Abstract
Background/Aim: Prostate cancer is one of the most common cancers in men which remains a global public health issue. Treatment of prostate cancer is becoming increasingly intensive and aggressive, with a corresponding increase in resistance, toxicity and side effects. This has revived an interest in nontoxic and cost-effective preventive strategies including dietary compounds due to the multiple effects they have been shown to have in various oncogenic signalling pathways, with relatively few significant adverse effects. Materials and Methods: To identify such dietary components and micronutrients and define their prostate cancer-specific actions, we systematically reviewed the current literature for the pertinent mechanisms of action and effects on the modulation of prostate carcinogenesis, along with relevant updates from epidemiological and clinical studies. Results: Evidence from various recent experimental, clinical and epidemiological studies indicates that select dietary micronutrients (i.e., lycopene, epigallocatechin gallate, sulforaphane, indole-3-carbinol, resveratrol, quercetin, curcumin & piperine) and zinc play a key role in prostate cancer prevention and progression and therefore hold great promise for the future overall management of prostate cancer. Conclusion: A formulation that comprises these micronutrients using the optimal, safest form and dosing should be investigated in future prostate cancer chemoprevention studies and as part of standard prostate cancer therapy.
Prostate cancer is the second cause of cancer death in men accounting for an estimated 1.28 million deaths in 2018 (1, 2). The incidence of prostate cancer has been increasing globally with 1.3 million new cases reported in 2018 (3, 4). Prostate cancer is still considered the most common life-threatening malignancy affecting the male population in most European countries. In the UK, prostate cancer is the most common cancer among men accounting for 13% of all cancer deaths in males. Furthermore, the incidence of prostate cancer in British men has increased by more than two-fifths (44%) since the early 1990s (5).
Based on clinical stage, histological grade and serum levels of prostate-specific antigen (PSA), current treatment options for prostate cancer include surgery, radiotherapy and/or chemotherapy (6-9). Such interventions are most effective in early disease, especially if it is still localised to the prostate. Once the tumour has metastasised to other organs of the body, it becomes highly resistant to currently available treatment modalities (10, 11).
For prostate cancer patients with locally advanced or metastatic disease, androgen deprivation therapy is the standard of treatment as pathogenesis of prostate cancer is highly dependent on androgen receptor signalling (12, 13). However, the efficacy of androgen-blockade as a treatment of prostate cancer is limited (14). After initial response to androgen deprivation therapy, most patients eventually progress to a highly aggressive, treatment-resistant form of the disease known as “castration-resistant” prostate cancer. This form of the disease poses a formidable therapeutic challenge and usually needs multiple combinations of therapeutic strategies to overcome (15-17).
While there are several chemotherapeutic agents targeting androgen receptor-dependent pathways, there is a relative lack of therapeutic options targeting androgen receptor-independent pathways, which would be of utility in the treatment of clinically aggressive castration-resistant disease (18). Whilst major advances have been made in the treatment of prostate cancer, the treatment options for locally advanced or metastasised prostate cancer are still limited and prognosis remains poor.
Chemoprevention
Further to the preceding discussion, prostate cancer is therefore an ideal candidate for chemopreventive interventions owing to its high incidence, clinical variability, molecular heterogeneity, typical long latency, identifiable pre-malignant lesions, early detection tools and availability of a specific biomarker (i.e., PSA) (19, 20).
One such class of agents considered for prostate chemoprevention are the 5-α reductase inhibitors, such as finasteride and dutasteride. Their efficacy as chemopreventive agents has been borne out in clinical trials, albeit with a significant adverse effect profile. The FDA has recommended against the approval for these drugs for the prevention of prostate cancer based on risk-benefit analyses. Specifically, while they showed significant effects in reducing prostate cancer risk, these drugs have been reported to increase the risk for high-grade disease (21, 22). In addition, physicians were not prescribing 5-α reductase inhibitors as chemopreventive drugs for prostate cancer. Whereas the majority of primary care physicians and urologists did not know that finasteride could be used for prostate cancer chemoprevention or never prescribe it for prevention, there have been major concerns of inducing high-grade tumours (23). An ideal preventive approach should delay prostate carcinogenesis, inhibit development of pre-malignant lesions into malignant disease and reduce the risk of reoccurrence for those who underwent successful primary treatment effectively with non-toxic features.
The epidemiology of prostate cancer shows strong geographic variations and substantial differences in incidence and mortality worldwide. Migrant studies have shown that Asian populations have a relatively lower incidence rate of prostate cancer in comparison to black and white Americans (24). In addition to genetic factors (25), environmental, especially nutritional influences, have been cited as potential causes for some of this variability and therefore might play significant roles in prostate carcinogenesis (3, 26).
The reported increased risk in populations emigrating from low to high risk countries provides strong support for modifiable environmental, particularly dietary, factors. Studies from populations of similar genetics but with different dietary and lifestyle-related factors have determined that immigrants from Asian countries to the USA who adopted a “Western-style” diet rich in meat and processed foods and lacking certain micronutrients of their native Asian diet had dramatically higher incidence and mortality rates of prostate cancer compared to their countries of origin. Although the rates of prostate cancer incidence in Asian countries has been increasing in recent years partly due to life-style changes particularly adopting “Western-style” diet, it is still comparatively lower than Western countries (27-33). Asian populations with high consumption of specific micronutrients have lower prostate cancer incidences versus countries consuming a Westernised diet (34).
Although it has been proposed that the reported lower rates of prostate cancer incidence in Asians were partly due to the insufficient practice of PSA testing among those populations (4, 35), the role of diet unquestionably cannot be discounted in relation to risk of prostate cancer (36, 37). Numerous studies have indicated that a poor diet contributes to 10% to 75% of various cancer-related deaths and that eating a healthy diet rich in fruits and vegetables may lower risk of prostate cancer risk by 75% (38).
Multiple studies evaluating empirically derived dietary patterns have reported an increased risk of prostate cancer, especially aggressive prostate cancer, with ‘Westernised’ dietary habits (39-41). In the Physicians' Health Study (926 men diagnosed with nonmetastatic prostate cancer and 8,093 participants), a post-diagnostic western diet was significantly associated with a higher risk of prostate cancer–specific and all-cause mortality, and hazard ratios (HRs) were 2.53 (95%CI=1.00-6.42; ptrend=0.02) and 1.67 (95%CI=1.16-2.42; ptrend=0.01), respectively (42). A dietary pattern characterised by higher intake of vegetables, fruits, legumes, whole grains and fish has been associated with a significantly reduced all-cause mortality (HR=0.64; 95%CI=0.44-0.93; ptrend=0.02) (42).
There is sufficient evidence that constituents of the Mediterranean diet are inversely associated with risk of overall cancer including the prostate. Coastal countries in Southern Europe have lower prostate cancer incidence and mortality rates compared to other European countries (43). Greek migrant men in Australia who retained their native traditional Mediterranean diet have a lower risk of prostate cancer than those born in Australia or other migrants who adopted ‘Western’ dietary habits (44). A meta-analysis of data from 18 prospective cohort studies involving a total of 2,190,627 subjects with a follow-up time ranged from 4 to 20 years has provided a pooled relative risk of overall cancer of 0.94 [RR=0.94; 95%CI=0.92-0.96; p<0.00001 (I2=6%; p=0.38)] for a 2-point increase in adherence to the Mediterranean diet (45). Analogously, a meta-analysis of observational studies including 1,784,404 subjects has reported that highest adherence to a Mediterranean diet was significantly associated with reduced overall cancer mortality (RR=0.87, 95%CI=0.81-0.93, I2=84%) and risk of prostate cancer (RR=0.96, 95%CI=0.92-1.00, I2=0%) (46).A prospective study involving 47,867 men in the USA has concluded that greater adherence to the Mediterranean diet after prostate cancer diagnosis was associated with a 22% reduction in overall mortality (HR=0.78; 95%CI=0.67-0.90; ptrend=0.0007) (47).
Deviating from previous findings of inverse associations with prostate cancer, a Northern European case–control study (1,482 patients and 1,108 population-based controls) has found little support for an association between the Mediterranean diet and total prostate cancer risk in this population (48). The residual confounding and recall bias as well as limitations inherent in the study design and the construction of the Mediterranean Diet Score (MDS) leading to misclassification of exposure could explain the borderline association reported.
