Bioactive compounds of the Mediterranean diet and prostate cancer

Abstract

Objective: The purpose of this review is to examine the evidence on the effects of bioactive constituents of the Mediterranean diet (MeDi) on prostate cancer (PCa) risk.

Methods: The search for articles came from extensive research in the following databases: PubMed, Scopus, and Web of Science. We used the search terms “Mediterranean diet,” “lycopene,” “vitamin E,” “vitamin C,” “Selenium,” “resveratrol,” “prostate cancer,” and combinations, such as “lycopene and prostate cancer” or “resveratrol and prostate cancer.”

Results: Numerous studies investigating the effect of various dietary nutrients on PCa have suggested that selenium is probably the most promising. Several studies reported reduced PCa risk associated with vitamin C and E intake, while other studies reported no association. Lycopene inhibits cell proliferation and inducts apoptosis, thus protecting against cancer. Also, it has been found in various in vivo and in vitro studies that resveratrol, inhibits PCa development.

Conclusions: The high content of bioactive phytochemicals in the MeDi is of particular interest in the prevention of PCa. Further large-scale studies are required to clarify the effect of MeDi bioactive compounds on prostate health, in order to establish the role of this diet in the prevention of PCa.

Keywords:

• Mediterranean diet
• bioactive compounds
• prostate cancer
• lycopene
• vitamin E
• vitamin C
• selenium
• resveratrol

Introduction

Prostate cancer (PCa) is the most common malignancy among elderly men and has emerged as the most frequent cancer amongst men in Europe, with incidence increasing rapidly over the past two decades. Countries following the traditional Mediterranean diet (MeDi), particularly Southern European countries, have lower PCa incidence and mortality compared to other European regions [1]. The MeDi contains many bioactive compounds that are likely to protect against PCa. To better understand the underlying scientific foundation of the cancer-protective benefits of the MeDi, it seems important to direct research efforts in specifying the characteristics and functions involving beneficial bioactive constituents.

There are a few studies that have assessed the effect of the MeDi on cancer prostate incidence. A comprehensive review of studies on cancer and the Mediterranean dietary pattern in the Mediterranean region incidence [2] concluded that adherence to principles of the MeDi may significantly reduce PCa incidence. Trichopoulou et al. used effect estimates from studies of dietary intake and cancer in the Mediterranean region, incidence rates of PCa, and food consumption patterns to calculate the fraction of PCa incidence that could be avoided by adherence to the principles of the MeDi. They estimated that approximately 10% of PCa cases in the United States could be prevented by adherence to the traditional healthy MeDi. Kenfield et al. [3] described that adherence to a MeDi evaluated through a Mediterranean diet score (MDS) was not associated with risk of advanced PCa or disease progression in a prospective study following 47,867 US men in the Health Professionals Follow-up Study. However, greater adherence to the MeDi after diagnosis of nonmetastatic cancer was associated with lower overall mortality. Bosire et al. [4] examined the relationship between diet quality and the risk of PCa in the National Institutes of Health (NIH)-AARP Diet and Health Study cohort (293,464 US men) using the alternate Mediterranean diet score (aMED). There was no association between total PCa and the aMED score (HR = 0.97, 95% CI: 0.91, 1.03, p = .09). In addition, it was found little support for an association between the MeDi and PCa in a Northern European case-control study [5]. Recently, Ax et al. [6] studied the relationship between adherence to a modified Mediterranean diet score (mMDS) and PCa risk in the Uppsala Longitudinal Cohort Study of Adult Men. No associations were found between Mediterranean dietary patterns and PCa in the whole study population (HR = 1.0, 95% CI: 0.75–1.34; p = .91).

The MeDi contains many bioactive compounds that are likely to protect against PCa. To better understand the underlying scientific foundation of the cancer-protective benefits of the MeDi, it seems important to direct research efforts in specifying the characteristics and functions involving beneficial bioactive constituents. Therefore, the purpose of this review is to examine the evidence to date on the effects of bioactive constituents of the MeDi on PCa risk.

