Dietary Agents in the Chemoprevention of Prostate Cancer

NUTRITION AND CANCER, 53(1), 18–32
Copyright © 2005, Lawrence Erlbaum Associates, Inc.
Dietary Agents in the Chemoprevention of Prostate Cancer
Sanjeev Shukla and Sanjay Gupta
Abstract: Nutritional factors have been estimated to contribute 20–60% of cancers around the globe, and almost
one-third of deaths are being reported in Western countries.
According to estimates by the American Cancer Society, during the year 2005 about 232,090 new cases of prostate cancer will be diagnosed alone in the United States and 30,350
men will die of this disease. The high incidence and long latency period of prostate cancer offer plenty of time to pursue
strategies toward prevention and/or treatment to suppress or
revert this disease. Epidemiological evidence suggests that
plant-based dietary agents decrease the risk of some types of
human cancer, including prostate cancer. Intake of 400–600
g/day of fruits and vegetables is associated with reduced risk
of several cancers. The use of micronutrients and/or other
phenolic agents in the diet or synthetic exogenous supplements to prevent neoplastic transformation of normal cells or
to slow the progression of established malignant changes in
cancer cells is termed “chemoprevention.” Considerable attention has been devoted to identify plant-based dietary
agents that may serve as natural inhibitors of prostate carcinogenesis. Much progress has been made in the last decade
in this area of investigation through identification of pathways that play important roles in prostate tumorigenesis.
This article summarizes epidemiological, clinical, and mechanistic studies and the significance of plant-derived dietary
agents such as flavonoids, indoles, isothiocyanates, phenolics, monoterpenes, and complementary and alternative
agents in the management of prostate cancer with recommendations for future studies to advance this area of research.
Introduction
Prostate cancer is the most common non-skin malignancy
and the second leading cause of cancer death (after lung) in
U.S. males. According to estimates by the American Cancer
Society, 232,090 new cases of prostate cancer will be diagnosed, and 30,350 deaths are estimated from this disease, in
the year 2005 (1). Although the death rate of prostate cancer
is on the decline, in the past few years the number of new
cases has been on the rise due to an increase in the aging population. In fact, by 2015 there will be >300,000 new prostate
cancer cases each year, with a 50% increase (1). Epidemiological studies have suggested that diet and nutrition are
critical determinants of prostate cancer risk, with dramatic
variations in prostate cancer incidence and mortality between
different geographic regions (2–4). Prostate cancer rates are
high in North America and northern Europe, intermediate in
Mediterranean nations, and relatively low in many parts of
Asia (2–4). The low incidence of prostate cancer in Asian
countries has been attributed to diets (the substances a person
eats and drinks) that are low in animal fat and rich in
plant-based agents. On the other hand, the incidence of prostate cancer is significantly higher in industrialized Western
countries where the diet is typically high in animal fat
(30–40% of calories from fat) (4,5). It is emphasized that,
with a diet composed according to the guidelines by the
American Institute for Cancer Research, it is likely that there
would be at least a 60–70% decrease in breast, colorectal,
and prostate cancers and even a 40–50% decrease in lung
cancer along with similar reductions in cancers at other sites
(Ref. 5 and references therein). It is also notable that Asian
men who immigrate to the United States and adopt Western
diets have a risk of developing prostate cancer that approaches the average U.S. incidence within one generation
(6,7). This information suggests that environmental factors
and lifestyle play significant roles in the initiation of prostate
cancer; however, more importantly, these factors may also influence the rate of progression of established prostate cancers. Men above the age of 50 have about a 40% chance of
having cancer in the prostate, regardless of nationality, race,
and/or ethnicity. Autopsy studies have shown that malignant
changes begin in the prostate as early as the 3rd decade of
life, yet most men are not diagnosed with clinically evident
prostate cancer until they are in their sixties (7,8). Therefore,
the initiation of prostate cancer probably occurs somewhat
similarly throughout the various nations of the world, but
progression of prostate cancer to a clinically detectable state
differs between countries (7,8). The discrepancy between the
frequency of “latent” and “clinically evident” cancer has
been attributed to variations in environmental and lifestyle
factors that control progression of previously initiated cancers. The addition of vegetables and fruits to meals to prevent
prostate cancer has gained considerable attention as research
Both authors are affiliated with the Department of Urology, Case Western Reserve University, Cleveland, Ohio 44106 and the University Hospitals of Cleveland, Cleveland, Ohio 44106. S. Gupta is also affiliated with the Ireland Cancer Center, Cleveland, Ohio 44106.
demonstrates that various plant-based dietary agents
(flavonoids, indoles, isothiocyanates, phenolics, carotenoids,
and monoterpenes) and/or supplements (vitamins and minerals) may help to reduce the risk of developing clinically evident prostate cancer (9,10).
neoplastic effects, including antioxidant effects, modulation
of detoxification enzymes, stimulation of the immune system, reduction of inflammation, modulation of steroid metabolism, and antibacterial and antiviral effects.