The main characteristics of Mediterranean diet typically include high intake of cruciferous vegetables, fruits, legumes, cereals and moderate to high consumption of fish and olive oil (49). The individual constituents of the Mediterranean diet have been extensively investigated in relation to prostate cancer. A meta-analysis of data on cancer incidence from large-scale multi-centre prospective cohort studies in 22 centres in nine European countries has reported a significant inverse association for vegetables and fruit intake and various cancers and concluded that selected European countries may benefit the most from nutritional intervention by increasing vegetable and fruit intake to reduce overall cancer risks (50). The association between fruit and vegetables intake and the risk of fourteen different common cancers was evaluated in a network of Italian and Swiss case–control studies (10,000 cases with 1,294 prostate cancer cases and 17,000 controls) demonstrating a favourable role of high consumption of vegetables and fruits for the risk of various common cancers including the prostate. The inverse correlations reported were for both raw and cooked vegetables and cruciferous vegetables and the odds ratios for the highest compared with the lowest levels of consumption vegetables and fruits for prostate cancer risk was 0.9 (51). A relatively small case-control study (157 prostate cancer case and 158 controls) has shown a significant inverse correlation between prostate cancer risk and the consumption of vegetables and fruits (p=0.029) (52). Furthermore, a statistically significant inverse association between the vegan diets and risk of prostate cancer was reported (HR=0.65; 95%CI=0.49-0.85). When the analyses were stratified by race, this statistically significant protective association with a vegan diet remained for the whites (HR=0.63; 95%CI=0.46-0.86) (53). The North Carolina-Louisiana Prostate Cancer Project (855 African Americans and 945 European Americans) has reported that total antioxidant capacity from supplements and diet was correlated with significantly lower odds of high aggressive prostate cancer in all participants, OR=0.31 [95%CI=0.15-0.67; p-trend<0.01] and African Americans and European Americans, OR=0.28 [95%CI=0.08-0.96; p-trend<0.001] and OR=0.36 (95%CI=0.15-0.86; p-trend=0.58), respectively (54).
The findings strongly suggest that a diet rich in specific naturally available micronutrients and phytochemicals with antioxidant properties may prevent or delay development, progression and/or recurrence of prostate cancer (26, 55-57). Vitamins, minerals, carotenoids, flavonoids and polyphenols that are abundant at high levels in vegetables and fruits have been extensively studied to explore their chemopreventive properties for prostate cancer. A major factor in the efficacy of dietary agents lies in their natural and raw form. In addition to generating by-products and altering the structure and digestibility of food, cooking can cause considerable losses in essential micronutrients (58-62). Pooled analysis of case–control studies have reported that the inverse association between consumption of raw and cooked vegetables and prostate cancer risk was somewhat stronger for raw compared to cooked vegetables [OR for the highest vs. the lowest intakes were 0.87 and 0.74, respectively] (51).
There is a limited number of micronutrients and phytochemicals that have been evaluated in clinical studies, with varying success yet mostly favourable results. There is increasing evidence from a myriad of laboratory, animal, epidemiologic studies and available clinical trials that specific dietary agents (namely Lycopene, Epigallocatechin gallate, Sulforaphane, Indole-3-Carbinol, Resveratrol, Quercetin, Curcumin & Piperine) and Zinc display the ability to inhibit signalling pathways which lead to prostate carcinogenesis (3, 63). Prostate tumour mass has been shown to comprise a highly heterogeneous population of cancerous cells and carcinogenesis is considered a process with multiple stages through which cancer cells often activate alternative survival oncogenic signalling pathways leading to development of drug resistance and failure of targeted therapy (20, 64). These dietary agents with their multi-targeted ‘pleiotropic’ effects are expected to be exceedingly effective due to their ability to regulate the activation of alternative survival oncogenic signalling pathways, with favourable side effects and, therefore, could play a crucial role in prostate cancer prevention. Combinations containing such micronutrients have been shown to exert potentially synergistic protective effects against prostate cancer and thus produce a more robust inhibition of carcinogenesis than each component separately (65). Furthermore, findings from systematic reviews of randomised controlled trials and prospective cohort studies have shown that adding micronutrients to cancer patients' treatment increases patient adherence to therapy, enhances response to the treatment, reduces side effects and dose-limiting toxicities, reduces disease recurrence and mortality and improves overall prognosis and quality of life (66-70). Hence, it is also prudent that prostate cancer patients, with or without concurrent treatment, to supplement their diets with certain immuno-stabilising and antioxidant micronutrients during treatment.
Materials and Methods
The methodology for this review involved electronic searches across NCBI's PubMed database, MEDLINE and the Cochrane Library up to July 2019 for epidemiological and clinical trial studies reporting prostate cancer-specific risks and recurrence in relation to intake of dietary agents. In vitro and animal studies investigating the effects of dietary components on prostate tumours and prostate cancer cells were included in the search. In order to stay within the scope of a concise review, we have restricted our search to the key search terms ‘prostate cancer and vitamins’, ‘prostate cancer and minerals’, ‘prostate cancer and nutrients’, ‘prostate cancer and nutrition’, ‘prostate cancer and diet’, ‘prostate cancer prevention’ and ‘prostate cancer and natural products’.
Abstracts were initially screened and agents that were consistently found to be associated with lower risk of prostate cancer development and/or recurrence, and those for which there was robust molecular evidence of activity against prostate cancer cells were selected. Reference list search yielded a total of 12,677 potentially relevant publications. Two reviewers independently further evaluated relevance and quality of the identified studies. References within the identified studies were consulted as well. After removing duplicates and using the most updated meta-analyses and systematic reviews when conflicting results were found and the latest publication when multiple articles for a single study existed, a total of 30 articles and reviews with sufficient quality that matched our initial search criteria remained for full-text evaluation.
Animal and in vitro studies with the most robust and highest levels of molecular evidence for a protective effect and epidemiological studies demonstrating statistically significant inverse associations were selected to identify the dietary agents to be covered in our review. Dietary factors associated with no evidence, weak or frequently inconsistent evidence for protective effects against prostate cancer were not included in this review. For each compound identified in the relevant studies, the hazard ratio (HR) or relative risk (RR) and 95% confidence intervals (CI) are reported.
Results
We have identified 6 micronutrients i) Lycopene, ii) Epigallocatechin gallate, iii) Sulforaphane, iv) Indole-3-Carbinol, v) Resveratrol and vi) Quercetin), 2 spices i) curcumin and ii) piperine and one mineral, namely Zinc, that correlated with lower risks of prostate cancer and/or recurrence. Results of this literature search for epidemiological studies demonstrating the chemopreventive effects of these micronutrients against prostate cancer are shown in Table I. The mechanisms of action by which these micronutrients exert their protective effects on prostate cancer are presented in Table II.
Lycopene
Lycopene is one of the main antioxidant carotenoids that gives tomatoes and tomato-derived products their colour. There is sufficient evidence that high intake of tomato, tomato products or lycopene supplementation can decrease the risk of prostate cancer. There have been no significant adverse effects attributed to lycopene supplementation when consumed for a long period (71, 72). The denoted protective effects of tomato and tomato products are largely conferred by high concentration of lycopene (73). While lycopene is the most effective scavenger of singlet oxygen among the main naturally occurring carotenoids (74, 75), its prostate cancer protective effects were difficult to explain by its potent antioxidant effects. The anticarcinogenic activities of Lycopene are considered to be exerted via other multiple mechanisms including protection of vital cellular biomolecules such as DNA and lipoproteins, intercellular gap junction communication, inhibition of proliferation of cancerous cells at the G0-G1 cell cycle phase and modulation of hormonal and immune systems (76-78). Lycopene has also been reported to inhibit prostate cancer cell proliferation via activation of the peroxisome proliferator-activated receptor gamma (PPARγ)-liver X receptor alpha (LXRα)-ATP-binding cassette transporter 1 (ABCA1) pathway (PPARγ-LXRα-ABCA1 pathway) and modulation of the expression of genes related to growth and apoptosis such as cyclin-dependent kinase 7 (CDK7), epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R) and BCL2 (79, 80).