Methods

The search for articles came from extensive research in the following databases: PubMed, Scopus, and Web of Science. We focus on MeDi bioactive compounds which have been associated in numerous studies with PCa risk. We used the search terms “Mediterranean diet,” “lycopene,” “vitamin E,” “vitamin C,” “Selenium,” “resveratrol,” “prostate cancer,” and combinations, such as “lycopene and prostate cancer” or “resveratrol and prostate cancer.” The titles and abstracts of the located documents were initially reviewed and the reference lists of selected papers were searched to identify additional articles. We narrowed the search to studies published in English. From an initial 150 potentially relevant articles, we included 88 studies in our analysis.

Results and discussion

Components of the Mediterranean diet and prostate cancer

The MeDi’s key characteristics are high intake of vegetables, legumes, fruits, and cereals; moderate to high intake of fish; low intake of saturated lipids and high intake of unsaturated lipids, particularly olive oil; low to moderate intake of dairy products, low intake of meat; and modest intake of ethanol, mostly in the form of wine. There is evidence that specific components of MeDi are involved in prostate carcinogenesis prevention.

Olive oil is the major common characteristic of diet in Mediterranean populations. An Australian case-control study compared subjects consuming <0.25 and ≥0.25 L/month to non-users of olive oil, and reported no significant association between olive oil consumption and PCa risk (both ORs = 0.8) [7]. However, increasing levels of MUFA-rich vegetable oil intake were associated with a progressive reduction in PCa risk [8].

Fish consumption is a characteristic component of the traditional MeDi. Cross-national studies showed inverse associations between per capita consumption of fish and the incidence of and mortality rates from PCa [9,10], and a case-control study found an inverse association between PCa risk and the intake of fish [11]. Pre-clinical studies utilizing xenografts and genetically engineered mouse models demonstrated that reducing dietary fat from corn oil and increasing fish oil intake delays the development and progression of PCa [12,13].

Fruits and vegetables are an important element of the MeDi and are rich in fiber, micronutrients, and phytochemicals which may have anti-carcinogenic actions [14]. A few case-control studies, such as Pascual-Geler et al. [11] have reported an overall inverse association between intake of fruits and vegetables and the risk for advanced PCa. However, the results from cohort studies examining the association between intake of fruits and vegetables and the risk of advanced PCa were largely inconsistent [15].

Cereals and legumes are the main energy sources in the MeDi. It should be noted that high consumption of these foods, increases the intake of vegetable fiber, which is involved in the neoplastic risk by reducing the glycemic load, improving insulin sensitivity, and decreasing the concentration of IGF-1 [16]. Deschasaux et al. [17] showed that PCa risk was inversely associated with legume fiber intakes (HR = 0.55, 95% CI: 0.32–0.95; p = .04). In contrast, there was no significant association between PCa risk and cereal fiber (p = .7).

Mediterranean eating also typically includes low to moderate consumption of dairy products. The positive association between dairy product intake and PCa has been reported in several studies, including the European Prospective Investigation into Cancer and Nutrition [18] and studies in Canada [19] and Japan [20].

MeDi is associated with moderate alcohol consumption, especially of red wine, usually at meals. Red wine contains high concentrations of polyphenols and potent antioxidants that are particularly prevalent in the skin and seed of grapes and may alter cell growth. While many epidemiologic studies have investigated associations between alcohol consumption and PCa with largely null results, fewer have investigated associations between specific alcoholic beverages, such as red wine, and PCa [21]. These studies did not find any appreciable role for moderate red wine drinking on the risk of PCa [21–26].

MeDi also includes food rich in phytoestrogens [27], which lower the symptoms of benign prostate hyperplasia [28] and isoflavones may make males less prone to develop PCa [29].

