Dietary Antioxidants in the Chemoprevention of Prostate Cancer

*Dwayne Tucker, Melisa Anderson, Fabian Miller, Kurt Vaz, Lennox Anderson-Jackson and Donovan McGrowder*

## **Abstract**

Prostate cancer is the second most common cancer and the fifth leading cause of cancer death. The incidence of prostate cancer is rising due to increased screening and awareness, and there is epidemiological evidence suggesting an interaction among biological and environmental risk factors in the development and progression of prostate cancer. Vegetables and fruits provide a wide range of antioxidants and phytochemicals that have been demonstrated to have a negative, positive, or no association with prostate cancer risk. Therefore, it is evident that the effect of dietary antioxidants on risk of prostate cancer remains undecided and inconclusive. The main focus of this review was to examine recent and past literature of the chemoprotective properties of five major groups of phytochemicals against prostate cancer development including both *in vivo* and *in vitro* findings.

**Keywords:** antioxidants, prostate, cancer, risk, association

#### **1. Introduction**

Among men worldwide, prostate cancer is the second most common cancer and the fifth leading cause of cancer death, with an estimated recorded amount of 1.3 million cases and 359,000 deaths in 2018 [1]. The incidence of prostate cancer is rising due to increased awareness and screening, and it is estimated that 42% of prostate cancer cases occur in men over 50 years old [2]. There is epidemiological proof that suggests an interaction among several known biological and environmental risk factors in the development and progression of prostate cancer [3]. These include age, race, family history, genetic risk, socioeconomic status, and modifiable risk factors such as physical activity, obesity, and possibly dietary factors [4].

Oxidative stress defined as an imbalance between prooxidant and antioxidant processes, and interference of the oxidation-reduction circuitry is one of the many proposed underlying mechanisms of prostate carcinogenesis [5, 6]. There is increasing epidemiological data that diet plays a key role in the biology and tumorigenesis of prostate cancer, and higher intake of the main phytochemical-containing diets lowers the risk of the disease [7]. Vegetables and fruits provide a wide range of phytochemicals and antioxidants that have been demonstrated to have a positive effect on decreasing the incidence or averting the occurrence of prostate cancer [8]. Several of these antioxidants may attenuate prostate cancer development, given that oxidative stress from reactive oxygen species and loss of antioxidant enzymes may contribute to genomic instability prior to prostate cancer [9].

This paper will review information in the literature on the relationship between nutrients with antioxidant properties from the diet, and the risk of prostate cancer.

## **2. Method of article selection**

A literature search was conducted for all English language literature published before December 2018. The search was conducted using the electronic databases, including PubMed, Embase, Web of Science, and Cochrane Library. The search strategy included keywords such as prostate cancer, epidemiology, incidence, mortality, risk factor, selenium, vitamin E, vitamin C, carotenoids, and polyphenols.

The authors include many interventional and observational studies that have reported findings of dietary antioxidants, prostate cancer incidence, and progression. The majority of these studies focused on vitamins E and C, carotenoids, specifically beta- and alpha-carotene and lycopene, phenols including tea and coffee, and the flavonoids, as well as selenium.

#### **3. Vitamin E and prostate cancer**

Vitamin E is a potent lipid-soluble antioxidant, which is well recognized for safeguarding the body against free radical-mediated peroxidative damage. It is a naturally occurring essential vitamin mainly found in foods such as nuts, oils, fruits, and vegetables and is available as a dietary supplement. Vitamin E scavenges highly reactive free radical species such as hydroxyls, superoxides, lipid peroxyls, hydroperoxyls, and nitrogen radicals; and prevents lipid peroxidation related to carcinogen-induced DNA damage [10].

It is known that a deficient antioxidant defense system can result in oxidative stress. As such, increased levels of reactive oxygen species over time may have an etiological role in the development of malignancies such as prostate cancer [11]. Vitamin E may therefore be considered as adjuvant therapy for the prevention of prostate cancer [12]. However, despite emerging evidence supporting vitamin E as a powerful antioxidant, its effect on prostate cancer risk remains poorly understood.

Two categories of vitamin E compounds exist: tocopherols (α, β, γ, and δ-Toc) and tocotrienols (α, β, γ, and δ-T3) [12]. Despite structural differences between both categories, tocopherols and tocotrienols each have sufficient antioxidant properties [12].

#### **3.1 Alpha-, gamma-, and delta-tocopherols**

Alpha-tocopherol accounts for the most abundant and active isoform of vitamin E in human tissues and is the most widely used in dietary supplements [10]. Alphatocopherol terminates free radical chain reactions by transferring hydrogen protons to free radicals yielding nonradical products [13]. Fairly stable alpha-tocopheroxyl radicals are generated, which do not react with polyunsaturated fatty acids but with each other or couples with other free radicals to form nonradical products [13]. The generation of nonradical products by vitamin E may therefore provide a protective effect against free radical-mediated cell membrane damage and consequently reduces mutagenesis and carcinogenesis.

A number of studies have reported findings on vitamin E supplementation (alpha-, gamma-, and delta-tocopherols) and risk of prostate cancer [14–18].