A prospective cohort study of 47,365 participants for 12 years has revealed a statistically significant association between lycopene intake and prostate cancer risk; The reduction in prostate cancer risk was 17% (RR for high vs. low quintiles=0.83; 95%CI=0.70-0.98; ptrend=0.02) and 22% when the deciles rather than quintiles were analysed (RR for high vs. low deciles=0.78; 95%CI=0.65-0.94) (81). A smaller yet more recent nested case-control study involving 1,806 prostate cancer cases and 12,005 controls has shown that adherence to intake of tomato products was inversely associated with 18% overall prostate cancer risk (OR=0.82; 95%CI=0.70-0.97; p=0.02) (82). In line with the previous studies, a more recent meta-analysis of 22 case-control (13,999 cases and 22,028 controls) and 5 cohort studies (8,619 cases and 187,417 participants) has reported a statistically significant inverse association between lycopene and raw or cooked tomatoes intake and prostate cancer (OR=0.94, 95%CI=0.89-1.00) and (RR=0.9, 95%CI=0.85-0.95), respectively (83).
Analogously, a recent and more inclusive meta-analysis of thirty studies (24,222 cases and 260,461 participants) has also demonstrated significant inverse associations between consumption of total tomato, tomato foods, and cooked tomatoes and sauces and prostate cancer risk (RR=0.81, 95%CI=0.71-0.92, p=0.001), (RR=0.84, 95%CI=0.72-0.98, p=0.030) and (RR=0.84, 95%CI=0.73-0.98, p=0.029), respectively. Nevertheless, there were no associations reported for raw tomatoes and prostate cancer risk (RR=0.96, 95%CI=0.84-1.09, p=0.487). Whereas significant dose–response associations were reported for total intake of tomato (p=0.040), cooked tomatoes and sauces (p<0.001) and raw tomatoes (p=0.037), there was no significant association with tomato foods (plinear=0.511, pnonlinear=0.289). When further stratified by study design, the pooled RR were 0.68 (95%CI=0.55-0.84, p<0.001, I2=77.4%) and 0.92 (95%CI=0.86-0.98, p=0.013, I2=41.1%) for case-control and cohort studies, respectively. Interestingly, regarding tomato foods, the pooled RR for case-control studies was 0.69 (95%CI=0.53-0.91, p=0.008, I2=80.3%) and 1.00 (95%CI=0.87-1.15, p=0.963, I2=57%) for cohort and nested case-control studies. For cooked tomatoes and sauces, the pooled RR was 0.63 (95%CI=0.40-1.00, p=0.052, I2=69.1%) for case-control studies and 0.92 (95%CI=0.85-0.99, p=0.025, I2=0%) for cohort and nested case-control studies. For raw tomatoes, the pooled RR was 0.95 (95%CI=0.76-1.19, p=0.729, I2=55.9%) for case-control studies and 0.96 (95%CI=0.81-1.14, p=0.557, I2=60.6%) for cohort and nested case-control studies. The pooled RR for associations between tomato consumption and advanced prostate cancer was 0.89 (95%CI=0.77-1.03, p=0.113, I2=35.3%. The pooled RR was 1.10 (95%CI=0.84-1.44, p=0.493, I2=0%) for case-control studies and 0.81 (95%CI=0.68-0.97, p=0.019, I2=16.3%) for cohort studies (84).
Summary of studies selected in our review reporting on risk estimates of the associations between intake of selected micronutrients (highest vs. lowest or frequent vs. nonfrequent) and prostate cancer risk.
A systematic review and meta-analysis of prospective studies (11 cohort studies and 6 nested case-control studies) has reported inverse associations between intake of tomato/tomato products and lycopene and prostate cancer risk (86). However, the associations were all suggestive but not statistically significant. The pooled risk estimates of prostate cancer incidence among consumers of higher raw tomato and cooked tomato (which accounted for 82% of lycopene consumption) versus consumers of lower intakes were 0.81 (95%CI=0.59-1.10) (I2=74%) and 0.85 (95%CI=0.69-1.06) (I2=64%), respectively. The effect-estimate found by increasing lycopene consumption was slightly higher than that of concentrations of serum lycopene; The odds ratio of higher versus lower lycopene consumption and serum lycopene were 0.93 (95%CI=0.86-1.01) (I2=18%) and 0.97 (95%CI=0.88-1.08) (I2=0%), respectively. Subgroup analysis demonstrated that the RR for advanced prostate cancer of combined consumption of both tomatoes and cooked tomato products (which accounted for 82% of lycopene intake) was 0.65 (95%CI=0.44-0.95) for consumption frequency >10 versus <1.5 servings weekly. The odds ratio of the highest serum lycopene with the lowest in association with the risk of advanced prostate cancer was 0.77 (95%CI=0.49-1.20) (I2=74%) (85). A meta-analysis of observational studies (11 case-control studies and 5 cohort studies and 5 nested case-control studies) has revealed that high intake of raw tomatoes and cooked tomato products, which provide the bulk of lycopene, decrease the risk of prostate cancer by 11% (RR high vs. low intake=0.89 (95%CI=0.80-1.00) and 19% (RR=0.81 (95%CI=0.71-0.92), respectively. Importantly, the protective effect shown by increased serum or plasma concentrations of lycopene was higher than that of raw tomatoes or cooked tomato products intake; serum or plasma concentrations of lycopene were associated with 26% decrease of prostate cancer risk for all studies [high vs. low serum concentrations RR=0.74 (95%CI=0.59-0.92)], 45% for case-control studies [RR=0.55 (95%CI=0.32-0.94)] and 22% for cohort studies [RR=0.78 (95%CI=0.61-1.00)] (86). A pooled analysis of 15 prospective studies (11,239 cases including 1,654 advanced-stage and 1741 aggressive, and 18,541 controls) has demonstrated that plasma level of lycopene was associated with lower risk of aggressive prostate cancer (OR=0.65 (95%CI=0.46-0.91; p-trend=0.032) (87). It should be noted that lycopene absorption can be influenced by numerous factors such as processing or cooking, the lipid content of the diet, and possibly genetic factors and therefore dietary evaluation of consumption of lycopene might not reflect its bioavailability (88). It should be noted that the magnitude of the correlations between intake of raw tomatoes with lycopene plasma level is modest and the bioavailability of lycopene has been reported to be higher from tomato products than raw tomatoes (86, 89, 90). The above empirical approach based on plasma lycopene level avoids several assumptions about validity of responses for various co-occurring components, nutrient composition and portion sizes (91).