Bioactive components of Mediterranean diet and prostate cancer

The high content of bioactive phytochemicals in the MeDi is of particular interest in the prevention of cancer. Next, it has been described as the involvement of selected specific compounds that are typical of a Mediterranean eating pattern in PCa prevention. Table 1 summarizes the characteristics of studies that analyze the effect of the principal MeDi bioactive components that are related to PCa prevention.

Table 1. Description of the studies that have assessed the effect of the principal MeDi bioactive components that are related to PCa prevention.

Nutrient	Reference	Country	Subjects	Results	Statistical results
Lycopene	[75]	USA	Prospective study N = 51,529 males Aged 40–75 years	Dietary intake of lycopene was associated with reduced risk of lethal PCa and with a lesser degree of angiogenesis in the tumor	For lethal PCa: HR = 0.47; 95% CI = 0.29–0.75; p=.009
	[74]	Canada	Case-cohort study N = 661 cases, 1864 subcohort	Intake of lycopene was associated with a reduced risk of PCa	HR= 0.71, 0.77 and 0.77 This observation was slightly stronger and statistically significant when analysis was restricted to incident cases identified after 2 years of follow-up.
Vitamin E	[37]	USA	NIH-AARP diet and health study Prospective study N  =  295,314	Dietary γ-tocopherol was significantly inversely related to the risk of advanced PCa	OR = 0.68; 95% CI, 0.56–0.84; p = .001
	[39]	USA	CLUE I Case-control observational study N = 182 cases, 364 controls	Concentrations of α-tocopherol were slightly lower in cases but differences were not statistically significant γ-tocopherol was significantly lower in cases	p = .02
	[39]	USA	CLUE II Case-control observational study N = 142 cases, 284 controls	Concentrations of α-tocopherol were slightly lower in cases but differences were not statistically significant γ-tocopherol was significantly lower in cases than in controls	p = .0001
	[32]	US, Canada,and Puerto Rico	N = 35,533 SELECT	PCa incidence was increased in men receiving only the α-T supplement	HR = 1.17; 99% CI = 1.004–1.36, p = .008
Se	[67]	USA	N = 621 Se supplementation, 629 placebo	PCa incidence was significantly reduced by selenium supplementation (Se yeast 200 µg/1x/d)	HR = 0.48, 95% CI = 0.28–0.80; p = .005
	[65]	USA	N = 621 Se supplementation, 629 placebo	The Se supplementation (Se yeast, 200 µg/1x/d) reduced significant (49%) PCa incidence	RR = 0.51; 95% CI = 0.29–0.88; p = .009
	[66]	USA	N = 653 Se supplementation, 659 placebo	Men receiving supplemental Se in the form of high-Se yeast (200 µg of Se/d) had 50% reduced incidence of PCa	RR = 0.37; 95% CI = 0.18–0.71; p = .002
	[55]	USA	N = 249 cases, 249 controls	Serum Se was inversely related to the risk of PCa	OR = 0.5; 95% CI= 0.3– 0.9; p = .02. RR comparing highest (≥147.2 ng/mL) to lowest quartile (119.32 ng/mL) of plasma Se
	[59]	USA	N = 52 cases, 996 controls	Low plasma Se is associated with a 4 to5-fold increased risk of PCa	OR = 0.24; CI: 0.08–00.77; p = .01 RR comparing highest (13.3–18.2 μg/dl) with the lowest quartile (range 8.2–10.7 μg/dl) of plasma Se
	[58]	USA	N = 212 cases, 233 controls	Serum Se was inversely associated with risk of PCa	OR = 0.71; 95% CI 0.39–1.28; p = .11 RR comparing highest (≥151 µg/mL) to lowest quartile (≤0.119 µg/mL) of plasma Se
	[57]	USA	N = 181 cases, 181controls	Serum Se was inversely associated with risk of advanced PCa	OR = 0.49; 95% CI = 4 0.25–0.96; p = .11 OR for comparison of highest (0.94–7.09 ppm) to lowest quintile (0.53–0.73 ppm) of toenails Se level.
	[56]	USA	N = 117 cases, 233 controls	The risk of PCa was lower among men with higher concentrations of Se	OR = 0.38; 95% CI= 0.17–0.85; p=.12 OR comparing highest (0.91 ppm) to lowest quintile (0.69 ppm) of toenail concentration for Se
	[54]	Netherlands	N = 540 cases, 1211 controls	Higher Se intake may reduce PCa risk	RR = 0.69; 95% CI= 0.48–0.99; p = .008 RR comparing highest (>0.616 µg/g) to lowest toenail selenium quintile (≤0.467 µg/g)
	[53]	USA	N = 586 cases, 577 controls	Serum Se was inversely associated PCa risk	OR = 0.78; 95% CI = 0.54–01.13, p trend = .16) OR comparing highest (0.12–0.19 ppm) to lowest (0.06–0.09 ppm) plasma selenium quintile
	[61]	USA	724 cases, 879 controls	In smokers high serum Se concentrations were related to reduced PCa risk	OR = 0.65; 95% CI: 0.44, 0.97; p = .09 OR comparing the highest (≥158.0–253.0 ng/mL) with the lowest quartile (50.5–126.8 ng/mL) of plasma Se. An inverse association between Se and PCa cancer in smokers

