate cancer. Prostate
Cancer Prostatic Dis 2014, 17:252–258.
15. Rothermundt C, Hayoz S, Templeton AJ, Winterhalder R, Strebel RT, Bartschi
D, Pollak M, Lui L, Endt K, Schiess R, Rüschoff JH, Cathomas R, Gillessen S:
Metformin in Chemotherapy-naive Castration-resistant Prostate Cancer:
A Multicenter Phase 2 Trial (SAKK 08/09). Eur Urol 2014, 66:468–474.
16. Allott EH, Abern MR, Gerber L, Keto CJ, Aronson WJ, Terris MK, Kane CJ,
Amling CL, Cooperberg MR, Moorman PG, Freedland SJ: Metformin does
not affect risk of biochemical recurrence following radical
prostatectomy: results from the SEARCH database. Prostate Cancer
Prostatic Dis 2013, 16:391–397.
17. Rieken M, Kluth LA, Xylinas E, Fajkovic H, Becker A, Karakiewicz PI, Herman
M, Lotan Y, Seitz C, Schramek P, Remzi M, Loidl W, Pummer K, Lee RK,
Faison T, Scherr DS, Kautzky-Willer A, Bachmann A, Tewari A, Shariat SF:
Association of diabetes mellitus and metformin use with biochemical
recurrence in patients treated with radical prostatectomy for prostate
cancer. World J Urol 2014, 32:999–1005.
18. Margel D, Urbach D, Lipscombe LL, Bell CM, Kulkarni G, Austin PC, Fleshner
N: Association between metformin use and risk of prostate cancer and
its grade. J Natl Cancer Inst 2013, 105:1123–1131.
19. Franciosi M, Lucisano G, Lapice E, Strippoli GF, Pellegrini F, Nicolucci A:
Metformin therapy and risk of cancer in patients with type 2 diabetes:
systematic review. PLoS One 2013, 8:e71583.
20. Kaushik D, Karnes RJ, Eisenberg MS, Rangel LJ, Carlson RE, Bergstralh EJ:
Effect of metformin on prostate cancer outcomes after radical
prostatectomy. Urol Oncol 2014, 32:43 e41–47.
21. Bensimon L, Yin H, Suissa S, Pollak MN, Azoulay L: The use of metformin in
patients with prostate cancer and the risk of death. Cancer Epidemiol
Biomarkers Prev 2014, 23:2111–2118.
22. Tsilidis KK, Capothanassi D, Allen NE, Rizos EC, Lopez DS, van Veldhoven K,
Sacerdote C, Ashby D, Vineis P, Tzoulaki I, Ioannidis JP: Metformin does not
affect cancer risk: a cohort study in the U.K. Clinical Practice Research
Datalink analyzed like an intention-to-treat trial. Diabetes Care 2014,
37:2522–2532.
23. Levine ME, Suarez JA, Brandhorst S, Balasubramanian P, Cheng CW, Madia F,
Fontana L, Mirisola MG, Guevara-Aguirre J, Wan J, Passarino G, Kennedy BK,
Wei M, Cohen P, Crimmins EM, Longo VD: Low protein intake is associated
with a major reduction in IGF-1, cancer, and overall mortality in the 65
and younger but not older population. Cell Metab 2014, 19:407–417.
24. Solon-Biet SM, McMahon AC, Ballard JW, Ruohonen K, Wu LE, Cogger VC,
Warren A, Huang X, Pichaud N, Melvin RG, Gokarn R, Khalil M, Turner N,
Cooney GJ, Sinclair DA, Raubenheimer D, Le Couteur DG, Simpson SJ: The
ratio of macronutrients, not caloric intake, dictates cardiometabolic
health, aging, and longevity in ad libitum-fed mice. Cell Metab 2014,
19:418–430.
25. Richman EL, Stampfer MJ, Paciorek A, Broering JM, Carroll PR, Chan JM:
Intakes of meat, fish, poultry, and eggs and risk of prostate cancer
progression. Am J Clin Nutr 2010, 91:712–721.
26. Joshi AD, John EM, Koo J, Ingles SA, Stern MC: Fish intake, cooking
practices, and risk of prostate cancer: results from a multi-ethnic
case–control study. Cancer Causes Control 2012, 23:405–420.
27. Joshi AD, Corral R, Catsburg C, Lewinger JP, Koo J, John EM, Ingles SA,
Stern MC: Red meat and poultry, cooking practices, genetic susceptibility
and risk of prostate cancer: results from a multiethnic case–control
study. Carcinogenesis 2012, 33:2108–2118.
28. Catsburg C, Joshi AD, Corral R, Lewinger JP, Koo J, John EM, Ingles SA,
Stern MC: Polymorphisms in carcinogen metabolism enzymes, fish
intake, and risk of prostate cancer. Carcinogenesis 2012, 33:1352–1359.
29. Pettersson A, Kasperzyk JL, Kenfield SA, Richman EL, Chan JM, Willett WC,
Stampfer MJ, Mucci LA, Giovannucci EL: Milk and dairy consumption
among men with prostate cancer and risk of metastases and prostate
cancer death. Cancer Epidemiol Biomarkers Prev 2012, 21:428–436.
30. Deneo-Pellegrini H, Ronco AL, De Stefani E, Boffetta P, Correa P,
Mendilaharsu M, Acosta G: Food groups and risk of prostate cancer: a
case–control study in Uruguay. Cancer Causes Control 2012, 23:1031–1038.
31. Park SY, Murphy SP, Wilkens LR, Stram DO, Henderson BE, Kolonel LN:
Calcium, vitamin D, and dairy product intake and prostate cancer risk:
the Multiethnic Cohort Study. Am J Epidemiol 2007, 166:1259–1269.
32. Song Y, Chavarro JE, Cao Y, Qiu W, Mucci L, Sesso HD, Stampfer MJ,
Giovannucci E, Pollak M, Liu S, Ma J: Whole milk intake is associated with
prostate cancer-specific mortality among U.S. male physicians. J Nutr Feb
2013, 143:189–196.
33. Young NJ, Metcalfe C, Gunnell D, Rowlands MA, Lane JA, Gilbert R, Avery
KN, Davis M, Neal DE, Hamdy FC, Donovan J, Martin RM, Holly JM: A crosssectional
analysis of the association between diet and insulin-like growth
factor (IGF)-I, IGF-II, IGF-binding protein (IGFBP)-2, and IGFBP-3 in men in
the United Kingdom. Cancer Causes Control 2012, 23:907–917.
34. Christensen MJ, Quiner TE, Nakken HL, Lephart ED, Eggett DL, Urie PM:
Combination effects of dietary soy and methylselenocysteine in a mouse
model of prostate cancer. Prostate 2013, 73:986–995.