Cancer Chemoprevention
Prostate Cancer Development
and Progression
Chemoprevention is defined as pharmacological intervention with naturally occurring and/or synthetic compounds
that may prevent, inhibit, or reverse carcinogenesis or suppress the development of invasive cancer (9,10). The expanded definition of cancer chemoprevention is to inhibit or
delay the onset of neoplasia by blocking neoplastic inception
as well as reversing the progression of transformed cells before the appearance of malignant lesions (10–12). Chemoprevention of cancer thus differs from cancer treatment in
that the goal of this approach is to lower the rate of cancer incidence (13). Micronutrients (antioxidant vitamins and trace
minerals) as well as certain phenolic compounds present in
vegetables and fruits are regarded as the most desirable class
of chemopreventive agents (14). This information is supported by the fact that populations consuming low amounts
of vegetables and fruits have higher incidence and mortality
from cancers of several organ sites as well as epidemiological studies suggesting that consumption of fresh fruits and
yellow-green vegetables reduces cancer incidence and mortality (15,16). Extended studies have suggested that micronutrients present in vegetables are more effective than fruits
in possessing potential anticarcinogenic properties (14–16).
Some chemopreventive agents, in addition to preventing or
delaying the onset of carcinogenesis, have also exhibited potential therapeutic effects (17–19). According to a bulletin
from the National Cancer Institute, at present, approximately
400 compounds are being studied as potential chemopreventive agents, primarily in laboratory research (20).
Over 40 of these compounds and agent combinations exist or
are undergoing clinical evaluation (20). The protective effect
of fruits and vegetables against carcinogenesis may be derived from many different plant components that include vitamins, minerals, fiber, and micronutrients, each acting via a
variety of distinct and potentially interactive mechanisms
(21,22). Some of these potentially beneficial components
have been incorporated into herbal medicines, which have
grown in popularity in recent years (23). Approximately 40%
of Americans use alternative remedies, including herbal
medicine, for disease prevention and therapy (24). The increasing cost, side effects of drugs, and therapeutic limitations of conventional medications are key factors that enhance interest in herbal medicines. Herbal medicines and/or
botanical supplements are available without a prescription
and, despite the fact that their safety and efficacy are generally not established by rigorous scientific testing, they are
widely used (25–28). Given the wide range of botanical species and plant parts from which these herbal elements are derived, they may potentially contribute overlapping anti-
Accumulated evidence indicates that prostate cancer results from the accumulation of multiple sequential genetic alterations and mutations in nuclear and cytoplasmic molecules (29,30). These events occur in three phases: initiation,
promotion, and progression. Prostate cancer most likely develops initially as high-grade intraepithelial neoplasia
(HGPIN). HGPIN is an androgen-dependent proliferation of
neoplastic cells, occurring in the peripheral and transition
zones and giving rise to small, latent low-grade carcinomas
that may subsequently progress to large, high-grade potentially metastatic tumors (31). Promotion and progression of
prostate cancer are controlled by cascades of signal
transduction molecules (32–34). Generally, these cascades
are triggered by hormones or growth factors, and in
carcinogenesis they are either faultily expressed or activated
by tumor-promoting stimuli (32–34).
Recent population-based perspective studies and clinical
observations have provided evidence in support of the hypothesis that longstanding chronic prostatic inflammation
leads to cumulative oxidative damage in prostatic epithelium
(35,36). Chronic inflammation may influence the pathogenesis of prostate cancer by inflicting cell and/or genome
damage, triggering restorative cell proliferation to replace
damaged cells, and/or elaborating a portfolio of cytokines
that promote cell replication, angiogenesis, and tissue repair
(37). Oxidative damage to DNA and other cellular components accompanying chronic or recurrent inflammation may
connect prostate inflammation with prostate cancer (38,39).