In dose–response analysis of the above-mentioned meta-analysis of thirty studies (24,222 cases and 260,461 participants), significant nonlinear dose–response association between total tomato consumption and prostate cancer was observed (plinear=0.099, pnonlinear=0.017); Prostate cancer risk decreased by 13% at 200 g/week, 28% at 500 g/week, 46% at 1,000 g/week, and 56% for 1,350 g/week. Nevertheless, there was not any dose–response association between consumption of tomato foods and risk of prostate cancer (plinear=0.400, pnonlinear=0.173). There was a significant dose–response association between cooked tomatoes and sauces and prostate cancer risk (plinear<0.001, pnonlinear<0.001); Prostate cancer risk decreased by 3% for 60 g/week, 12% for 120 g/week, 19% for 240 g/week, and 49% for 420 g/week in the nonlinear model and decreased by 3.5% for each additional 30 g/week. A significant linear dose–response association was observed between raw tomatoes and prostate cancer risk (plinear=0.037, pnonlinear=0.099); Prostate cancer risk decreased by 2% for each additional 100 g of raw tomatoes consumed per week (84). The most recent dose–response meta-analysis of twenty-six studies with 17,517 cases of prostate cancer reported from 563,299 participants has revealed that higher lycopene intake was associated inversely with risk of prostate cancer (RR=0.910 (95%CI=0.819-1.011, p=0.078). [moderate heterogeneity (I2=45.5%, p=0.037)]. When one study was excluded and several sensitivity analyses were performed, the overall pooled risk estimates became more significant (RR=0.935, 95%CI=0.881-0.993, p=0.030). [(I2 changed from 45.5% to 0.0%)]. The concentration of circulating lycopene between 2.17 and 85 μg/dL was linearly inversely associated with prostate cancer risk [RR=0.821 (95%CI=0.711-0.949, p=0.008)] [little heterogeneity (I2=16.9%, p=0.269)]. When results were adjusted by the body mass index or age for studies with high quality and a follow-up period >10 years, the circulating lycopene concentration was more effective in preventing prostate cancer. Dose-response analysis indicated that each 5 mg/day increase of lycopene consumption decreased the risk of prostate cancer with RR 0.975 [RR=0.975 (95%CI=0.940-1.010, p=0.160)] for all studies. [moderate heterogeneity (I2=50.2%, p=0.020)]. When several sensitivity analyses were performed and one study removed, each 5 mg/day increase of lycopene intake decreased the risk of prostate cancer with pooled risk estimate (RR=0.979, 95%CI=0.962-0.996, p=0.017) [(I2 changed from 50.2% to 0.0%)] (92). A dose-response meta-analysis of 34 studies (10 cohorts, 13 case-control studies and 11 nested case-control) involving 15,891 cases and 592,479 participants has revealed that lycopene dietary intake and its blood concentrations were both significantly associated with reduced risk of prostate cancer, (RR=0.86, 95%CI=0.75-0.98) and (RR=0.81, 95%CI=0.69-0.96), respectively. Dose-response analysis has found that risk of prostate cancer was reduced by 3% per 1 mg/day (95%CI=0.94-0.99) increment of dietary lycopene consumption (93). The most recent and comprehensive dose-response meta-analysis of forty-two studies (43,851 cases, 692,012 participants) has demonstrated that both dietary high-lycopene intake and circulating lycopene concentrations were significantly associated with reduced prostate cancer risk, (RR=0.88, 95%CI=0.78-0.98, p=0.017) and (RR=0.88, 95%CI=0.79-0.98, p=0.019), respectively. When stratified by study design, case–control studies have indicated even a greater reduced prostate cancer risk with high-lycopene intake (pooled RR= 0.82 (95%CI=0.68-0.999, p=0.049). There was a trend for chemoprevention against prostate cancer aggressiveness (RR=0.74, 95%CI=0.55-1.00, p=0.052). Sensitivity and dose-response analyses revealed a significant linear dose-response and that prostate cancer risk decreased by 1% for every additional 2 mg of lycopene consumed (p=0.026). For each additional 10 μgdl-1 of circulating lycopene, prostate cancer risk decreased by 3.5 to 3.6% (plinear=0.004, pnonlinear=0.006) (94).
As a final point, when the joint effect between lycopene and green tea consumption was investigated, interaction analysis showed that the chemoprotective effect from green tea and lycopene intake was synergistic and stronger than either agent alone (p<0.01) (65). Intriguingly, compared with other chemopreventive compounds, a recent meta-analysis of 13 studies involving 3,020 patients has reported that lycopene exerts superior chemopreventive effects than most of other chemopreventive compounds including Dutasteride with the exception of green tea catechins (95).
Summary of the mechanisms of action of phytochemicals selected in our review with associated signalling pathways in prostate cancer chemoprevention.
Epigallocatechin gallate (EGCG)
Green tea has been extensively investigated for its protective role against various types of human cancers including prostate cancer (96). The inhibitory action of green tea on carcinogenesis was attributed to its active compounds present in higher amounts called polyphenols which consist mainly of catechins, especially epigallocatechin-3-gallate (EGCG) which accounts for more than 50% of total polyphenols (97, 98). Short-term intervention with green tea has been shown to increase the levels of epigallocatechin gallate (EGCG) in prostate tissues supporting its prostate-specific bioavailability; Both methylated and nonmethylated forms of EGCG have been detected in prostatectomy tissues from patients who have been consuming 6 cups green tea per day for 3-8 weeks compared to samples from patients consuming water (99). Analogously, a randomised clinical trial has shown uptake of green tea polyphenols by prostate tissue and evidenced their induced changes in systemic oxidation and nuclear factor-ĸB (NF-ĸB); Both urinary 8-Hydroxy-2-deoxyguanosine (8OHdG) and NF-ĸB in radical prostatectomy tissue have been found to be statistically significantly reduced in men consuming 6 cups/day for 3-8 weeks of green tea (p=0.013) compared to individuals consuming water (100).
Despite the fact that clinical evidence is still sparse with regard to EGCG, numerous epidemiological studies have demonstrated lower incidence of prostate cancer in Asian populations where consumption of green tea is high and regular as compared to Western countries (27). A meta-analysis of thirteen observational studies in Asian populations has documented a moderately significant inverse association between green tea intake and prostate cancer risk (OR=0.62; 95%CI=0.38-1.01). When analyses were stratified by study design, the pooled estimate reached a more statistically significant level for case-control studies (OR=0.43; 95%CI=0.25-0.73) (101). Similarly, the stratified analyses of an updated meta-analysis of 21 studies has shown a protective effect for tea intake against prostate cancer in 18 case-control studies (OR=0.77, 95%CI=0.55-0.98) (102). A pooled analysis of 21 studies (104) has shown that total consumption of tea (both green and black) was significantly associated with reduced prostate cancer risk (OR=0.84, 95%CI=0.71-0.98) (104). Importantly, subgroup analyses showed that consumption of tea significantly reduced risk of prostate cancer in China and India, (OR=0.40 and, 95%CI=0.25-0.66) and (OR=0.48, 95%CI=0.24-0.97), respectively. In stage subgroup analyses, the highest level of tea intake was associated with a significant protective effect on low-grade prostate cancer (OR=0.66, 95%CI=0.46-0.93) (103).
More importantly, several studies have demonstrated that green tea is an effective chemopreventive agent, predominantly in prostate cancer patients with high-grade prostate intraepithelial neoplasia. In high-grade intraepithelial neoplasia patients, green tea catechins showed superiority in decreasing prostate cancer in high-grade intraepithelial neoplasia patients over all other natural chemoprevention agents. A systematic review and stratified analyses of observational studies and randomised controlled trials (RCTs) using stringent inclusion criteria, namely Newcastle-Ottawa Scale (NOS) and the Jadad scale as quality assessment tools, have concluded that green tea is an effective chemopreventive agent, particularly in prostate cancer patients with high-grade prostate intraepithelial neoplasia (104). A subgroup analysis of a recent meta-analysis comprised 13 studies involving 3,020 patients has reported that green tea catechins significantly decreased prostate cancer in high-grade intraepithelial neoplasia patients (RR=0.39, 95%CI=0.16-10.97, p=0.044), with moderate heterogeneity (I2=47.9%, x2=1.92, p=0.166) (95). Furthermore, a recent meta-analysis has reported that green tea catechins had a significant protective effect against prostate cancer (RR=0.38 (95%CI=0.16-0.86, p=0.02), particularly in patients with high-grade prostatic intraepithelial neoplasia disease or atypical small acinar proliferation (105). Men with high-grade intraepithelial neoplasia, which is the most established precursor of prostate cancer, are at high-risk for prostate cancer as they have a 30% chance of developing prostate cancer within a year of detection. The fact that high-grade intraepithelial neoplasia manifests similar cytological features to prostate cancer and is considered easily identifiable makes it an invaluable candidate for chemopreventive interventions (98, 106).