35. Bosland MC, Kato I, Zeleniuch-Jacquotte A, Schmoll J, Enk Rueter E,
Melamed J, Kong MX, Macias V, Kajdacsy-Balla A, Lumey LH, Xie H, Gao W,
Walden P, Lepor H, Taneja SS, Randolph C, Schlicht MJ, Meserve-Watanabe
H, Deaton RJ, Davies JA: Effect of soy protein isolate supplementation on
biochemical recurrence of prostate cancer after radical prostatectomy: a
randomized trial. JAMA 2013, 310:170–178.
36. Chiyomaru T, Yamamura S, Fukuhara S, Yoshino H, Kinoshita T, Majid S, Saini
S, Chang I, Tanaka Y, Enokida H, Seki N, Nakagawa M, Dahiya R: Genistein
inhibits prostate cancer cell growth by targeting miR-34a and oncogenic
HOTAIR. PLoS One 2013, 8:e70372.
37. Zhang S, Wang Y, Chen Z, Kim S, Iqbal S, Chi A, Ritenour C, Wang YA, Kucuk
O, Wu D: Genistein enhances the efficacy of cabazitaxel chemotherapy
in metastatic castration-resistant prostate cancer cells. Prostate 2013,
73:1681–1689.38. van Die MD, Bone KM, Williams SG, Pirotta MV: Soy and soy isoflavones in
prostate cancer: a systematic review and meta-analysis of randomized
controlled trials. BJU Int 2014, 113:E119–E130.
39. Hamilton-Reeves JM, Banerjee S, Banerjee SK, Holzbeierlein JM, Thrasher JB,
Kambhampati S, Keighley J, Van Veldhuizen P: Short-term soy isoflavone
intervention in patients with localized prostate cancer: a randomized,
double-blind, placebo-controlled trial. PLoS One 2013, 8:e68331.
40. Pavese JM, Krishna SN, Bergan RC: Genistein inhibits human prostate
cancer cell detachment, invasion, and metastasis. Am J Clin Nutr 2014,
100:431S–436S.
41. Gonzalez-Menendez P, Hevia D, Rodriguez-Garcia A, Mayo JC, Sainz RM:
Regulation of GLUT transporters by flavonoids in androgen-sensitive and
-insensitive prostate cancer cells. Endocrinology 2014, 155:3238–3250.
42. Hirata H, Hinoda Y, Shahryari V, Deng G, Tanaka Y, Tabatabai ZL, Dahiya R:
Genistein downregulates onco-miR-1260b and upregulates sFRP1 and
Smad4 via demethylation and histone modification in prostate cancer
cells. Br J Cancer 2014, 110:1645–1654.
43. Handayani R, Rice L, Cui Y, Medrano TA, Samedi VG, Baker HV, Szabo NJ,
Shiverick KT: Soy isoflavones alter expression of genes associated with
cancer progression, including interleukin-8, in androgen-independent
PC-3 human prostate cancer cells. J Nutr 2006, 136:75–82.
44. Travis RC, Allen NE, Appleby PN, Price A, Kaaks R, Chang-Claude J, Boeing H,
Aleksandrova K, Tjønneland A, Johnsen NF, Overvad K, Ramón Quirós J,
González CA, Molina-Montes E, Sánchez MJ, Larrañaga N, Castaño JM,
Ardanaz E, Khaw KT, Wareham N, Trichopoulou A, Karapetyan T, Rafnsson
SB, Palli D, Krogh V, Tumino R, Vineis P, Bueno-de-Mesquita HB, Stattin P,
Johansson M, et al: Prediagnostic concentrations of plasma genistein and
prostate cancer risk in 1,605 men with prostate cancer and 1,697
matched control participants in EPIC. Cancer Causes Control 2012,
23:1163–1171.
45. Jackson MD, McFarlane-Anderson ND, Simon GA, Bennett FI, Walker SP:
Urinary phytoestrogens and risk of prostate cancer in Jamaican men.
Cancer Causes Control 2010, 21:2249–2257.
46. Lazarevic B, Hammarström C, Yang J, Ramberg H, Diep LM, Karlsen SJ,
Kucuk O, Saatcioglu F, Taskèn KA, Svindland A: The effects of short-term
genistein intervention on prostate biomarker expression in patients with
localised prostate cancer before radical prostatectomy. Br J Nutr 2012,
108:2138–2147.
47. Epstein MM, Kasperzyk JL, Mucci LA, Giovannucci E, Price A, Wolk A,
Håkansson N, Fall K, Andersson SO, Andrén O: Dietary fatty acid intake and
prostate cancer survival in Orebro County, Sweden. Am J Epidemiol 2012,
176:240–252.
48. Kobayashi N, Barnard RJ, Said J, Hong-Gonzalez J, Corman DM, Ku M,
Doan NB, Gui D, Elashoff D, Cohen P, Aronson WJ: Effect of low-fat diet on
development of prostate cancer and Akt phosphorylation in the Hi-Myc
transgenic mouse model. Cancer Res 2008, 68:3066–3073.
49. Ngo TH, Barnard RJ, Cohen P, Freedland S, Tran C, deGregorio F, Elshimali
YI, Heber D, Aronson WJ: Effect of isocaloric low-fat diet on human
LAPC-4 prostate cancer xenografts in severe combined immunodeficient
mice and the insulin-like growth factor axis. Clin Cancer Res 2003,
9:2734–2743.
50. Huang M, Narita S, Numakura K, Tsuruta H, Saito M, Inoue T, Horikawa Y,
Tsuchiya N, Habuchi T: A high-fat diet enhances proliferation of
prostate cancer cells and activates MCP-1/CCR2 signaling. Prostate 2012,
72:1779–1788.
51. Chang SN, Han J, Abdelkader TS, Kim TH, Lee JM, Song J, Kim KS, Park JH,
Park JH: High animal fat intake enhances prostate cancer progression
and reduces glutathione peroxidase 3 expression in early stages of
TRAMP mice. Prostate 2014, 74:1266–1277.
52. Bidoli E, Talamini R, Bosetti C, Negri E, Maruzzi D, Montella M, Franceschi S,
La Vecchia C: Macronutrients, fatty acids, cholesterol and prostate cancer
risk. Ann Oncol 2005, 16:152–157.
53. Park SY, Murphy SP, Wilkens LR, Henderson BE, Kolonel LN: Fat and meat
intake and prostate cancer risk: the multiethnic cohort study. Int J Cancer
2007, 121:1339–1345.
54. Wallstrom P, Bjartell A, Gullberg B, Olsson H, Wirfalt E: A prospective study
on dietary fat and incidence of prostate cancer (Malmo, Sweden).
Cancer Causes Control 2007, 18:1107–1121.