**221**

*Dietary Antioxidants in the Chemoprevention of Prostate Cancer*

Notably, in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC), daily supplementation of alpha-tocopherol (50 mg) reduced the risk of prostate cancer [17] and moderate dose decreased posttrial mortality [15]. However, a follow-up of the Physicians Health Study II, a large-scale randomized trial, suggested that vitamin E supplementation had no immediate or long-term effect on the incidence of prostate cancer (HR 0.99; 95% CI: 0.89–1.10) [14]. Conversely, findings from the large-scale selenium and vitamin E cancer prevention trial (SELECT) demonstrated that the risk of prostate cancer was significantly increased with dietary vitamin E supplementation containing alpha-tocopherol [16]. However, it was found that the incidence of prostate cancer did not increase in men who received combination therapy of vitamin E and selenium [19]. As such, it can be speculated that there may be a synergistic effect between both antioxidants which attenuates prostate cancer risk [19]. The increased risk of the disease associated with vitamin E therapy could be attributed to the disturbance of the normal physiological balance of vitamin E isomers by the high dosage of alpha-tocopherol, which may result in depletion of other important isomers such as gamma-tocopherol [20]. Studies have supported that gamma-tocopherol may have more superior chemopreventive effects than alpha-tocopherol, considering its stronger antiinflammatory and antinitrative effects [12]. However, it is important to note that analysis of 15 prospective studies involving data for prostate cancer cases and controls and using risk estimation by multivariable-adjusted conditional logistic regression found that gamma-tocopherol was not associated with risk of aggressive prostate cancer, and the latter was inversely associated with alpha-tocopherol [21]. As such, it was suggested that the protective effect against prostate cancer may be lost with impaired balance of vitamin E isomers [20]. Findings from the SELECT trial were later recapitulated, as alpha-tocopherol was found to upregulate prostate cancer cell proliferation in the early stages of the disease [22]. It was found that premalignant rather than benign or malignant prostate cells had increased proliferation in response to vitamin E [22]. These data indicate that the effect of vitamin E antioxidant activity may be dependent on the stage of the prostate cells in the tumor development process [22]. Conversely, it was later found that combination therapy of delta-tocotrienol and gamma-tocopherol was efficacious in inhibiting the proliferation of prostate cancer cells by apoptosis and cell cycle arrest in the G1

A recent study conducted on mice revealed that delta-tocopherol and not alphatocopherol blocks the activation of the Akt pathway which drives tumorigenesis, inhibiting the survival of prostate cancer cells [23]. Another study which supports the chemopreventative activity of delta-tocopherol is that of Wang et al. which reported a novel mechanism by which this antioxidant inhibits prostate cancer cell growth by the attenuation of EGF/IGF-induced activation of Akt on T308 [24]. In examining the efficacy of other tocopherol, gamma-tocopherol (0.3% in diet) supplementation was found to significantly reduce the development of mouse prostatic intraepithelial neoplasia lesions and 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine-induced elevation of nitrotyrosine, 8-oxo-deoxyguanosine, p-Akt,

There is supporting evidence that gamma-tocopherol significantly inhibits the growth of human prostate PC-3 tumor cell line by decreasing progression into the S-phase, upregulation of transglutaminase 2 and downregulation of (TG2), and downregulation of cyclin D1 and cyclin E levels [26]. These findings suggest that different isoforms of vitamin E may differ in their influence on prostate cancer risk and that alpha-tocopherol supplementation alone may increase the risk of the disease. It was reported that the association between vitamin E and prostate cancer risk may be linked to genetic variation in genes that regulate antioxidant and vitamin E

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

and G2/M phases of the cell cycle [12].

Ki-67 and COX-2, and the loss of Nrf2 and PTEN [25].

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

*Antioxidants*

**2. Method of article selection**

coffee, and the flavonoids, as well as selenium.

**3. Vitamin E and prostate cancer**

carcinogen-induced DNA damage [10].

**3.1 Alpha-, gamma-, and delta-tocopherols**

reduces mutagenesis and carcinogenesis.

oxidative stress from reactive oxygen species and loss of antioxidant enzymes may

This paper will review information in the literature on the relationship between nutrients with antioxidant properties from the diet, and the risk of prostate cancer.

A literature search was conducted for all English language literature published before December 2018. The search was conducted using the electronic databases, including PubMed, Embase, Web of Science, and Cochrane Library. The search strategy included keywords such as prostate cancer, epidemiology, incidence, mortality, risk factor, selenium, vitamin E, vitamin C, carotenoids, and polyphenols. The authors include many interventional and observational studies that have reported findings of dietary antioxidants, prostate cancer incidence, and progression. The majority of these studies focused on vitamins E and C, carotenoids, specifically beta- and alpha-carotene and lycopene, phenols including tea and

Vitamin E is a potent lipid-soluble antioxidant, which is well recognized for safeguarding the body against free radical-mediated peroxidative damage. It is a naturally occurring essential vitamin mainly found in foods such as nuts, oils, fruits, and vegetables and is available as a dietary supplement. Vitamin E scavenges highly reactive free radical species such as hydroxyls, superoxides, lipid peroxyls, hydroperoxyls, and nitrogen radicals; and prevents lipid peroxidation related to

