**4. Carotenoids and prostate cancer**

Fruits and vegetables supply dietary carotenoids, which are potent antioxidants as they modify cell growth and induce apoptosis [8]. Epidemiological studies indicate that consuming more fruits and vegetables containing plant carotenoids such as beta-carotene and lycopene may decrease the risk of prostate cancer as indicated by an inverse association [21, 29–31]. In addition to these two carotenoids, alpha-carotene, beta-cryptoxanthin, zeaxanthin, and lutein are commonly studied because of their potential protective benefit, although lycopene and, to some extent, beta-carotene have demonstrated so far the strongest evidence while that of the others have proven inconclusive [32, 33].

Carotenoids possess distinctive antioxidative properties including the protection of important biomolecules such as DNA from free radicals [34]. Peto et al. in 1981 hypothesized that β-carotene from vegetables and fruits could possibly decrease incidence rates of human cancers [35], and subsequently, there have been a number of epidemiological studies addressing this topic [7, 36, 37]. For many years, carotenes such as alpha-carotene and beta-carotene have been investigated relating to prostate cancer risk, but the results have proved mostly inconclusive.

#### **4.1 Beta-carotene**

Several epidemiological studies have investigated the relationship between beta-carotene and prostate cancer risk [38–48]. In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, subjects receiving beta-carotene supplementation had a 23% increase in prostate cancer incidence and 15% higher mortality from the disease [17]. However, during the postintervention follow-up, the effect of supplemental beta-carotene was no longer evident (RR 1.01, 95% CI: 0.96–1.05) [44]. In a case-control study involving men with primary histologically confirmed prostate cancer and population-based controls, beta-carotene (OR 0.60, 95% CI: 0.47–0.97) and alpha-carotene (OR 0.67, 95% CI: 0.47–0.97) were inversely associated with the risk of prostate cancer. Similarly, dietary beta-carotene intake had a protective effect for prostate cancer (RR 0.30, 95% CI: 0.13–0.66) among subjects younger than 68 years of age in a case control study conducted in the United States [47] (**Table 1**) and another in Japan [43]. In a recent study, circulating beta-carotene (RR 0.55, 95% CI: 0.28–1.08) and alpha-carotene (RR 0.31, 95% CI: 0.15–0.63) were inversely associated with risk of high-grade prostate cancer, especially among those with specific somatic variations [39] (**Table 1**).

**223**

**Table 1.**

*Dietary Antioxidants in the Chemoprevention of Prostate Cancer*

**Year of study**

1989 β-carotene

2016 β-carotene

2018 Lycopene

2005 β-carotene

2014 α-carotene

2012 β-carotene

2002 β-carotene

2003 β-carotene

2018 β-carotene

2017 β-carotene

2015 α-carotene

*RR = relative risk, CI = confidence interval, P.R.E = percentage relative effect, Sel. Sup = selenium supplement.*

Zu et al. [54] 2014 Lycopene

(sup.)

(diet) α-carotene (diet) Lycopene (diet)

(diet)

(diet) α-carotene (diet) Lycopene (diet)

(diet)

(serum)

(diet)

(diet)

(diet)

(diet)

(serum)

(diet) Lycopene (diet)

**Carotenoids Risk 95% CI P.R.E** 

RR = 0.31 RR = 0.34 RR = 0.55

OR = 0.53 OR = 0.67 OR = 0.62

RR = 0.60 0.47–0.97 40%

0.15–0.63 0.18–0.66 0.28–1.08

OR = 0.46 0.27–0.77 54%

0.36–0.79 0.47–0.97 0.37–0.81

OR = 0.50 0.26–0.98 50%

RR = 2.29 1.12–4.66 129%

HR = 0.72 0.56–0.94 28%

0.84 0.73–0.96 16%

RR = 1.07 1.02–1.12 7%

OR = 0.94 0.89–1.00 6%

RR = 0.88 0.79–0.98 12%

0.76–0.99 0.75–0.98 13% 14%

2015 β-carotene RR = 0.65 0.46–0.91 35%

RR = 0.87 RR = 0.86 **outcome**

69% 66% 45%

47% 33% 38%

There are epidemiological studies that have found no protective effect of carotenes on prostate cancer risk [7, 21, 44–50]. In a recent case-control study involving incident prostate cancer patients, no statistically significant was observed for dietary beta-carotene intake as well as for alpha-carotene and beta-cryptoxanthin [45]. In the Japan Collaborative Cohort study, beta-carotene had no protective effect