55. Crowe FL, Key TJ, Appleby PN, Travis RC, Overvad K, Jakobsen MU,
Johnsen NF, Tjønneland A, Linseisen J, Rohrmann S, Boeing H, Pischon T,
Trichopoulou A, Lagiou P, Trichopoulos D, Sacerdote C, Palli D, Tumino R,
Krogh V, Bueno-de-Mesquita HB, Kiemeney LA, Chirlaque MD, Ardanaz E,
Sánchez MJ, Larrañaga N, González CA, Quirós JR, Manjer J, Wirfält E, Stattin
P, et al: Dietary fat intake and risk of prostate cancer in the European
Prospective Investigation into Cancer and Nutrition. Am J Clin Nutr 2008,
87:1405–1413.
56. Ohwaki K, Endo F, Kachi Y, Hattori K, Muraishi O, Nishikitani M, Yano E:
Relationship between dietary factors and prostate-specific antigen in
healthy men. Urol Int 2012, 89:270–274.
57. Bassett JK, Severi G, Hodge AM, MacInnis RJ, Gibson RA, Hopper JL,
English DR, Giles GG: Plasma phospholipid fatty acids, dietary fatty acids
and prostate cancer risk. Int J Cancer 2013, 133:1882–1891.
58. Richman EL, Kenfield SA, Chavarro JE, Stampfer MJ, Giovannucci EL, Willett
WC, Chan JM: Fat intake after diagnosis and risk of lethal prostate cancer
and all-cause mortality. JAMA Intern Med 2013, 173:1318–1326.
59. Williams CD, Whitley BM, Hoyo C, Grant DJ, Iraggi JD, Newman KA, Gerber
L, Taylor LA, McKeever MG, Freedland SJ: A high ratio of dietary n-6/n-3
polyunsaturated fatty acids is associated with increased risk of prostate
cancer. Nutr Res 2011, 31:1–8.
60. Chua ME, Sio MC, Sorongon MC, Dy JS: Relationship of dietary intake of
omega-3 and omega-6 fatty acids with risk of prostate cancer
development: a meta-analysis of prospective studies and review of
literature. Prostate Cancer 2012, 2012:826254.
61. Berquin IM, Edwards IJ, Kridel SJ, Chen YQ: Polyunsaturated fatty acid
metabolism in prostate cancer. Cancer Metastasis Rev 2011, 30:295–309.
62. Aronson WJ, Kobayashi N, Barnard RJ, Henning S, Huang M, Jardack PM, Liu
B, Gray A, Wan J, Konijeti R, Freedland SJ, Castor B, Heber D, Elashoff D, Said
J, Cohen P, Galet C: Phase II prospective randomized trial of a low-fat diet
with fish oil supplementation in men undergoing radical prostatectomy.
Cancer Prev Res (Phila) 2011, 4:2062–2071.
63. Hughes-Fulford M, Li CF, Boonyaratanakornkit J, Sayyah S: Arachidonic acid
activates phosphatidylinositol 3-kinase signaling and induces gene
expression in prostate cancer. Cancer Res 2006, 66:1427–1433.
64. Moreel X, Allaire J, Leger C, Caron A, Labonte ME, Lamarche B, Julien P,
Desmeules P, Têtu B, Fradet V: Prostatic and dietary omega-3 fatty acids
and prostate cancer progression during active surveillance. Cancer Prev
Res (Phila) 2014, 7:766–776.
65. Spencer L, Mann C, Metcalfe M, Webb M, Pollard C, Spencer D, Berry D,
Steward W, Dennison A: The effect of omega-3 FAs on tumour angiogenesis
and their therapeutic potential. Eur J Cancer 2009, 45:2077–2086.
66. Gu Z, Suburu J, Chen H, Chen YQ: Mechanisms of omega-3 polyunsaturated
fatty acids in prostate cancer prevention. Biomed Res Int 2013, 2013:824563.
67. Lloyd JC, Masko EM, Wu C, Keenan MM, Pilla DM, Aronson WJ, Chi JT,
Freedland SJ: Fish oil slows prostate cancer xenograft growth relative to
other dietary fats and is associated with decreased mitochondrial and
insulin pathway gene expression. Prostate Cancer Prostatic Dis 2013,
16:285–291.
68. Williams CM, Burdge G: Long-chain n-3 PUFA: plant v. marine sources.
Proc Nutr Soc 2006, 65:42–50.
69. Galet C, Gollapudi K, Stepanian S, Byrd JB, Henning SM, Grogan T, Elashoff
D, Heber D, Said J, Cohen P, Aronson WJ: Effect of a low-fat fish oil diet
on proinflammatory eicosanoids and cell-cycle progression score in
men undergoing radical prostatectomy. Cancer Prev Res (Phila) 2014,
7:97–104.
70. Bosire C, Stampfer MJ, Subar AF, Park Y, Kirkpatrick SI, Chiuve SE, Hollenbeck
AR, Reedy J: Index-based dietary patterns and the risk of prostate cancer
in the NIH-AARP diet and health study. Am J Epidemiol 2013, 177:504–513.
71. Aronson WJ, Barnard RJ, Freedland SJ, Henning S, Elashoff D, Jardack PM,
Cohen P, Heber D, Kobayashi N: Growth inhibitory effect of low fat diet
on prostate cancer cells: results of a prospective, randomized dietary
intervention trial in men with prostate cancer. J Urol 2010, 183:345–350.
72. Brouwer IA, Geleijnse JM, Klaasen VM, Smit LA, Giltay EJ, de Goede J,
Heijboer AC, Kromhout D, Katan MB: Effect of alpha linolenic acid
supplementation on serum prostate specific antigen (PSA): results from
the alpha omega trial. PLoS One 2013, 8:e81519.
73. Chua ME, Sio MC, Sorongon MC, Morales ML Jr: The relevance of serum
levels of long chain omega-3 polyunsaturated fatty acids and prostate
cancer risk: A meta-analysis. Can Urol Assoc J 2013, 7:E333–E343.
74. Yue S, Li J, Lee SY, Lee HJ, Shao T, Song B, Cheng L, Masterson TA, Liu X,
Ratliff TL, Cheng JX: Cholesteryl ester accumulation induced by PTEN loss
and PI3K/AKT activation underlies human prostate cancer
aggressiveness. Cell Metab 2014, 19:393–406.

75. Sun Y, Sukumaran P, Varma A, Derry S, Sahmoun AE, Singh BB: Cholesterolinduced
activation of TRPM7 regulates cell proliferation, migration,
and viability of human prostate cells. Biochim Biophys Acta 1843,
2014:1839–1850.
76. Murai T: Cholesterol lowering: role in cancer prevention and treatment.
Biol Chem 2014. doi:10.1515/hsz-2014-0194. [Epub ahead of time]
77. Zhuang L, Kim J, Adam RM, Solomon KR, Freeman MR: Cholesterol
targeting alters lipid raft composition and cell survival in prostate cancer
cells and xenografts. J Clin Invest 2005, 115:959–968.