In order to quantitatively evaluate the association of green tea consumption with prostate cancer risk, a dose–response analysis of a case-control study involving 253 patients with prostate cancer and 419 controls has shown that habitual total tea consumption was associated with lower risk of prostate cancer; Relative to participants drinking <100 ml/day, the adjusted odds ratios were 0.52 (95%CI=0.35-0.79) and 0.30 (95%CI=0.18-0.48) for participants drinking 100-500 ml/day and >500 ml/day, respectively (107). The most recent dose–response meta-analysis of seven observational studies and three randomised controlled trials has reported an inverse association between consumption of green tea and prostate cancer risk with a linear dose–response effect (106). Consumption of more than 7 cups per day of green tea was linearly associated with a statistically significant reduced prostate cancer risk (RR=0.81 (95%CI=0.67-0.97). When subgroup analysis was conducted by study design, the case–control studies demonstrated a stronger protective effect of green tea consumption against prostate cancer (RR=0.453, 95%CI=0.249-0.822) and that the approximate RR for each 1 cup per day increase of green tea was 0.893, (95%CI=0.796-1.002, p=0.054) (105). A large prospective study involving 49,920 men has demonstrated that green tea consumption was correlated with a dose-dependent decrease of advanced prostate cancer risk (<1 cup/day: reference; 3-4 cups/day: RR=0.86, 95%CI=0.50-1.47; ≥5 cups/day: RR=0.60, 95%CI=0.34-1.06; ptrend=0.03). When all potential confounding factors were adjusted, the inverse association was strengthened to statistical significance (highest vs. lowest RR=0.52, 95%CI=0.28-0.96) (ptrend=0.01) (31). Similarly, a placebo-controlled, double-blinded, randomised clinical trial of a mix of catechins containing 400 mg EGCG per day for 1 year in 97 men with high-grade prostatic intraepithelial neoplasia and/or atypical small acinar proliferation prostate disease has reported a reduction in atypical small acinar proliferation prostate disease, which is associated with prostate cancer, observed in 11.5% of patients in the intervention group versus 40% in the control group (p=0.024) (109). There was also a significantly greater decrease in serum levels of PSA in the intervention group in comparison with the control group (p=0.029) [−0.87 ng/ml; 95%CI=−1.66 to −0.09] with no significant adverse events between both groups (108). In patients with high-grade prostatic intraepithelial neoplasia and precancerous lesions, supplementation with green tea catechins was associated with lower prostate cancer incidence, reduced PSA level, delay in the onset of prostate cancer, reduced lower urinary tract symptoms and further improvement in quality of life (a total of 600 mg daily of green tea catechins). After a one-year follow-up, there was only 3% incidence in the green tea catechins group compared to 30% in the placebo group (p<0.01), suggesting a 90% chemopreventive effect of green tea catechins. There was also a significant decrease in International Prostate Symptom Score in the green tea catechins group compared to placebo group with no significant adverse effects. After a two-year follow-up, further reduction in prostate cancer incidence was observed suggesting a long-lasting effect of green tea catechins; 2 of the 9 placebo men and only 1 of the 13 the green tea catechins patients were diagnosed with prostate cancer, indicating an 80% decrease in diagnosis of prostate cancer in patients with high-grade prostatic intraepithelial neoplasia (98, 109).
The mechanisms by which EGCG exerts its anticancer potential comprise modulating multiple cellular signalling pathways involved in inflammation, angiogenesis, metastasis and invasion in both androgen-dependent and androgen-independent human prostate cancers (110). Prostate cancers that do not respond to hormonal treatment, which is the therapeutic mainstay for patients with prostate cancer, eventually become androgen-independent and therefore refractory to anti-androgen therapeutics leading to cancer recurrence (15, 64).
Multiple studies have demonstrated that EGCG can regulate androgen activity in target organs and induce significant changes in several endocrine parameters as well as inhibit the prostatic enzyme that transforms testosterone into 5-α-dihydrotestosterone, namely 5-α-reductase (111, 112). A small trial involving twenty-six men with prostate cancer scheduled for radical prostatectomy has also reported that short-term supplementation with EGCG had significantly reduced serum levels of biomarkers such as PSA, vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) (113). These results support a possible role for EGCG in the prevention of prostate cancer. Furthermore, numerous experiments have revealed that EGCG can inhibit clonal expansion of cancer stem cells, cyclo-oxygenase-2 (COX-2) overexpression, proteasome activity, inducible nitric oxide synthase (iNOS), matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF) and activator protein 1 (AP-1) and MAPKs (115-117). Along with inhibition of HER-2/neu signalling, EGCG has been shown to inhibit both insulin-like growth factor-1 (IGF-1)-mediated signalling, nuclear factor-ĸB and EGF-mediated transduction signalling pathways, modulate cyclin kinase inhibitor (CKI)–cyclin–cyclin-dependent kinase (CDK) machinery, and multiple reversible epigenetic mechanisms (110, 114-116). Data from in vitro and in vivo studies have revealed that green tea polyphenols can trigger apoptosis in cancerous cells via the epigenetic modulation of the expression of apoptosis-associated genes including human telomerase reverse transcriptase (hTERT) and/or induction of reactive oxygen species (ROS) (117, 118). Although certain phytochemicals such as green tea (EGCG), resveratrol and curcumin display antioxidant and anti-ROS activities, there is ample evidence that these phytochemicals can also exert pro-oxidant activity particularly in the presence of redox active transition ions leading to production of ROS and oxidative DNA and proteins damage resulting in cell cycle arrest or apoptotic cell death (119-122). This pro-oxidant action represents a vital pathway via which transformed cells are preferentially targeted by such phytochemicals whereas normal cells survive.
Indole-3-Carbinol & Sulforaphane
Because Mediterranean diet and dietary patterns rich in vegetables and fruits have been associated with significantly reduced all-cause mortality and may reduce prostate cancer risk by up to 75% (38, 42, 52), phytochemicals that are present at high levels in vegetables and fruits have been extensively investigated to explore their chemopreventive properties against prostate cancer. Cruciferous vegetables contain high levels of glucosinolates, whose major breakdown product, by the action of myrosinase enzymes, is indole-3-carbinol. Both in vitro and in vivo experimental studies have shown that indole-3-carbinol exhibits potent anticarcinogenic properties against prostate cancer (123). Indole-3-carbinol has been shown to exert robust cancer-preventive properties primarily via its ability to selectively induce G1/S arrest of the cell cycle and apoptosis in cancer cells, which are considered key processes in the prevention of tumour growth (124, 125). The cell-cycle arrest by indole-3-carbinol involves up-regulation of p27, p21, p15, and down-regulation of cyclin-dependent kinases CDK2, CDK4, and CDK6, and cyclin D1 and cyclin E. Apoptosis induced by indole-3-carbinol involves activation of cas-9 and cas-3, release of mitochondrial cytochrome C, up-regulation of proapoptotic protein Bax, down-regulation of antiapoptotic gene products such as Fas-associated death domain protein-like interleukin-1-beta-converting enzyme inhibitory protein (FLIP), inhibitor-of-apoptosis protein (IAP), X chromosome-linked IAP (XIAP), Bcl-2, Bcl-xL and survivin. In addition to its ability to potentiate the effects of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), indole-3-carbinol inhibits the activation of nuclear factor-kappa B (NF-ĸB), oestrogen receptor signalling, androgen receptor signalling and nuclear factor-E2-related factor 2 (Nrf2) (126). Recently, indole-3-carbinol has been found to target cancer stem cells and modulate epigenetic alterations including histone modification, CpG methylation and aberrant expression of microRNA (127).
Another phytochemical that occurs ubiquitously in cruciferous vegetables is an isothiocyanate called Sulforaphane. It has been reported that Sulforaphane can induce G2/M cell-cycle arrest and influence human prostate cancer development and progression via disruption of signalling within tumour microenvironments and activation of apoptotic cell death (128, 129). In addition to its inhibition of the nuclear translocation of p65 and IKKα/β-IĸBα-p65 signalling pathway in prostate cancer cells, sulforaphane has been reported to strongly inhibit NF-ĸB activity and NF-ĸB-regulated VEGF, cyclin D1, and Bcl-XL gene expression (130, 131). Moreover, sulforaphane and other isothiocyanates have been found to activate ERK1/2 and JNK signalling pathway resulting in phosphorylation of Nrf2 and its translocation to the nucleus which in turn activates ARE elements and induces expression of stress-responsive genes, including HO-1. Nuclear Nrf2 (132). Additionally, in vitro and in vivo studies have reported that sulforaphane can potently increase phase II enzyme expression; Loss of phase II enzyme expression occurs early and almost universally in prostate cancer (133, 134). In animal models, sulforaphane has also been shown to target epigenetic events that can occur at various stages of carcinogenesis and metastasis including inhibition of histone deacetylase activity in benign prostate hyperplasia and both androgen-dependent and androgen-independent prostate cancer cells (135, 136).