PCa: prostate cancer; HR: Hazard ratio; OR: odds ratio; CI: confidence interval.

Vitamin E and C

The MeDi is high in antioxidants, such as Vitamin C and E which are a key component of many plant foods. The major dietary sources of vitamin E are fruits, vegetables, nuts, and oils. Vitamin E is known to inhibit lipid peroxidation eventually protecting DNA from damage involved in the pathogenesis of cancer [30]. There are different forms of vitamin E: four tocopherols (α-T, β-T, δ-T, and γ-T) and four tocotrienols (α, β, δ, and γ). All the tocopherols are antioxidants but γ-T and δ-T are more effective that α-T in the catching of reactive oxygen and nitrogen species [31].

The effect of dietary and supplemental vitamin E on PCa in humans is not well understood. Many clinical studies have reported findings on vitamin E and PCa [32–38]. Observational studies have shown an inverse association between dietary or blood levels of tocopherols and risk of PCa [31]. Two nested case-control studies reported significant inverse association between levels of γ-T and PCa, but not with α-T [39]. Furthermore, the National Institute of Health-American Association of Retired Persons Diet and Health Study detected that dietary γ-T and δ-T were found to be significantly related to a reduced risk of advanced PCa [37].

Studies on vitamin E supplemental consumption have reported inconsistent results. The Alpha-Tocopherol-Beta-Carotene Cancer Prevention Study (ATBC) found that α–T supplementation decreased risk and mortality from PCa [34]. However, the selenium and vitamin E cancer prevention trial (SELECT) showed that men taking vitamin E supplement had a 17% increased risk of PCa compared to men taking the placebo. Further studies have been performed in order to assess the relationship between vitamin E supplement and PCa, suggesting that supplemental vitamin E does not protect against PCa [37–39].

Vitamin C is a water-soluble vitamin commonly known as an antioxidant. Vitamin C is found in abundance in fruit, such as oranges, grapefruit, and lemons, and in green leafy vegetables, tomatoes, potatoes, strawberries, and red or green peppers. It has been shown that vitamin C prevents oxidative damage to cells by scavenging free radicals, recycles vitamin E, and inhibits the growth and viability of PCa cells [40]. In the Physicians’ Health Study II, a randomized, double-blind, placebo-controlled factorial trial of vitamin C a total of 14,641 male physicians in the United States initially aged 50 years or older, including 1307 men with a history of prior cancer at randomization, were enrolled. Individual supplements of 500 mg of vitamin C were consumed daily for eight years. There was no significant effect of vitamin C on PCa (9.4 cases per 1000 person-years; HR = 1.02, 95% CI: 0.90–1.15; p = .80) [33]. Two prospective [41,42] and three case-control [43–45] studies of dietary or supplemental vitamin C and PCa have been reported. Of these, two case-control studies [43,44] reported reduced PCa risk associated with vitamin C intake, while other studies reported no association. The study by McCann et al. [44] found that the effect of vitamin C was attenuated after adjusting for total vegetable intake, while the other study made no such adjustments. Thus it seems likely that vitamin C does not influence PCa risk, but rather may indicate vegetable intake [46].