78. Mostaghel EA, Solomon KR, Pelton K, Freeman MR, Montgomery RB:
Impact of circulating cholesterol levels on growth and intratumoral
androgen concentration of prostate tumors. PLoS One 2012,
7:e30062.
79. Morote J, Celma A, Planas J, Placer J, de Torres I, Olivan M, Carles J,
Reventós J, Doll A: Role of serum cholesterol and statin use in the risk of
prostate cancer detection and tumor aggressiveness. Int J Mol Sci 2014,
15:13615–13623.
80. Allott EH, Howard LE, Cooperberg MR, Kane CJ, Aronson WJ, Terris MK,
Amling CL, Freedland SJ: Postoperative statin use and risk of biochemical
recurrence following radical prostatectomy: results from the Shared
Equal Access Regional Cancer Hospital (SEARCH) database. BJU Int 2014,
114:661–666.
81. Jespersen CG, Norgaard M, Friis S, Skriver C, Borre M: Statin use and risk of
prostate cancer: A Danish population-based case–control study,
1997–2010. Cancer Epidemiol 2014, 38:42–47.
82. Meyers CD, Kashyap ML: Pharmacologic elevation of high-density
lipoproteins: recent insights on mechanism of action and atherosclerosis
protection. Curr Opin Cardiol 2004, 19:366–373.
83. Xia P, Vadas MA, Rye KA, Barter PJ, Gamble JR: High density lipoproteins
(HDL) interrupt the sphingosine kinase signaling pathway. A possible
mechanism for protection against atherosclerosis by HDL. J Biol Chem
1999, 274:33143–33147.
84. Kotani K, Sekine Y, Ishikawa S, Ikpot IZ, Suzuki K, Remaley AT: High-density
lipoprotein and prostate cancer: an overview. J Epidemiol 2013,
23:313–319.
85. Soni MG, Thurmond TS, Miller ER 3rd, Spriggs T, Bendich A, Omaye ST:
Safety of vitamins and minerals: controversies and perspective. Toxicol
Sci 2010, 118:348–355.
86. Neuhouser ML, Barnett MJ, Kristal AR, Ambrosone CB, King I, Thornquist M,
Goodman G: (n-6) PUFA increase and dairy foods decrease prostate
cancer risk in heavy smokers. J Nutr 2007, 137:1821–1827.
87. Karppi J, Kurl S, Laukkanen JA, Kauhanen J: Serum beta-carotene in relation
to risk of prostate cancer: the Kuopio Ischaemic Heart Disease Risk
Factor study. Nutr Cancer 2012, 64:361–367.
88. Margalit DN, Kasperzyk JL, Martin NE, Sesso HD, Gaziano JM, Ma J, Stampfer
MJ, Mucci LA: Beta-carotene antioxidant use during radiation therapy
and prostate cancer outcome in the Physicians’ Health Study. Int J Radiat
Oncol Biol Phys 2012, 83:28–32.
89. Roswall N, Larsen SB, Friis S, Outzen M, Olsen A, Christensen J, Dragsted LO,
Tjønneland A: Micronutrient intake and risk of prostate cancer in a
cohort of middle-aged, Danish men. Cancer Causes Control 2013,
24:1129–1135.
90. Gilbert R, Metcalfe C, Fraser WD, Donovan J, Hamdy F, Neal DE, Lane JA,
Martin RM: Associations of circulating retinol, vitamin E, and 1,25-
dihydroxyvitamin D with prostate cancer diagnosis, stage, and grade.
Cancer Causes Control 2012, 23:1865–1873.
91. Bistulfi G, Foster BA, Karasik E, Gillard B, Miecznikowski J, Dhiman VK,
Smiraglia DJ: Dietary folate deficiency blocks prostate cancer progression
in the TRAMP model. Cancer Prev Res (Phila) 2011, 4:1825–1834.
92. Collin SM: Folate and B12 in prostate cancer. Adv Clin Chem 2013,
60:1–63.
93. Tio M, Andrici J, Cox MR, Eslick GD: Folate intake and the risk of prostate
cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic
Dis 2014, 17:213–219.
94. Vollset SE, Clarke R, Lewington S, Ebbing M, Halsey J, Lonn E, Armitage J,
Manson JE, Hankey GJ, Spence JD, Galan P, Bønaa KH, Jamison R, Gaziano
JM, Guarino P, Baron JA, Logan RF, Giovannucci EL, den Heijer M, Ueland
PM, Bennett D, Collins R, Peto R, B-Vitamin Treatment Trialists’ Collaboration:
Effects of folic acid supplementation on overall and site-specific cancer
incidence during the randomised trials: meta-analyses of data on 50,000
individuals. Lancet 2013, 381:1029–1036.
95. Verhage BA, Cremers P, Schouten LJ, Goldbohm RA, van den Brandt PA:
Dietary folate and folate vitamers and the risk of prostate cancer
in The Netherlands Cohort Study. Cancer Causes Control 2012,
23:2003–2011.
96. Tavani A, Malerba S, Pelucchi C, Dal Maso L, Zucchetto A, Serraino D, Levi F,
Montella M, Franceschi S, Zambon A, La Vecchia C: Dietary folates and
cancer risk in a network of case–control studies. Ann Oncol 2012,
23:2737–2742.
97. Moreira DM, Banez LL, Presti JC Jr, Aronson WJ, Terris MK, Kane CJ, Amling
CL, Freedland SJ: High serum folate is associated with reduced
biochemical recurrence after radical prostatectomy: results from the
SEARCH Database. Int Braz J Urol 2013, 39:312–318. discussion 319.
98. Han YY, Song JY, Talbott EO: Serum folate and prostate-specific antigen in
the United States. Cancer Causes Control 2013, 24:1595–1604.
99. Rycyna KJ, Bacich DJ, O’Keefe DS: Opposing roles of folate in prostate
cancer. Urology 2013, 82:1197–1203.
100. Gilbert R, Martin RM, Beynon R, Harris R, Savovic J, Zuccolo L, Bekkering GE,
Fraser WD, Sterne JA, Metcalfe: Associations of circulating and dietary
vitamin D with prostate cancer risk: a systematic review and dose–
response meta-analysis. Cancer Causes Control 2011, 22:319–340.
101. Schenk JM, Till CA, Tangen CM, Goodman PJ, Song X, Torkko KC, Kristal AR,
Peters U, Neuhouser ML: Serum 25-hydroxyvitamin d concentrations and
risk of prostate cancer: results from the Prostate Cancer Prevention Trial.
Cancer Epidemiol Biomarkers Prev 2014, 23:1484–1493.
102. Schwartz GG: Vitamin D, in blood and risk of prostate cancer: lessons
from the Selenium and Vitamin E Cancer Prevention Trial and the
Prostate Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev 2014,
23:1447–1449.