In response to infections, inflammatory cells produce a variety of toxic compounds designed to eradicate microorganisms. These include superoxide ion, hydrogen peroxide, singlet oxygen, and nitric oxide that can react further to form the
highly reactive peroxynitrite anion. Some of these highly reactive oxygen and nitrogen species can directly interact with
DNA in the host bystander cells or react with other cellular
components such as lipid, initiating a free-radical chain reaction (40). If the damage is severe, these compounds can kill
host bystander cells as well as pathogens and can produce
DNA damage and mutations among host cell survivors. We
and others have shown that, within the prostate, chronic inflammation is commonly associated with postatrophic hyperplasia (PAH) and proliferative inflammatory atrophy,
with significant up-regulation of cell survival signaling molecules in the prostatic epithelial cells close to inflammatory
regions (41,42). It has been suggested that these morphological transitions occur frequently within the same acinar/duct
between HGPIN and PAH that could lead to prostate carcinogenesis (43). This carcinogenic process may be accelerated
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19
under altered physiological conditions, such as inappropriate
diet, exposure to environmental pollutants, high circulating
testosterone levels, viral infection, or preexisting genetic
switch. The inflammation-carcinoma sequence has been believed to be a potential mechanism in the initiation and development of prostate cancer (44). This hypothesis has been
supported by the evidence that age-related increase in the
proportion of hydroxyl radical induces mutagenic base lesions, which is likely a significant factor in prostate cancer
development and in characterizing cancer-like phenotypes
(45). Other support for the concept that prostate cancer can
result from oxidative damage through excess oxidants and
electrophiles comes from epidemiological studies suggesting
that decreased prostate cancer risk is associated with intake
of various antioxidants and nonsteroidal anti-inflammatory
drugs (39).
Prostate Cancer Chemoprevention
There is considerable interest in ascertaining whether diets rich in fruits and vegetables offer protection against prostate cancer (14–16,46). A number of macronutrients, micronutrients, and other dietary constituents have been or are
currently being evaluated as potential prostate cancer
chemopreventive agents (5,14–16,47). Dietary agents have
gained considerable attention as chemopreventive agents
against many forms of cancer including prostate cancer
(46–48). This approach has practical implication in reducing
prostate cancer risk. Although several carcinogenic environmental factors that are beyond anyone’s control also play a
role, individuals are free to modify their dietary habits and
lifestyles. Several studies have focused on the antioxidant
and nonantioxidant effects of various dietary substances in
the prevention of prostate cancer (49–54). In last 2 decades,
there has been substantial progress in identifying the cellular
events that play a major role in the process of carcinogenesis,
and now we know how the dietary phytochemicals are able to
modulate these events. Identification of numerous oncogenes; tumor suppressor genes; specific genes encoding for
carcinogen-metabolizing enzymes, DNA repair enzymes,
and proteins; and regulators of apoptosis and cell cycle, some
of the events related to cell-signaling pathways that regulate
cell proliferation and differentiation, has provided us with accurate in-depth knowledge of molecular neoplastic transformation events. Some of the dietary phytochemicals, which
are present in fruit and vegetables, have been shown to possess potential anticarcinogenic effects. These include numerous agents such as carotenoids, vitamins, dietary fiber, selenium, glucosinolates, indoles, isothiocyanates, flavonoids,
phenols, protease inhibitors, plant sterols, and other complementary agents (55–63). These agents display complementary and overlapping mechanisms of action, including induction of detoxification enzymes, antioxidant effects, and
inhibition of the formation of nitrosamines; binding/dilution
of carcinogens in the digestive tract; alteration of hormone
metabolism; and modulation of carcinogenic cellular events.
20
Long latency of disease to develop the malignant form of
prostate cancer affords opportunities for intervention with
chemopreventive agents to delay disease initiation or progression. This article focuses on epidemiological, clinical,
and mechanistic studies that have evaluated the antioxidant
and/or anticarcinogenic activity of chemopreventive agents
in prostate cancer. Some of the agents that are being investigated for prostate cancer chemoprevention are discussed
subsequently.
Carotenoids and Prostate Cancer
Chemoprevention
Among the carotenoids, β-carotene and lycopene have
been most extensively studied with respect to their possible
roles in preventing prostate cancer (64). The results of a number of epidemiological studies investigating the relationship
between β-carotene intake and the risk of prostate cancer
have been inconsistent (65,66). Prospective cohort studies on
intake of α-and β-carotene, vitamins A, C, and E, and lycopene have shown inverse associations for vitamin A and αand β-carotene in prostate cancer risk (67). Another
case-control study evaluating an association between retinol
and various carotenoids has shown a weak protective effect
of carotene, particularly β-carotene, on the risk of prostate
cancer (68). Although the results are encouraging, it is difficult to analyze the complex network and the protective role
of dietary antioxidants in such clinical settings. Due to the
complexity of results little preclinical research has been conducted with β-carotene and prostate cancer.