Selenium

Numerous studies investigating the effect of various dietary nutrients on PCa have suggested that selenium (Se) is probably the most promising [40,47,48]. Dietary sources of selenium include fish, meat, eggs, and cereals (whole grains). The major determinant factor in the plasma concentration of Se is the dietary intake, and there is large variation in the selenium content of the same food depending on the geographic regions [49,50]. Marine foods are integral to the Mediterranean eating pattern. Simopoulos [51] reports that the traditional Cretan MeDi of the 1960 s was high in selenium from fish and seafood (particularly octopus) which are likely to protect against PCa.

A systematic review undertaken by an expert panel on behalf of the World Cancer Research Fund and the American Institute for Cancer Research (WCRF–AICR) concluded that selenium and foods containing selenium probably protect against PCa [52]. Selenium’s anti cancerous properties against PCa have been evaluated in in vitro and in vivo studies, epidemiologic and clinical trials. The results of observational studies on selenium in the diet and PCa are inconclusive and there are large variations in the results. In fact, in several studies the concentration of selenium in biological samples showed a protective association [53–59] while other nested case-control studies revealed no relation between selenium biological samples levels and PCa risk [60–62].

There are several clinical studies using the role of nutritional strategies, such as dietary selenium supplementation in PCa prevention. Selenium supplementation has shown to reduce the risk of PCa [63–66], in some cases reducing its incidence to 50% [65,66]. In several studies, the protective effect of selenium on PCa was restricted to men with the lowest plasma selenium concentration at baseline [65–67]. Etminan et al. [68], in a meta-analysis of 16 epidemiologic studies, reported that PCa cases have a lower selenium concentration than controls, concluding that Se intake may prevent the risk of developing PCa. This meta-analysis included studies assessing selenium intake by dietary questionnaires and studies using a selenium supplement in the participants. Similar results were reported by Brinkman et al. [69]. Donaldson [70] recommended for an anticancer diet a supplement of 200 μg/d of selenium.

SELECT, one of the largest studies of chemoprevention for PCa [71], showed the efficacy of daily supplementation with 200 μg selenium. In 2011, Algotar et al. [63] demonstrated that supplementation with selenized yeast for 4–6 weeks significantly increases prostate tissue selenium levels in patients with PCa in a dose-dependent manner. In contrast, other clinical studies showed no effect of selenium supplementation on PCa risk [32,61,72]. The discordance between the clinical studies could be in part due to the different forms of selenium supplement used. A few studies used L-selenomethionine and other high-selenium yeast containing multiple organic and inorganic forms of selenium. Timing and duration of supplement use is also an important determinant of the efficacy. The beneficial effect of dietary selenium and supplements on PCa remains inconclusive. Further studies to determine its efficacy, dose, and formulation of selenium on reducing the risk of PCa are needed.

Lycopene

Lycopene is a carotenoid that forms red pigment in fruit, such as tomatoes, apricots, guavas, pink grapefruits, rosehips, or watermelons, and it forms part of products, such as tomato juice or sauces. Most of the important dietary sources of lycopene are tomato products. It has been suggested that lycopene exhibits antioxidant activities, anti-inflammatory properties, inhibits cell proliferation, and inducts apoptosis, thus protecting against cancer (in particular PCa) and providing health benefits for cancer patients by being considered as an anticarcinogenic and chemopreventive agent [73]. Intake of lycopene was associated with a reduced risk of PCa [48,74].