103. Giangreco AA, Vaishnav A, Wagner D, Finelli A, Fleshner N, Van der Kwast T,
Vieth R, Nonn L: Tumor suppressor microRNAs, miR-100 and -125b, are
regulated by 1,25-dihydroxyvitamin D in primary prostate cells and in
patient tissue. Cancer Prev Res (Phila) 2013, 6:483–494.
104. Hollis BW, Marshall DT, Savage SJ, Garrett-Mayer E, Kindy MS, Gattoni-Celli S:
Vitamin D3 supplementation, low-risk prostate cancer, and health
disparities. J Steroid Biochem Mol Biol 2013, 136:233–237.
105. Sha J, Pan J, Ping P, Xuan H, Li D, Bo J, Liu D, Huang Y: Synergistic effect
and mechanism of vitamin A and vitamin D on inducing apoptosis of
prostate cancer cells. Mol Biol Rep 2013, 40:2763–2768.
106. Chandler PD, Giovannucci EL, Scott JB, Bennett GG, Ng K, Chan AT, Hollis
BW, Emmons KM, Fuchs CS, Drake BF: Null association between Vitamin D
and PSA levels among black men in a Vitamin D supplementation trial.
Cancer Epidemiol Biomarkers Prev 2014, 23:1944–1947.
107. Skaaby T, Husemoen LL, Thuesen BH, Pisinger C, Jorgensen T, Roswall N,
Larsen SC, Linneberg A: Prospective population-based study of the
association between serum 25-hydroxyvitamin-D levels and the
incidence of specific types of cancer. Cancer Epidemiol Biomarkers Prev
2014, 23:1220–1229.
108. Holt SK, Kolb S, Fu R, Horst R, Feng Z, Stanford JL: Circulating levels of
25-hydroxyvitamin D and prostate cancer prognosis. Cancer Epidemiol
2013, 37:666–670.
109. Wong YY, Hyde Z, McCaul KA, Yeap BB, Golledge J, Hankey GJ, Flicker L:
In older men, lower plasma 25-hydroxyvitamin D is associated with
reduced incidence of prostate, but not colorectal or lung cancer.
PLoS One 2014, 9:e99954.
110. Xu Y, Shao X, Yao Y, Xu L, Chang L, Jiang Z, Lin Z: Positive association
between circulating 25-hydroxyvitamin D levels and prostate cancer risk:
new findings from an updated meta-analysis. J Cancer Res Clin Oncol
2014, 140:1465–1477.
111. Meyer HE, Robsahm TE, Bjorge T, Brustad M, Blomhoff R: Vitamin D, season,
and risk of prostate cancer: a nested case–control study within
Norwegian health studies. Am J Clin Nutr 2013, 97:147–154.
112. Kristal AR, Till C, Song X, Tangen CM, Goodman PJ, Neuhauser ML, Schenk
JM, Thompson IM, Meyskens FL Jr, Goodman GE, Minasian LM, Parnes HL,
Klein EA: Plasma vitamin D and prostate cancer risk: results from the
Selenium and Vitamin E Cancer Prevention Trial. Cancer Epidemiol
Biomarkers Prev 2014, 23:1494–1504.
113. Weinstein SJ, Mondul AM, Kopp W, Rager H, Virtamo J, Albanes D:
Circulating 25-hydroxyvitamin D, vitamin D-binding protein and risk of
prostate cancer. Int J Cancer 2013, 132:2940–2947.
114. Guo Z, Wen J, Kan Q, Huang S, Liu X, Sun N, Li Z: Lack of association
between vitamin D receptor gene FokI and BsmI polymorphisms and prostate cancer risk: an updated meta-analysis involving 21,756 subjects. Tumour Biol 2013, 34:3189–3200115. Wang L, Sesso HD, Glynn RJ, Christen WG, Bubes V, Manson JE, Buring JE,
Gaziano JM: Vitamin E and C supplementation and risk of cancer in men:
posttrial follow-up in the Physicians’ Health Study II randomized trial.
Am J Clin Nutr 2014, 100:915–923.
116. Virtamo J, Taylor PR, Kontto J, Mannisto S, Utriainen M, Weinstein SJ,
Huttunen J, Albanes D: Effects of alpha-tocopherol and beta-carotene
supplementation on cancer incidence and mortality: 18-year
postintervention follow-up of the Alpha-tocopherol, Beta-carotene
Cancer Prevention Study. Int J Cancer 2014, 135:178–185.
117. Basu A, Imrhan V: Vitamin E and prostate cancer: is vitamin E succinate a
superior chemopreventive agent? Nutr Rev 2005, 63:247–251.
118. Lawson KA, Wright ME, Subar A, Mouw T, Hollenbeck A, Schatzkin A,
Leitzmann MF: Multivitamin use and risk of prostate cancer in the
National Institutes of Health-AARP Diet and Health Study. J Natl Cancer
Inst 2007, 99:754–764.
119. Calle EE, Rodriguez C, Jacobs EJ, Almon ML, Chao A, McCullough ML,
Feigelson HS, Thun MJ: The American Cancer Society Cancer Prevention
Study II Nutrition Cohort: rationale, study design, and baseline
characteristics. Cancer 2002, 94:2490–2501.
120. Weinstein SJ, Peters U, Ahn J, Friesen MD, Riboli E, Hayes RB, Albanes D:
Serum alpha-tocopherol and gamma-tocopherol concentrations and
prostate cancer risk in the PLCO Screening Trial: a nested case–control
study. PLoS One 2012, 7:e40204.
121. Cui R, Liu ZQ, Xu Q: Blood alpha-tocopherol, gamma-tocopherol levels
and risk of prostate cancer: a meta-analysis of prospective studies.
PLoS One 2014, 9:e93044.
122. Major JM, Yu K, Weinstein SJ, Berndt SI, Hyland PL, Yeager M, Chanock S,
Albanes D: Genetic variants reflecting higher vitamin e status in men are
associated with reduced risk of prostate cancer. J Nutr May 2014,
144:729–733.
123. Klein EA, Thompson IM Jr, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ,
Minasian LM, Ford LG, Parnes HL, Gaziano JM, Karp DD, Lieber MM, Walther
PJ, Klotz L, Parsons JK, Chin JL, Darke AK, Lippman SM, Goodman GE,
Meyskens FL Jr, Baker LH: Vitamin E and the risk of prostate cancer: the
Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2011,
306:1549–1556.
124. Albanes D, Till C, Klein EA, Goodman PJ, Mondul AM, Weinstein SJ, aylor PR,
Parnes HL, Gaziano JM, Song X, Fleshner NE, Brown PH, Meyskens FL Jr,
Thompson IM: Plasma tocopherols and risk of prostate cancer in the
Selenium and Vitamin E Cancer Prevention Trial (SELECT). Cancer Prev Res
(Phila) 2014, 7:886–895.