It seems that the mechanisms of the anticarcinogenic effects of cruciferous vegetables involve the early rather than the later stages of carcinogenesis (137, 138). In a double-blinded, randomised placebo-controlled multicentre trial, 78 prostate cancer patients who had rising levels in PSA after radical prostatectomy were treated with either 60 mg sulforaphane or placebo for 6 months and then followed for 2 months with no treatment. PSA increased significantly >20% in the placebo group (71.8%) compared with the sulforaphane group (44.4%, p=0.0163). Also, the doubling time of PSA was 86% longer in the sulforaphane compared with the placebo group (28.9 and 15.5 months, respectively (139). PSA plays a key role in prostate tumour growth mainly via regulating numerous proangiogenic and anti-angiogenic growth factors. Despite its low sensitivity, PSA is the key marker for prostate cancer risk including high-grade tumours and therefore interventions that aim to inhibit its production in the prostate might have a beneficial role in prevention of prostate cancer. Elevated PSA serum levels reflect not only the presence of cancer but also chronic inflammation in the prostate which may enhance prostate carcinogenesis and induce a further elevation of PSA level (140). In addition to its utility as a clinical biomarker for prostate cancer diagnosis, prognosis, progression and response to therapy (141, 142), PSA levels have been widely used as an established continuous variable to define risk categories in prostate cancer chemoprevention studies (143-148). Numerous epidemiological studies investigating associations between consumption of cruciferous vegetables and risk of cancer have confirmed that the high intake of cruciferous vegetables has advantageous effects on the risk of various common cancers including prostate cancer. This protective effect is largely attributed to the presence of sulforaphane and Indole-3-carbinol. Analysis of a network of Italian and Swiss case–control studies (10,000 cases with 1294 prostate cancer cases and 17,000 controls) has reported an inverse association between consumption of vegetables and fruits in the risk of various common cancers including the prostate OR=0.9. The OR for cruciferous vegetables and prostate cancer risk was 0.87 (for the highest v. the lowest levels of consumption of cruciferous ≥1 vs. <1 portion/week) (OR=0.87, 95%CI=0.70-1.09) (51). The first meta-analysis of 13 studies (seven were cohort and six population-based case–control studies) evaluating the association between consumption of cruciferous vegetables and prostate cancer risk has found that high consumption of cruciferous vegetables was significantly associated with 10% decreased risk of prostate cancer (RR=0.90, 95%CI=0.85-0.96) in all studies and 21% decreased risk of prostate cancer in population-based case–control studies (RR=0.79; 95%CI=0.69-0.89). Interestingly, the inverse relationship was stronger for high-stage advanced disease (RR=0.69; 95%CI=0.53-0.86) (149). Another meta-analysis of studies conducted over 18 years in Europe including a total of 1294 of prostate cancer patients and 11,492 controls has shown that consumption of cruciferous vegetables was associated with a 13% reduction in prostate cancer risk (OR=0.87, 95%CI=0.72-1.06) (150). Furthermore, a study involving 1,560 cases and 2,134 participants has found that post-diagnostic consumption of cruciferous vegetables was associated with a 59% reduced risk of prostate cancer progression (HR=0.41, 95%CI=0.22-0.76; p-trend=0.003) (151).
It should be noted that consumption of cruciferous vegetables might not always be a practical way to obtain the daily required quantities of sulforaphane and Indole-3-carbinol; Concentration of sulforaphane and Indole-3-carbinol in cruciferous vegetables is highly variable depending on various factors including the amount of sunlight, soil, rainfall, seed strain and myrosinase enzyme activity. Therefore, particularly for Indole-3-carbinol, semisynthetic sources and extracts of cruciferous vegetables are considered to be more practical (123).
Resveratrol
Resveratrol, a naturally occurring polyphenolic phytoalexin that is present in grapes and berries, has various health benefits, particularly the mitigation of age-related diseases and carcinogenesis (152, 153). It has been shown that resveratrol can inhibit the promotion and growth of several cancers including the prostate (154, 155). It has been shown that resveratrol exerts potent anti-initiation, anti-promotion and anti-progression activities throughout the multi-stage process of carcinogenesis (153). Resveratrol can augment cellular antioxidant defence capacity and sensitise prostate cancer cells to treatment through reducing both undesired basal reactive oxygen species (ROS) and reactive nitrogen species (RNS) as well as inducing antioxidant enzymes such as heme-oxygenase-1 (HO-1) through ARE-mediated transcriptional activation of Nrf2 (156-158). In addition to its inhibition of COX-2 expression, resveratrol has been found to interfere with pro-inflammatory signalling pathways triggered by IL1-β leading to inhibition of inflammation, which is often involved in cancer onset and progression by regulating proliferation, apoptotic cell death and angiogenesis (159). Pro-inflammatory mediators such as cyclooxygenase-2 (COX2) have been reported to enhance carcinogenesis as their aberrant expression was observed in both premalignant and malignant human tumours including prostate cancer (160, 161). Furthermore, resveratrol has been shown to induce a potent anti-inflammatory mediator, namely MAP kinase phosphatase-5, resulting in inhibition of both JNK and the stress-activated protein kinase p38 in prostate cancer cells. The latter is known to regulate pro-inflammatory responses and its inhibition results in reduced pro-inflammatory cytokine release, cytokine-induced NF-ĸB activation, COX-2 expression, IL-6 and IL-8 (162).
Other verified mechanisms associated with cancer-preventing and anti-cancer effects of resveratrol on human cancer cells include modulation of i) transcription factors c-Fos, c-Jun, AP-1 and NF-ĸB, ii) angiogenic and metastatic factors, VEGF and matrix metalloprotease 2/9, iii) apoptotic and survival regulators, Bcl-2, Bcl-XL Bax, Bak, PUMA, Noxa, TRAIL, Apoptotic Protease Activating Factor (APAF) and Protein kinase B (Akt), iv) tumour suppressors p53 and Rb; cell cycle regulators, p21and p27 cyclins, CDKs and the checkpoint kinases ATM/ATR (123, 164-170), v) epigenetic mechanisms such as promotion of acetylation, reactivation of PTEN tumour suppressor and post-translational modifications leading to inhibition of the Akt pathway (170) and vi) post-translational modifications and regulation of microRNAs expression and chromatin modifier metastasis-associated protein 1 (MTA1) (171). Resveratrol ability to decrease cyclin B/Cdk1 kinase activity and cyclin B and Cdk1 expression was observed in both androgen-sensitive and androgen-insensitive prostate cancer cells (172). In addition to its anti-androgenic properties through its ability to down-regulate the expression of androgen receptor (173), resveratrol has been found to down-regulate the expression of both androgen receptor and oestrogen receptor alpha-dependent phosphoinositide-3-kinase PI3K in prostate cancer cells (174). In castration-resistant prostate cancer, resveratrol can inhibit hypoxia-inducible factor-1α-mediated androgen receptor signalling and thus inhibit β-catenin-mediated androgen receptor function, which is driving both primary and recurrent disease (175). Approximately 90% of prostate cancer patients who respond to androgen deprivation therapy undergo rapid progression and become castration-resistant prostate cancer patients, which remains an incurable disease (15).
Although no human clinical trial has been performed to assess the preventative effects of resveratrol specifically on prostate cancer, data from a few small studies support its advantageous use in prostate cancer prevention. A 4-month randomised placebo-controlled clinical trial was conducted to assess the effects of resveratrol on seventy-six middle-aged men with metabolic syndrome, which is associated with the development, progression and worse oncological outcomes of several neoplasms including prostate cancer (176). The trial has determined that administration of a high dose of resveratrol (1000 mg/d) for 4 months significantly decreased serum levels of the androgen precursors androstenedione 24% (p=0.052), dehydroepiandrosterone (DHEA) 41% (p<0.01), and dehydroepiandrosterone-sulphate (DHEAS) 50% (p<0.001), compared to the control group. While an optimal dose of resveratrol in primary chemoprevention settings has not yet been determined, longer-term supplementation has greater effects (177). A single-arm phase I study in men with biochemically recurrent prostate cancer (n=14, 71% Caucasian, 29% black) with a median follow-up of 19.2 (6.2-29.7) months has demonstrated that a resveratrol-rich muscadine-grape skin extract extended doubling time of PSA by 5.3 months (178). Interestingly, combinations of resveratrol with other micronutrients, such as quercetin, curcumin and epigallocatechin gallate, have been found to have greater inhibitory activities against diverse cancer models than either of these agents alone (179-181).