*DOI: http://dx.doi.org/10.5772/intechopen.85770*

**author(s)**

Mettlin et al. [47]

Nordstrom et al. [43]

Van Hoang et al. [45]

McCann et al. [66]

Umesawa et al. [46]

Karppi et al. [50]

Giovanucci et al. [53]

Virtamo et al. [44]

Catano et al. [56]

Rowles et al. [58]

> Key et al. [21]

Wang et al. [33]

*Showing studies on the effect of carotenoids on prostate cancer.*

Randomized control trial

Meta-analysis

**Method Name of** 

Case-control

Cohort


#### *Dietary Antioxidants in the Chemoprevention of Prostate Cancer DOI: http://dx.doi.org/10.5772/intechopen.85770*

*Antioxidants*

cancer.

**4.1 Beta-carotene**

confer prostate cancer risk.

**4. Carotenoids and prostate cancer**

the others have proven inconclusive [32, 33].

with specific somatic variations [39] (**Table 1**).

metabolism [18, 27]. Furthermore, it was found that genetic variation in SOD genes responsible for detoxifying superoxide free radicals and protecting cells from oxidative stress may be associated with an increased risk of high-grade prostate cancer and disease recurrence [18]. Similarly, it was shown that single nucleotide polymorphisms (SNPS) in genes associated with vitamin E metabolism such as SEC14L2, SOD1, and TTPA may influence an individual's response to vitamin E supplementation and associated prostate cancer risk [28]. As such, inherited genotypes may

It is therefore anticipated that clinical trials will be undertaken with vitamin E isomers combination therapy for further assessment of prostate cancer risk. It may be useful to conduct more studies including isomers other than alpha-tocopherol. Men with a strong family history of prostate cancer should undergo genetic testing, to identify antioxidant gene mutations that may be implicated in prostate

Fruits and vegetables supply dietary carotenoids, which are potent antioxidants

Carotenoids possess distinctive antioxidative properties including the protection of important biomolecules such as DNA from free radicals [34]. Peto et al. in 1981 hypothesized that β-carotene from vegetables and fruits could possibly decrease incidence rates of human cancers [35], and subsequently, there have been a number of epidemiological studies addressing this topic [7, 36, 37]. For many years, carotenes such as alpha-carotene and beta-carotene have been investigated relating to

Several epidemiological studies have investigated the relationship between beta-carotene and prostate cancer risk [38–48]. In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, subjects receiving beta-carotene supplementation had a 23% increase in prostate cancer incidence and 15% higher mortality from the disease [17]. However, during the postintervention follow-up, the effect of supplemental beta-carotene was no longer evident (RR 1.01, 95% CI: 0.96–1.05) [44]. In a case-control study involving men with primary histologically confirmed prostate cancer and population-based controls, beta-carotene (OR 0.60, 95% CI: 0.47–0.97) and alpha-carotene (OR 0.67, 95% CI: 0.47–0.97) were inversely associated with the risk of prostate cancer. Similarly, dietary beta-carotene intake had a protective effect for prostate cancer (RR 0.30, 95% CI: 0.13–0.66) among subjects younger than 68 years of age in a case control study conducted in the United States [47] (**Table 1**) and another in Japan [43]. In a recent study, circulating beta-carotene (RR 0.55, 95% CI: 0.28–1.08) and alpha-carotene (RR 0.31, 95% CI: 0.15–0.63) were inversely associated with risk of high-grade prostate cancer, especially among those

as they modify cell growth and induce apoptosis [8]. Epidemiological studies indicate that consuming more fruits and vegetables containing plant carotenoids such as beta-carotene and lycopene may decrease the risk of prostate cancer as indicated by an inverse association [21, 29–31]. In addition to these two carotenoids, alpha-carotene, beta-cryptoxanthin, zeaxanthin, and lutein are commonly studied because of their potential protective benefit, although lycopene and, to some extent, beta-carotene have demonstrated so far the strongest evidence while that of

prostate cancer risk, but the results have proved mostly inconclusive.