125. Kristal AR, Darke AK, Morris JS, Tangen CM, Goodman PJ, Thompson IM,
Meyskens FL Jr, Goodman GE, Minasian LM, Parnes HL, Lippman SM,
Klein EA: Baseline selenium status and effects of selenium and vitamin e
supplementation on prostate cancer risk. J Natl Cancer Inst 2014,
106:djt456.
126. Jamison JM, Gilloteaux J, Taper HS, Summers JL: Evaluation of the in vitro
and in vivo antitumor activities of vitamin C and K-3 combinations
against human prostate cancer. J Nutr 2001, 131:158S–160S.
127. Nimptsch K, Rohrmann S, Kaaks R, Linseisen J: Dietary vitamin K intake
in relation to cancer incidence and mortality: results from the
Heidelberg cohort of the European Prospective Investigation into
Cancer and Nutrition (EPIC-Heidelberg). Am J Clin Nutr 2010,
91:1348–1358.
128. Ma RW, Chapman K: A systematic review of the effect of diet in prostate
cancer prevention and treatment. J Hum Nutr Diet 2009, 22:187–199.
quiz 200–182.
129. Bristow SM, Bolland MJ, MacLennan GS, Avenell A, Grey A, Gamble GD, Reid
IR: Calcium supplements and cancer risk: a meta-analysis of randomised
controlled trials. Br J Nutr 2013, 110:1384–1393.
130. Williams CD, Whitley BM, Hoyo C, Grant DJ, Schwartz GG, Presti JC Jr, Iraggi
JD, Newman KA, Gerber L, Taylor LA, McKeever MG, Freedland SJ: Dietary
calcium and risk for prostate cancer: a case–control study among US
veterans. Prev Chronic Dis 2012, 9:E39.
131. Hori S, Butler E, McLoughlin J: Prostate cancer and diet: food for thought?
BJU Int 2011, 107:1348–1359.
132. Geybels MS, Verhage BA, van Schooten FJ, Goldbohm RA, van den Brandt
PA: Advanced prostate cancer risk in relation to toenail selenium levels.
J Natl Cancer Inst 2013, 105:1394–1401.
133. Singh RP, Agarwal R: Prostate cancer chemoprevention by silibinin: bench
to bedside. Mol Carcinog 2006, 45:436–442.
134. Ting H, Deep G, Agarwal R: Molecular mechanisms of silibinin-mediated
cancer chemoprevention with major emphasis on prostate cancer.
AAPS J 2013, 15:707–716.
135. Ting HJ, Deep G, Jain AK, Cimic A, Sirintrapun J, Romero LM, Cramer SD,
Agarwal C, Agarwal R: Silibinin prevents prostate cancer cell-mediated
differentiation of naive fibroblasts into cancer-associated fibroblast
phenotype by targeting TGF beta2. Mol Carcinog 2014. doi:10.1002/
mc.22135. [Epub ahead of time]
136. Goel A, Aggarwal BB: Curcumin, the golden spice from Indian saffron, is a
chemosensitizer and radiosensitizer for tumors and chemoprotector and
radioprotector for normal organs. Nutr Cancer 2010, 62:919–930.
137. Khan N, Adhami VM, Mukhtar H: Apoptosis by dietary agents for
prevention and treatment of prostate cancer. Endocr Relat Cancer 2010,
17:R39–R52.
138. Heber D: Pomegranate ellagitannins. In Herbal Medicine: Biomolecular and
Clinical Aspects. 2nd edition. Edited by Benzie IF, Wachtel-Galor S. Boca
Raton, FL: CRC Press; 2011.
139. Pantuck AJ, Leppert JT, Zomorodian N, Aronson W, Hong J, Barnard RJ,
Seeram N, Liker H, Wang H, Elashoff R, Heber D, Aviram M, Ignarro L,
Belldegrun A: Phase II study of pomegranate juice for men with rising
prostate-specific antigen following surgery or radiation for prostate
cancer. Clin Cancer Res 2006, 12:4018–4026.
140. Paller CJ, Ye X, Wozniak PJ, Gillespie BK, Sieber PR, Greengold RH, Stockton
BR, Hertzman BL, Efros MD, Roper RP, Liker HR, Carducci MA: A randomized
phase II study of pomegranate extract for men with rising PSA following
initial therapy for localized prostate cancer. Prostate Cancer Prostatic Dis
2013, 16:50–55.
141. Freedland SJ, Carducci M, Kroeger N, Partin A, Rao JY, Jin Y, Kerkoutian S,
Wu H, Li Y, Creel P, Mundy K, Gurganus R, Fedor H, King SA, Zhang Y,
Heber D, Pantuck AJ: A double-blind, randomized, neoadjuvant study of
the tissue effects of POMx pills in men with prostate cancer before
radical prostatectomy. Cancer Prev Res (Phila) 2013, 6:1120–1127.
142. Wang P, Aronson WJ, Huang M, Zhang Y, Lee RP, Heber D, Henning SM:
Green tea polyphenols and metabolites in prostatectomy tissue:
implications for cancer prevention. Cancer Prev Res (Phila) 2010,
3:985–993.
143. Kurahashi N, Sasazuki S, Iwasaki M, Inoue M, Tsugane S: Green tea
consumption and prostate cancer risk in Japanese men: a prospective
study. Am J Epidemiol 2008, 167:71–77.
144. McLarty J, Bigelow RL, Smith M, Elmajian D, Ankem M, Cardelli JA: Tea
polyphenols decrease serum levels of prostate-specific antigen,
hepatocyte growth factor, and vascular endothelial growth factor in
prostate cancer patients and inhibit production of hepatocyte growth
factor and vascular endothelial growth factor in vitro. Cancer Prev Res
(Phila) 2009, 2:673–682.
145. Bettuzzi S, Brausi M, Rizzi F, Castagnetti G, Peracchia G, Corti A:
Chemoprevention of human prostate cancer by oral administration of
green tea catechins in volunteers with high-grade prostate intraepithelial
neoplasia: a preliminary report from a one-year proof-of-principle study.
Cancer Res 2006, 66:1234–1240.
146. Fraser SP, Peters A, Fleming-Jones S, Mukhey D, Djamgoz MB: Resveratrol:
inhibitory effects on metastatic cell behaviors and voltage-gated Na(+)
channel activity in rat prostate cancer in vitro. Nutr Cancer 2014,
66:1047–1058.
147. Oskarsson A, Spatafora C, Tringali C, Andersson AO: Inhibition of CYP17A1
activity by resveratrol, piceatannol, and synthetic resveratrol analogs.
Prostate 2014, 74:839–851.