Quercetin
Quercetin, which is a bioactive flavonol pigment that is present at high concentrations in apples and onions, has been shown to exhibit inhibitory activities in various stages of tumour development. In addition to its potent antioxidant properties, quercetin's cancer-protecting effects mainly derive from promoting TRAIL-mediated cancer cell apoptosis and targeting several key oncogenic signalling transducers resulting in inhibition of expression of oncogenes and restoration of tumour suppressor genes (182-184). Quercetin has also reported to reverse epigenetic alterations associated with inactivation of tumour suppressor genes and activation of oncogenes (185). Moreover, quercetin has been found to reduce the insulin-like growth factors (IGFs) via increasing binding protein-3 (IGFBP-3) resulting in induction of apoptosis in human prostate cancer cells (186). Further, recent evidence has demonstrated that quercetin can inhibit prostate cancer stem cells via the PI3K/Akt and MAPK/ERK signalling pathways (187).
The potential of consumption of apples in prostate cancer prevention has long been recognised and was largely attributed to the presence of quercetin. A small hospital based case-control study (50 case and 100 controls) has reported a significant inverse association between apple intake and prostate cancer risk (p trends 0.01) (188). Data from a large network of case–control studies (1294 cases and 3094 controls) showed an inverse association between apple intake, ≥1 apple/day, and prostate cancer risk (95%CI=0.77-1.07) (189). Further, a meta-analysis of data from a network of Italian and Swiss case–control studies (10,000 cases with 1294 prostate cancer cases and 17,000 controls) has indicated that subjects who consumed at least one apple a day had a reduced risk of various common cancers including prostate cancers, OR=0.91 (95%CI=0.77-1.07) (51).
Finally, while repeated intake of quercetin was reported to lead to a build-up of the concentration in plasma, flavonols are bound to glycosides and their absorption from the diet is regarded to be negligible. As no enzymes can split the predominantly β-glyosidic bonds between flavonols and glycosides molecules found in intestinal lumen, only free flavonols without glycosides molecules, the so-called aglycones, are capable of passing the gut wall (190, 191).
Curcumin & Piperine
Curcumin is the most bioactive polyphenolic isoflavone of the rhizome of the plant Curcumin longa known as turmeric which has been renowned for its anti-inflammatory and anticancer proprieties (192, 193). The chemopreventive effects of curcumin towards tumorigenesis have been observed in both the initiation and the post-initiation phases (194). The turmeric spice curcumin has been reported to exhibit pleiotropic inhibitory actions towards carcinogenesis on a plethora of signalling pathways in various animal models at multiple organ sites especially the prostate (195, 196).
The key mechanisms underlying the anti-carcinogenic action of curcumin in both androgen-dependent and androgen-independent prostate cancer cells include i) down-regulation of inhibitor of DNA binding 1 by small interfering RNA, ii) restoration of tumour suppressor p53, iii) activation of Nrf2 signalling, iv) down-regulation of VEGF expression, v) modulation of toll-like receptors (TLR)/interleukin-1 receptor (IL-1R) pathway, vi) transformation of growth factor beta1 (TGF-β1), vii) modulation of inflammatory mediators such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2), ix) promotion of apoptosis by down-regulating Bcl-2 and up-regulating Bax and x) suppression of MMP9 (197-202). Pro-inflammatory mediators such as (iNOS) and (COX2) have been suggested to promote carcinogenesis as aberrant expression of (COX2) was reported in both premalignant and malignant human tumours including prostate cancer (160, 161). Matrix metalloproteinases (MMPs) are implicated in tumour angiogenesis, metastasis and invasion (203). Further, curcumin has been reported to modulate NFkB, PI3K/Akt/mTOR, MAPK, JAK/STAT signalling, inhibit ROS production and CXC chemokine receptor 4 (CXCR4) and interleukin-6 (IL-6) receptor expression in prostate cancer cells via MAOA/mTOR/HIF-1α signalling and inhibition of cancer-associated fibroblast-driven prostate cancer invasion (117, 204). Cancer-associated fibroblasts are crucial determinants of tumorigenesis, progression and metastasis of cancer. Additionally, curcumin has been reported to modify the chromatin landscape by supressing histone acetylation, coactivator protein p300, and element-binding protein occupancy at sites of androgen receptor function responsible for hormone therapy failures and aggressive phenotypes of prostate cancer (205).
While studies with curcumin have provided evidence regarding its tolerability and nontoxicity (206), the above molecular and preclinical success of curcumin in prostate cancer has not been reproduced in clinical trials. However, curcumin has still received much attention in prostate cancer chemoprevention because of its evidenced anti-inflammatory and antioxidant properties as well as robust evidence from in vitro and in vivo studies demonstrating its diverse anticarcinogenic effects against prostate cancer in cell lines and animal models.
Meta-analyses of randomised controlled trials, which assessed the effect of curcumin-containing supplements on oxidative stress and inflammation biomarkers, have suggested that curcumin-containing supplements exert antioxidant and anti-inflammatory effects through significant reductions in circulating serum concentrations of a panel of mediators such as malondialdehyde, interleukin 6 (IL-6) and TNF-α (207-210). While interleukin-6 is a multi-functional cytokine that plays a key role in carcinogenesis of many human cancers, TNF-α is one of the major molecular mediators of a wide range of chronic inflammation and inflammation-related disorders (211). There is increasing evidence from numerous molecular pathology, histopathological and epidemiological studies that chronic oxidation and inflammation in prostate plays a key role in the aetiology of its carcinogenesis (212, 213).
To evaluate the potential effects of curcumin as a prostate cancer preventive agent, a randomised double-blind placebo-controlled clinical trial involving 85 participants who had prostate biopsies but had neither prostatic intraepithelial neoplasia nor prostate cancer was undertaken. After six months of daily intake of curcumin in combination with isoflavones, the combination was found to significantly reduce PSA serum levels in the of participants who had a serum PSA level ≥10 μg/ml and supress androgen receptor expression in the supplement-treated group compared with that of the placebo (214). Moreover, supplementation of 3 g per day of curcumin for 3 months has been reported to increase plasma total antioxidant capacity significantly among 40 patients treated with radiotherapy for prostate cancer (p<0.001) (215). A prospective randomised phase III trial (ClinicalTrials.gov Identifier: NCT02064673) is on-going now to compare the effect of adjuvant supplementation of curcumin 500 mg twice a day for 6 months on recurrence-free survival as compared to placebo in the treatment of 600 prostate cancer patients after radical prostatectomy (216).
The first and foremost challenge to achieve desirable anticarcinogenic effects of curcumin remains its bioavailability, which cannot be overcome just by increasing the frequency of administration or the administered dose (217). To improve the bioavailability of curcumin, a combinatorial approach to obtain potentially synergistic or additive chemopreventive response can be used. A recent meta-analyses of randomised controlled trials has reported that the antioxidant activities were greater when curcumin was concomitantly taken with piperine compared with curcumin alone (208). Piperine does not only enhance the chemoprevention outcome of curcumin, but has been reported to significantly increase the absorption, serum concentration and bioavailability of curcumin in humans up to 20-fold when they are concomitantly administered (218, 219).
Piperine is a major bioactive alkaloid that is present in the black pepper at 5% to 9%. It has been shown that piperine exerts preventive and even therapeutic effects on both androgen-dependent and androgen-independent prostate cancers. A recent review on preclinical studies has demonstrated its selective cytotoxic properties on cancerous cells compared to normal cells (220). In human prostate cancer cells and animal models xeno-transplanted with prostate cancer cells, piperine has been reported to promote autophagy, induce cell cycle arrest at G0/G1 via down-regulation of cyclin D1 and cyclin A and up-regulation of p21 and p27, trigger apoptosis and inhibit the growth and proliferation of both androgen-sensitive and androgen-insensitive prostate tumours in dose-dependent manner (221, 222). Piperine has also been shown to inhibit expression of nuclear factor-kB (NF-kB) transcription factor and down-regulate phosphorylated STAT-3 (221). Additionally, in a xenograft models of human castration-resistant prostate cancer, piperine and docetaxel in combination have been reported to remarkably enhance the anti-tumour effectiveness of docetaxel (223).