**222**

*RR = relative risk, CI = confidence interval, P.R.E = percentage relative effect, Sel. Sup = selenium supplement.*

#### **Table 1.**

*Showing studies on the effect of carotenoids on prostate cancer.*

There are epidemiological studies that have found no protective effect of carotenes on prostate cancer risk [7, 21, 44–50]. In a recent case-control study involving incident prostate cancer patients, no statistically significant was observed for dietary beta-carotene intake as well as for alpha-carotene and beta-cryptoxanthin [45]. In the Japan Collaborative Cohort study, beta-carotene had no protective effect as there was no association with prostate cancer risk [46]. However, there are studies that have reported an adverse rather than a protective effect of beta-carotene on prostate cancer. In the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) cohort study conducted in Japan among middle-aged men, the highest levels of serum beta-carotene resulted in a 2.29-fold (RR 2.29, 95% CI: 1.12–4.6; P = 0.023) higher risk of prostate cancer compared to participants with lowest levels of the antioxidant [50]. In the 18-year postintervention follow-up of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, beta-carotene increased the posttrial prostate cancer mortality (RR 1.20, 95% CI: 1.01–1.42) [15] (**Table 1**). Thus, the effect of beta-carotene remains inconclusive and may involve an adverse effect where high serum concentrations may elevate prostate cancer risk and mortality.

#### **4.2 Lycopene**

Lycopene has been reported to possess more effective antioxidant properties compared to the carotenes and alpha-tocopherol [51]. Lycopene in the form of tomato-based products and to a lesser extent as a supplement is extensively studied with regards to risk of prostate cancer; however, the clinical evidence is inconclusive. In the prostate, lung, colorectal, and ovarian cancer screening trials, lycopene consumption decreased the risk of prostate cancer particularly in men with family history [52]. Similarly, in the Health Professionals Follow-Up Study, lycopene consumption was significantly associated with decreased prostate cancer risk (RR for high vs. low quintiles 0.84, 95% CI: 0.73–0.96; P = 0.003), and tomato sauce consumption had a greater reduction [53] (**Table 1**). Other prospective studies have reported that circulating levels of lycopene were inversely associated with highgrade prostate cancer (RR 0.55, 95% CI: 0.28–1.08) [39]; dietary intake of lycopene decreased the risk of lethal prostate cancer by lowering the degree of angiogenesis in the tumor [54], and lycopene consumption was associated with lower prostate cancer-specific mortality among men high-risk disease [55].

A number of meta-analysis sought to examine the efficacy of lycopene intake in primary prevention of prostate cancer. In a recent meta-analysis of 27 studies (22 were case studies), a statistically significant, though weak inverse association, was found between prostate cancer and lycopene [56]. In another systemic review and meta-analysis, circulating lycopene levels between 2.17 and 85 μg/dL were inversely associated with risk of prostate cancer; however, there was no linear association with levels greater than 85 μg/dL [57]. Further supporting evidence of the protective effect of lycopene intake was demonstrated in a recent meta-analysis of 42 studies where higher circulating and dietary lycopene levels were inversely associated with a 12% risk of prostate cancer but not with the advanced disease [58]. Other supporting evidence involves meta-analysis by Key et al. where lycopene though not associated with overall prostate cancer risk results in a 36% significantly lower risk with aggressive disease [21]; and a meta-analysis of 34 studies showed an association between reduced prostate cancer risk and dietary and blood lycopene levels [33]. Furthermore, Mariani et al. reported no overall benefit of decreasing the rate of high-grade prostatic intraepithelial neoplasia (HGPIN) progression from a 6-month lycopene supplementation [59].