148. Ferruelo A, Romero I, Cabrera PM, Arance I, Andres G, Angulo JC: Effects of
resveratrol and other wine polyphenols on the proliferation, apoptosis
and androgen receptor expression in LNCaP cells. Actas Urol Esp Jul-Aug
2014, 38:397–404.
149. Osmond GW, Masko EM, Tyler DS, Freedland SJ, Pizzo S: In vitro and in vivo
evaluation of resveratrol and 3,5-dihydroxy-4′-acetoxy-trans-stilbene in
the treatment of human prostate carcinoma and melanoma. J Surg Res
2013, 179:e141–e148.
150. Baur JA, Sinclair DA: Therapeutic potential of resveratrol: the in vivo
evidence. Nat Rev Drug Discov 2006, 5:493–506.
151. Klink JC, Tewari AK, Masko EM, Antonelli J, Febbo PG, Cohen P, Dewhirst
MW, Pizzo SV, Freedland SJ: Resveratrol worsens survival in SCID mice with prostate cancer xenografts in a cell-line specific manner, through paradoxical effects on oncogenic pathways. Prostate 2013, 73:754–762.

152. Huang EC, Zhao Y, Chen G, Baek SJ, McEntee MF, Minkin S, Biggerstaff JP,
Whelan J: Zyflamend, a polyherbal mixture, down regulates class I and
class II histone deacetylases and increases p21 levels in castrate-resistant
prostate cancer cells. BMC Complement Altern Med 2014, 14:68.
153. Huang EC, McEntee MF, Whelan J: Zyflamend, a combination of herbal
extracts, attenuates tumor growth in murine xenograft models of
prostate cancer. Nutr Cancer 2012, 64:749–760.
154. Yan J, Xie B, Capodice JL, Katz AE: Zyflamend inhibits the expression and
function of androgen receptor and acts synergistically with bicalutimide
to inhibit prostate cancer cell growth. Prostate 2012, 72:244–252.
155. Kunnumakkara AB, Sung B, Ravindran J, Diagaradjane P, Deorukhkar A, Dey
S, Koca C, Tong Z, Gelovani JG, Guha S, Krishnan S, Aggarwal BB: Zyflamend
suppresses growth and sensitizes human pancreatic tumors to
gemcitabine in an orthotopic mouse model through modulation of
multiple targets. Int J Cancer 2012, 131:E292–E303.
156. Capodice JL, Gorroochurn P, Cammack AS, Eric G, McKiernan JM, Benson
MC, Stone BA, Katz AE: Zyflamend in men with high-grade prostatic
intraepithelial neoplasia: results of a phase I clinical trial. J Soc Integr
Oncol 2009, 7:43–51.
157. Rafailov S, Cammack S, Stone BA, Katz AE: The role of Zyflamend, an
herbal anti-inflammatory, as a potential chemopreventive agent against
prostate cancer: a case report. Integr Cancer Ther 2007, 6:74–76.
158. Askari F, Parizi MK, Jessri M, Rashidkhani B: Fruit and vegetable intake in
relation to prostate cancer in Iranian men: a case–control study.
Asian Pac J Cancer Prev 2014, 15:5223–5227.
159. Liu B, Mao Q, Cao M, Xie L: Cruciferous vegetables intake and risk of
prostate cancer: a meta-analysis. Int J Urol 2012, 19:134–141.
160. Richman EL, Carroll PR, Chan JM: Vegetable and fruit intake after
diagnosis and risk of prostate cancer progression. Int J Cancer 2012,
131:201–210.
161. Hsing AW, Chokkalingam AP, Gao YT, Madigan MP, Deng J, Gridley G,
Fraumeni JF Jr: Allium vegetables and risk of prostate cancer: a
population-based study. J Natl Cancer Inst 2002, 94:1648–1651.
162. Chan R, Lok K, Woo J: Prostate cancer and vegetable consumption.
Mol Nutr Food Res 2009, 53:201–216.
163. Thomas R, Williams M, Sharma H, Chaudry A, Bellamy P: A double-blind,
placebo-controlled randomised trial evaluating the effect of a
polyphenol-rich whole food supplement on PSA progression in men
with prostate cancer-the UK NCRN Pomi-T study. Prostate Cancer Prostatic
Dis 2014, 17:180–186.
164. Yang CM, Lu IH, Chen HY, Hu ML: Lycopene inhibits the proliferation of
androgen-dependent human prostate tumor cells through activation of
PPARgamma-LXRalpha-ABCA1 pathway. J Nutr Biochem 2012, 23:8–17.
165. Qiu X, Yuan Y, Vaishnav A, Tessel MA, Nonn L, van Breemen RB: Effects of
lycopene on protein expression in human primary prostatic epithelial
cells. Cancer Prev Res (Phila) 2013, 6:419–427.
166. Boileau TW, Liao Z, Kim S, Lemeshow S, Erdman JW Jr, Clinton SK: Prostate
carcinogenesis in N-methyl-N-nitrosourea (NMU)-testosterone-treated
rats fed tomato powder, lycopene, or energy-restricted diets. J Natl
Cancer Inst 2003, 95:1578–1586.
167. Konijeti R, Henning S, Moro A, Sheikh A, Elashoff D, Shapiro A, Ku M,
Said JW, Heber D, Cohen P, Aronson WJ: Chemoprevention of prostate
cancer with lycopene in the TRAMP model. Prostate 2010, 70:1547–1554.
168. Giovannucci E, Rimm EB, Liu Y, Stampfer MJ, Willett WC: A prospective
study of tomato products, lycopene, and prostate cancer risk. J Natl
Cancer Inst 2002, 94:391–398.
169. Zu K, Mucci L, Rosner BA, Clinton SK, Loda M, Stampfer MJ, Giovannucci E:
Dietary lycopene, angiogenesis, and prostate cancer: a prospective
study in the prostate-specific antigen era. J Natl Cancer Inst 2014,
106:djt430.
170. Gann PH, Ma J, Giovannucci E, Willett W, Sacks FM, Hennekens CH, Stampfer
MJ: Lower prostate cancer risk in men with elevated plasma lycopene
levels: results of a prospective analysis. Cancer Res 1999, 59:1225–1230.
171. Kristal AR, Till C, Platz EA, Song X, King IB, Neuhouser ML, Ambrosone CB,
Thompson IM: Serum lycopene concentration and prostate cancer risk:
results from the Prostate Cancer Prevention Trial. Cancer Epidemiol
Biomarkers Prev 2011, 20:638–646.
172. Kirsh VA, Mayne ST, Peters U, Chatterjee N, Leitzmann MF, Dixon LB, Urban
DA, Crawford ED, Hayes RB: A prospective study of lycopene and tomato
product intake and risk of prostate cancer. Cancer Epidemiol Biomarkers
Prev 2006, 15:92–98.