It is known that a deficient antioxidant defense system can result in oxidative stress. As such, increased levels of reactive oxygen species over time may have an etiological role in the development of malignancies such as prostate cancer [11]. Vitamin E may therefore be considered as adjuvant therapy for the prevention of prostate cancer [12]. However, despite emerging evidence supporting vitamin E as a powerful antioxidant, its effect on prostate cancer risk remains poorly understood. Two categories of vitamin E compounds exist: tocopherols (α, β, γ, and δ-Toc) and tocotrienols (α, β, γ, and δ-T3) [12]. Despite structural differences between both categories, tocopherols and tocotrienols each have sufficient antioxidant

Alpha-tocopherol accounts for the most abundant and active isoform of vitamin E in human tissues and is the most widely used in dietary supplements [10]. Alphatocopherol terminates free radical chain reactions by transferring hydrogen protons to free radicals yielding nonradical products [13]. Fairly stable alpha-tocopheroxyl radicals are generated, which do not react with polyunsaturated fatty acids but with each other or couples with other free radicals to form nonradical products [13]. The generation of nonradical products by vitamin E may therefore provide a protective effect against free radical-mediated cell membrane damage and consequently

A number of studies have reported findings on vitamin E supplementation (alpha-, gamma-, and delta-tocopherols) and risk of prostate cancer [14–18].

contribute to genomic instability prior to prostate cancer [9].

**220**

properties [12].

Notably, in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC), daily supplementation of alpha-tocopherol (50 mg) reduced the risk of prostate cancer [17] and moderate dose decreased posttrial mortality [15]. However, a follow-up of the Physicians Health Study II, a large-scale randomized trial, suggested that vitamin E supplementation had no immediate or long-term effect on the incidence of prostate cancer (HR 0.99; 95% CI: 0.89–1.10) [14]. Conversely, findings from the large-scale selenium and vitamin E cancer prevention trial (SELECT) demonstrated that the risk of prostate cancer was significantly increased with dietary vitamin E supplementation containing alpha-tocopherol [16]. However, it was found that the incidence of prostate cancer did not increase in men who received combination therapy of vitamin E and selenium [19]. As such, it can be speculated that there may be a synergistic effect between both antioxidants which attenuates prostate cancer risk [19]. The increased risk of the disease associated with vitamin E therapy could be attributed to the disturbance of the normal physiological balance of vitamin E isomers by the high dosage of alpha-tocopherol, which may result in depletion of other important isomers such as gamma-tocopherol [20].

Studies have supported that gamma-tocopherol may have more superior chemopreventive effects than alpha-tocopherol, considering its stronger antiinflammatory and antinitrative effects [12]. However, it is important to note that analysis of 15 prospective studies involving data for prostate cancer cases and controls and using risk estimation by multivariable-adjusted conditional logistic regression found that gamma-tocopherol was not associated with risk of aggressive prostate cancer, and the latter was inversely associated with alpha-tocopherol [21]. As such, it was suggested that the protective effect against prostate cancer may be lost with impaired balance of vitamin E isomers [20]. Findings from the SELECT trial were later recapitulated, as alpha-tocopherol was found to upregulate prostate cancer cell proliferation in the early stages of the disease [22]. It was found that premalignant rather than benign or malignant prostate cells had increased proliferation in response to vitamin E [22]. These data indicate that the effect of vitamin E antioxidant activity may be dependent on the stage of the prostate cells in the tumor development process [22]. Conversely, it was later found that combination therapy of delta-tocotrienol and gamma-tocopherol was efficacious in inhibiting the proliferation of prostate cancer cells by apoptosis and cell cycle arrest in the G1 and G2/M phases of the cell cycle [12].

A recent study conducted on mice revealed that delta-tocopherol and not alphatocopherol blocks the activation of the Akt pathway which drives tumorigenesis, inhibiting the survival of prostate cancer cells [23]. Another study which supports the chemopreventative activity of delta-tocopherol is that of Wang et al. which reported a novel mechanism by which this antioxidant inhibits prostate cancer cell growth by the attenuation of EGF/IGF-induced activation of Akt on T308 [24]. In examining the efficacy of other tocopherol, gamma-tocopherol (0.3% in diet) supplementation was found to significantly reduce the development of mouse prostatic intraepithelial neoplasia lesions and 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine-induced elevation of nitrotyrosine, 8-oxo-deoxyguanosine, p-Akt, Ki-67 and COX-2, and the loss of Nrf2 and PTEN [25].

There is supporting evidence that gamma-tocopherol significantly inhibits the growth of human prostate PC-3 tumor cell line by decreasing progression into the S-phase, upregulation of transglutaminase 2 and downregulation of (TG2), and downregulation of cyclin D1 and cyclin E levels [26]. These findings suggest that different isoforms of vitamin E may differ in their influence on prostate cancer risk and that alpha-tocopherol supplementation alone may increase the risk of the disease.

It was reported that the association between vitamin E and prostate cancer risk may be linked to genetic variation in genes that regulate antioxidant and vitamin E 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 confer prostate cancer risk.

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 cancer.