Possible pathways involving multiple mechanisms exist through which lycopene intake may reduce prostate cancer risk. Lycopene attenuates prostate cancer risk by modulating the expression of genes such as EGFR, CDK7, BCL2, and IGF-1R which are related to growth and survival [60]. Another study showed that lycopene increases the expression of BCO2, a tumor suppressor which mediates the inhibition of NF-κB signaling [61]. There is also evidence that lycopene can inhibit the proliferation of prostate cancer cell via PPARγLXRα-ABCA1 pathway [62]. Additionally,

**225**

**5.1 Coffee**

*Dietary Antioxidants in the Chemoprevention of Prostate Cancer*

Akt/mTOR cascade, and androgen receptor signaling [65].

lycopene decreases prostate cancer cell proliferation partly by normal inhibition of cell cycle progression [63] and promotes cell cycle arrest in the G0/G1 phase [64]. The chemoprevention mechanism of lycopene could be the regulation of proteins involved in apoptosis, cytoprotection, growth inhibition, antioxidant responses, the

Other carotenoids such as alpha-carotene and that beta-cryptoxanthin have been investigated for possible association with prostate cancer risk. In a case control study, there was reduced risk of prostate cancer with lutein (OR 0.55, 95% CI: 0.37–0.81) and alpha-carotene (OR 0.67, 95% CI: 0.47–0.97) [66]. Nordström et al. found that circulating levels of alpha-carotene (RR 0.31, 95% CI: 0.15–0.63) were associated with decreased risk of prostate cancer [39]. Similarly, alpha-carotene intake was associated with decreased risk of prostate cancer (RR 0.87, 95% CI: 0.76–0.99) [33]. Further, a meta-analysis of 34 studies suggests that dietary

alpha-carotene intake was associated with reduced risk of prostate cancer [14], and a study by Schuurman et al. showed similar findings for beta-cryptoxanthin [7]. However, in a case-control study conducted in Vietnam, there was no statistically significant association between prostate cancer risk and intake of alphacarotene, beta-cryptoxanthin, zeaxanthin, and lutein [44]. Similarly, in the Japan Collaborative Cohort study, dietary alpha-carotene intake was not associated with risk of prostate cancer [46]. The absence of the association of dietary intakes of lutein, beta-cryptoxanthin, and zeaxanthin with prostate cancer risk requires

Dietary polyphenols (PPs) have gained much traction over the last years for their potential as reliable chemopreventive and antitumor agents. This was partly due to their presence in a range of foods and beverages commonly consumed by humans including fruits, vegetables, coffee, tea, and wine [67, 68]. In terms of chemical structure, polyphenols are compounds with at least one aromatic ring with one or more hydroxyl group attached [68]. They are grouped into four different classes based on their chemical structure and orientation of the number of phenolic rings bound to each other. These four classes are as follows: phenolic acids, flavonoids, stilbenes, and curcuminoids [67]. Phenolic acids are found in all plant materials and account for 30% of all polyphenols consumed. They are found mainly in acidictasting fruits, coffee, and green tea. As the most abundant group of polyphenols, flavonoids account for 60% of all polyphenols consumed by humans. Good sources of flavonoids include berries, black tea, all citrus fruits, and wine. Together, phenolic acids and flavonoids are the most abundant dietary polyphenols consumed by humans and, consequently, are the most studied with regard to their health benefits

There are studies that have investigated the relationship between coffee consumption and risk of prostate cancer [55, 69–75]. There are those which have found an inverse relationship between coffee consumption and risk of prostate cancer [73–75]. The "Coffee Consumption and Prostate Cancer Risk Progression in Health Professionals Follow Up" report shows that there is a lower risk for prostate cancer

*DOI: http://dx.doi.org/10.5772/intechopen.85770*

**4.3 Alpha-carotene and beta-cryptoxanthin**

confirmation in future studies.

to conditions including cancer.

**5. Polyphenols and prostate cancer**

lycopene decreases prostate cancer cell proliferation partly by normal inhibition of cell cycle progression [63] and promotes cell cycle arrest in the G0/G1 phase [64]. The chemoprevention mechanism of lycopene could be the regulation of proteins involved in apoptosis, cytoprotection, growth inhibition, antioxidant responses, the Akt/mTOR cascade, and androgen receptor signaling [65].