173. Mariani S, Lionetto L, Cavallari M, Tubaro A, Rasio D, De Nunzio C, Hong
GM, Borro M, Simmaco M: Low prostate concentration of lycopene is
associated with development of prostate cancer in patients with highgrade
prostatic intraepithelial neoplasia. Int J Mol Sci 2014, 15:1433–1440.
174. Kucuk O, Sarkar FH, Djuric Z, Sakr W, Pollak MN, Khachik F, Banerjee M,
Bertram JS, Wood DP Jr: Effects of lycopene supplementation in patients
with localized prostate cancer. Exp Biol Med (Maywood) 2002, 227:881–885.
175. Chen L, Stacewicz-Sapuntzakis M, Duncan C, Sharifi R, Ghosh L, van
Breemen R, Ashton D, Bowen PE: Oxidative DNA damage in prostate
cancer patients consuming tomato sauce-based entrees as a whole-food
intervention. J Natl Cancer Inst 2001, 93:1872–1879.
176. van Breemen RB, Sharifi R, Viana M, Pajkovic N, Zhu D, Yuan L, Yang Y,
Bowen PE, Stacewicz-Sapuntzakis M: Antioxidant effects of lycopene in
African American men with prostate cancer or benign prostate hyperplasia:
a randomized, controlled trial. Cancer Prev Res (Phila) 2011, 4:711–718.
177. Shafique K, McLoone P, Qureshi K, Leung H, Hart C, Morrison DS: Coffee
consumption and prostate cancer risk: further evidence for inverse
relationship. Nutr J 2012, 11:42.
178. Wilson KM, Kasperzyk JL, Rider JR, Kenfield S, van Dam RM, Stampfer MJ,
Giovannucci E, Mucci LA: Coffee consumption and prostate cancer risk
and progression in the Health Professionals Follow-up Study. J Natl
Cancer Inst 2011, 103:876–884.
179. Bosire C, Stampfer MJ, Subar AF, Wilson KM, Park Y, Sinha R: Coffee
consumption and the risk of overall and fatal prostate cancer in the
NIH-AARP Diet and Health Study. Cancer Causes Control 2013, 24:1527–1534.
180. Arab L, Su LJ, Steck SE, Ang A, Fontham ET, Bensen JT, Mohler JL: Coffee
consumption and prostate cancer aggressiveness among African and
Caucasian Americans in a population-based study. Nutr Cancer 2012,
64:637–642.
181. Phillips RL, Snowdon DA: Association of meat and coffee use with cancers
of the large bowel, breast, and prostate among Seventh-Day Adventists:
preliminary results. Cancer Res 1983, 43:2403 s–2408s.
182. Hsing AW, McLaughlin JK, Schuman LM, Bjelke E, Gridley G, Wacholder S,
Chien HT, Blot WJ: Diet, tobacco use, and fatal prostate cancer: results
from the Lutheran Brotherhood Cohort Study. Cancer Res 1990,
50:6836–6840.
183. Cao S, Liu L, Yin X, Wang Y, Liu J, Lu Z: Coffee consumption and risk of
prostate cancer: a meta-analysis of prospective cohort studies.
Carcinogenesis 2014, 35:256–261.
184. Nordmann AJ, Suter-Zimmermann K, Bucher HC, Shai I, Tuttle KR,
Estruch R, Briel M: Meta-analysis comparing Mediterranean to low-fat
diets for modification of cardiovascular risk factors. Am J Med 2011,
124:841–851. e842.
185. Kapiszewska M: A vegetable to meat consumption ratio as a relevant
factor determining cancer preventive diet. The Mediterranean versus
other European countries. Forum Nutr 2006, 59:130–153.
186. Kenfield SA, Dupre N, Richman EL, Stampfer MJ, Chan JM, Giovannucci EL:
Mediterranean diet and prostate cancer risk and mortality in the Health
Professionals Follow-up Study. Eur Urol 2014, 65:887–894.
187. Ambrosini GL, Fritschi L, de Klerk NH, Mackerras D, Leavy J: Dietary patterns
identified using factor analysis and prostate cancer risk: a case control
study in Western Australia. Ann Epidemiol 2008, 18:364–370.
188. Baade PD, Youlden DR, Krnjacki LJ: International epidemiology of prostate
cancer: geographical distribution and secular trends. Mol Nutr Food Res
2009, 53:171–184.
189. Muller DC, Severi G, Baglietto L, Krishnan K, English DR, Hopper JL, Giles GG:
Dietary patterns and prostate cancer risk. Cancer Epidemiol Biomarkers Prev
2009, 18:3126–3129.
190. Tseng M, Breslow RA, DeVellis RF, Ziegler RG: Dietary patterns and prostate
cancer risk in the National Health and Nutrition Examination Survey
Epidemiological Follow-up Study cohort. Cancer Epidemiol Biomarkers Prev
2004, 13:71–77.
191. Wu K, Hu FB, Willett WC, Giovannucci E: Dietary patterns and risk of
prostate cancer in U.S. men. Cancer Epidemiol Biomarkers Prev 2006,
15:167–171.
192. Daubenmier JJ, Weidner G, Marlin R, Crutchfield L, Dunn-Emke S, Chi C,
Gao B, Carroll P, Ornish D: Lifestyle and health-related quality of life of
men with prostate cancer managed with active surveillance. Urology
2006, 67:125–130.

193. Parsons JK, Newman VA, Mohler JL, Pierce JP, Flatt S, Marshall J: Dietary
modification in patients with prostate cancer on active surveillance: a
randomized, multicentre feasibility study. BJU Int 2008, 101:1227–1231.
194. Mosher CE, Sloane R, Morey MC, Snyder DC, Cohen HJ, Miller PE,
Demark-Wahnefried W: Associations between lifestyle factors and quality
of life among older long-term breast, prostate, and colorectal cancer
survivors. Cancer 2009, 115:4001–4009.
195. Bhindi B, Locke J, Alibhai SM, Kulkarni GS, Margel DS, Hamilton RJ, Finelli A,
Trachtenberg J, Zlotta AR, Toi A, Hersey KM, Evans A, van der Kwast TH,
Fleshner NE: Dissecting the association between metabolic syndrome
and prostate cancer risk: analysis of a large clinical cohort. Eur Urol 2014.
doi:10.1016/j.eururo.2014.01.040. [Epub ahead of time]
196. Esposito K, Chiodini P, Capuano A, Bellastella G, Maiorino MI, Parretta E,
Lenzi A, Giugliano D: Effect of metabolic syndrome and its components
on prostate cancer risk: meta-analysis. J Endocrinol Invest 2013,
36:132–139.
197. U.S. Department of Agriculture and U.S. Department of Health and
Human Services. Dietary Guidelines for Americans, 2010. 7th edition.
Washington, DC: U.S. Government Printing Office, December, 2010.

English EN Spanish ES