Zinc
Zinc plays a key role in the physiological function and regulation of prostate cell growth. Zinc dysregulation and imbalance of zinc transporters have been reported in numerous cancers including prostate cancer (224, 225). Alterations in Intracellular and serum zinc (II) levels as a result of imbalance of zinc transporters in prostate cancer patients has been previously delineated (226). While zinc is available at a very high concentration in healthy prostate tissues, it significantly diminishes in the course of prostate carcinogenesis and its intracellular level has been reported to be inversely correlated with prostate cancer progression (227). It has been noted that the level of zinc in prostate tissue declines early preceding histopathological alterations and continues to diminish throughout the progression phase toward castration-resistant disease (228-230). High tissue Zinc concentrations have been found to inhibit the conversion of testosterone to dihydrotestosterone (DHT). The latter is considered the preferred ligand of androgen receptor which plays a central role for growth regulation in benign hyperplasia, androgen-stimulated and castration-recurrent prostate cancers in all stages of the disease, even after pharmacological or surgical androgen deprivation (231). There is now strong evidence from animal and laboratory experimental studies suggesting that zinc has a protective effect on prostate cancer, albeit at high doses, and that loss of capability to amass high levels of zinc is a crucial factor in the development and progression of prostate cancer.
Zinc has been reported to induce cell-cycle arrest and apoptosis by acting on numerous molecular regulators of apoptotic cell death such as caspases and proteins from the Bcl and Bax families leading to inhibition of human prostatic carcinoma cell growth (232).
A recent systematic review and meta-analysis of fourteen studies (731 cases and 574 controls) has reported that zinc concentrations in prostatic fluid and seminal plasma from chronic prostatitis patients were significantly lower than normal controls [SMD (95%CI) −246.71 (−347.97, −145.44), −20.74 (−35.11, −6.37) respectively] (233). Another systematic review and meta-analysis of fourteen studies (1318 cases and 1413 controls) has shown that serum zinc concentrations in prostate cancer patients were statistically significantly lower than that of benign prostatic hyperplasia patients and normal controls (standard mean differences of the serum zinc concentrations: SMD (95%CI)=−0.94 [−1.57, −0.32]; −1.18 [−1.90, −0.45], respectively (234). In line with the above meta-analyses, a meta-analysis of 114 cross-sectional, cohort and case control studies involving 22,737 participants has illustrated that decreased serum zinc levels were associated with most cancers including prostate cancer (prostate serum (effect size=−1.36; 95%CI=−1.97 to −0.75), Heterogeneity I2=97.93) (235).
Although it has been hypothesised that prostate cancer risk may be reduced by zinc intake both from supplements and/or diet, a prospective cohort study involving 35,242 men has reported a significant inverse trend between 10-yr long-term supplemental zinc intake but not dietary zinc, and the risk of clinically-relevant advanced disease (regionally invasive or distant metastatic prostate cancer) (HR=0.34 (95%CI=0.13-1.09) for greater than 15 mg/day versus no use, p for trend 0.04) (236).
Limitations
This review represents an account of the latest and most robust available findings on naturally available micronutrients and phytochemicals that have been studied in chemoprevention of prostate cancer. Although generally considered as safe, several challenges exist in the translational development of chemopreventive dietary factors such as the lack of instantaneous effects and concerns over unexpected dose-limiting toxicities when long-term high-dose supplementation is used in primary chemoprevention to overcome low serum bioavailability and/or low target-organ. Furthermore, the variable and occasionally inconsistent findings along with scarcity of well-designed randomised controlled trials involving standardised formulations, dosages, dosing periods and larger sample sizes suggest that these results should be interpreted with some caution. The currently available randomised controlled trials have all involved different trial durations, treatment periods and dissimilar doses of micronutrients and phytochemicals. Regarding the epidemiological and observational correlation studies, there are concerns related to the precision of self-administered questionnaires and in-person interviews in evaluating dietary intake. There are also issues related to confounding genetically associated factors, lifestyle related influences, recall bias and variance in recall periods (ranging from prior to diagnosis or prior to onset of symptoms or before diagnosis). Dissimilar types and stages of prostate cancer were also evaluated in different studies; While several studies did not even provide information on the stage or type of prostate cancer, others either involved patients with high-grade prostatic intraepithelial neoplasia or focused on patients with atypical small acinar proliferation prostate disease.
To measure the effect of specific dietary agents against prostate cancer and allow a “personalised medicine” approach, well-designed clinical trials with rigorous methodological interpretations to define individuals who respond and those who do not respond to dietary interventions are required. A randomised large-scale phase III clinical trial (MEAL study) is currently underway to provide robust evidence regarding the efficacy of increased vegetable consumption to prevent progression in prostate cancer patients; 478 patients with clinically localised prostate cancer on active surveillance from 91 study sites were randomised to either a vegetable-intense dietary pattern group or a control dietary group (237, 238).
In view of the evidence of reduced bioavailability and highly plasma concentration variability of these micronutrients, reported in some clinical studies, supplementation or consumption of the pure compound extracts seems to be more promising. Nevertheless, to prevent potential drug interactions, instructions and guidelines should be drawn up regarding the administration schedule of these dietary agents. The limitations, as illustrated above, regarding the epidemiological and observational correlation studies and scarcity of well-designed randomised controlled trials are largely circumvented by several lines of evidence from in vitro and animal studies as well as evidence based on high quality epidemiological and clinical studies included in this review. Such studies proved invaluable in identifying and examining potential anticarcinogens.
Conclusion and Future Perspectives
With increasing life expectancy and the adoption of lifestyles, such as poor diet, that are considered to increase prostate cancer risk, the projected future prostate cancer burden is expected to be unquestionably relatively higher, particularly in countries with rapid economic and societal transition (239). As nutritional factors are modifiable with no significant dose-limiting toxicities, identifying plant-based micronutrients and dietary components that modulate prostate cancer risk and aggressiveness holds the potential for effective yet practical strategies for primary chemoprevention settings.
Cumulative and well-documented molecular, preclinical and sufficient clinical evidence demonstrates that certain micronutrients (namely Lycopene, Epigallocatechin gallate, Sulforaphane, Indole-3-Carbinol, Resveratrol, Quercetin, Curcumin & Piperine) and Zinc display multiple antitumoural and anticarcinogenic effects against prostate cancer. These effects are exerted via inhibition of proliferation, invasion, angiogenesis and metastasis. In addition to their antioxidant properties, the antitumorigenic and anticarcinogenic activities displayed by these phytochemicals against prostate cancer are mainly related to inducing cell cycle arrest, triggering apoptotic cell death, regulating oncogenic signalling pathways and hormone receptors including androgen receptor. As prostate cancer heterogeneity represents a challenge for clinical interventions where different survival oncogenic signalling pathways are activated, the utility of a combinatorial approach of these micronutrients with their multi-targeted ‘pleiotropic’ effects offers a real advantage for chemoprevention of prostate cancer and its recurrence and as an integrated part of standard prostate cancer therapy. Combining the identified dietary compounds, with or without concurrent treatment, is strongly suggested from emerging evidence in prostate cancer. Because there is little or no progress in the transition of these micronutrients to bedside as first line chemoprevention it is inevitable to rely upon the available animal, pre-clinical and epidemiological studies. Using the safest formulation and most effective dosage for prostate cancer chemoprevention, it would be prudent for men at increased risk of prostate cancer to consider using dietary sources or supplements that encompass these micronutrients.
Acknowledgements
This study was funded by grants from the Breast Cancer Hope Foundation (London, UK).
Footnotes
Authors' Contributions
Kinan Mokbel conceived the topic of the article and performed the literature review. Kefah Mokbel supervised the study and drafted the manuscript. Umar Wazir proof-read and critiqued the manuscript and drafted revisions. All Authors read and approved the final manuscript.
This article is freely accessible online.
Conflicts of Interest
The Authors declare that they have no competing interests regarding this study.
- Received August 15, 2019.
- Revision received September 1, 2019.
- Accepted September 10, 2019.
- Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