Some studies have hypothesized that the consumption of a diet rich in lycopene-containing foods reduces the aggressive potential of PCa by inhibiting the neoangiogenesis that occurs in tumor development [75].The main role of lycopene seems to be related to producing a modulation in redox activity, enzyme detoxification, inhibition of cell proliferation, and apoptosis induction [76]. Recent studies have proved that lycopene increased the amount of some protective enzymes, such as glutathione-S-transferase-omega-1, peroxiredoxin-1, and sulfide-quinone oxidoreductase. Proteins, such as ERO1-like protein-α or CLIC-1, usually involved in reactive oxygen species generation, have been shown to be downregulated after treatment with lycopene. This indicates a potential for lycopene to lower the risk for the generation of reactive oxygen species and to reduce oxidative stress [73].

Resveratrol

Resveratrol is a polyphenolic phytoalexin that can be found in plants like grapes, peanuts, and mulberries [77]. It has a broad range of biological activities, such as anti-oxidative and anti-inflammatory activity, cardiovascular protection, and cancer prevention [78]. Its cancer prevention activity was discovered in 1997 by Jang [79], reporting that it inhibits the carcinogenic process at its stages of initiation, promotion, and progression. Since this discovery, there has been plenty of research regarding resveratrol and different types of cancer including PCa.

It has been shown that diet and lifestyle may be of major importance in the development of PCa [80], making a supplement, such as resveratrol a candidate for PCa prevention [81]. Nevertheless, there are few in vivo studies that focus on the effects of resveratrol on PCa prevention and treatment [81]. Recently, two reviews studied the relationship between resveratrol and PCa [81,82]. The first focuses on the prevention of PCa, including resveratrol as one promising element, while the latter focuses on resveratrol and cancer on in vivo evidence, including PCa. Carter et al. [81] cite two studies that have used rodent models of spontaneous prostate tumor formation [83,84] and three studies that have used xenograft models [78,83,85]. None of the studies in rodent models found significant differences regarding tumor incidence, but in both studies there was a significantly reduced tumor development in the resveratrol-fed rodents. In xerograph models [78] found positive effects of resveratrol regarding PCa tumorigenesis. On the contrary, Wang et al. [85] found that resveratrol promoted angiogenesis and inhibition of apoptosis. Many in vitro and in vivo studies show that resveratrol inhibits PCa development in one way or another [83,85–90]. Nevertheless, it has also been found to reduce the survival of mice in LAPC4 xenograft model, while survival in LnCaP xenografts did not change [91], and the implications of these different results in these xenografts models are not clear [82].

Nevertheless, the therapeutic effectiveness of resveratrol is limited due to its low bioavailability and extensive metabolic clearance [82]. In fact, structural analogs of resveratrol with better bioavailability are being studied as potential therapeutic agents for cancer [77].

Conclusion

Epidemiological studies have suggested that MeDi can lead to a reduction of the incidence of major diseases, such as cancer and better physical and cognitive functions in older adults [92,93]. Furthermore, MeDi may play a role in PCa etiology because of the wide variation in its incidence across the European Union. There is strong evidence supporting associations between bioactive components that are typical of a Mediterranean eating pattern and reduced PCa risk; therefore, it could be argued that a combination of these compounds, as would be achieved in a Mediterranean eating pattern, would have synergistic effect providing greater protection against PCa. Further large-scale studies are required to clarify the effect of MeDi bioactive compounds on prostate health, in order to establish the role of this diet in the prevention of PCa.

Acknowledgments

This article will be part of Noelia Urquiza-Salvat's doctorate, which is being completed as part of the Doctorate Program in Pharmacy in the research line “Nuevas Dianas Terapéuticas” at the University of Granada, Spain.

Disclosure statement

Authors have nothing to disclose.

Additional information

Funding

This research received no specific grant from any funding agency, commercial or not-for-profit sectors.