Compelling epidemiological studies have suggested that a
diet rich in tomato products is associated with a reduction in
prostate cancer risk (69). Prospective case-control studies
and meta-analysis of observational studies have shown that
tomato products may play a role in the prevention of prostate
cancer (70,71). It is hypothesized that lycopene may be one
of the components of tomato that contributes to this association. Lycopene has been shown to be present in the human
prostate at significant concentrations, a finding that supports
the plausibility of a direct effect on prostate biology (72).
Studies of the cell culture system have shown that lycopene
inhibits growth of prostate cancer cells through the pathways
that influence expression of gap junction proteins and growth
factor signaling (73,74). A recent study on a preclinical
model of prostate cancer suggests that consumption of tomato powder but not lycopene inhibited prostate carcinogenesis, suggesting that tomato products contain compounds in addition to lycopene that modify the prostate
carcinogenic process (75). These studies are very encouraging and strongly support further mechanistic studies with
lycopene in preclinical models of prostate cancer.
Recent studies on men with prostate cancer supplemented
with lycopene-enriched enhancement or tomato products for
several weeks prior to radical prostatectomy demonstrated
that lycopene concentrations in the prostate could change
rapidly in response to dietary intake and induce apoptotic cell
death along with modulations in oxidative stress and tumor
Nutrition and Cancer 2005
biology markers (76,77). A phase II randomized clinical trial
of 15 mg of lycopene supplementation twice daily for 3 wk
before radical prostatectomy exhibited a decrease in the
plasma insulin-like growth factor-1 (IGF-1) levels with no
significant changes in Bax and Bcl-2 (78). Another study by
this group using tomato oleoresin extract containing the
equivalent of 30 mg/day of lycopene extract for 3 wk before
radical prostatectomy substantially reduced prostate volume
in prostate cancer patients (79). In another study, the efficacy
of 10 mg/day supplementation of lycopene to hormone-refractory prostate cancer patients was shown to be effective in
reducing serum prostate-specific antigen (PSA) levels, bone
pain, and lower urinary tract symptoms (LUTS) (80). A randomized trial for the lycopene is still on going to test the efficacy of this compound.
Vitamins and Prostate Cancer
Chemoprevention
A major portion of prostate cancer research on dietary influence has been focused on the antioxidant functions of vitamins. In this regard, vitamins A, C, D, and E have been most
extensively studied for their effects on prostate cancer.
Vitamin A (retinol) and its active metabolites are essential
for cell differentiation, visual function, and physiological
growth (81). Vitamin A and its analogs modulate the growth
of cancer cells, presumably by activating gene transcription
via the nuclear retinoic acid receptors α, β, and γ (82). The
chemopreventive effects of retinoids are exerted at the tumor
promotion phase through inhibition of cell proliferation, induction of apoptosis, cell cycle arrest, and/or a combination
of these actions (83,84). All-trans-retinoic acids reduce
urokinase-type plasminogen-mediated degradation of fibronectin and laminin (85). Despite numerous studies, no consistent association between vitamin A intake and prostate
cancer risk has been established (67,68,86). Some studies
have shown an inverse relationship between serum retinol
and the risk of prostate cancer, whereas others indicate a positive association, particularly in men more than 70 yr old
(86,87).
Vitamin C is a potent antioxidant that scavenges reactive
oxygen species and other free radicals capable of causing
damage to lipids and DNA (88). Vitamin C has been shown to
inhibit malignant transformation by diminishing cellular
chromosomal damage (89). Diets that include substantial
amounts of fruits and vegetables rich in vitamin C are associated with a low incidence of many forms of cancer (90). In
animal studies, vitamin C has been shown to inhibit prostate
tumor growth and viability in athymic nude mice transplanted with both androgen-sensitive and -insensitive human
prostate cancer cells (91,92). Studies have shown that combinations of vitamins C and E inhibit surviving protein, a promoter of prostate cancer cell growth (93).
The active form of vitamin D is calcitrol (1α,25-D3),
produced in the skin through exposure of 7-dehydrocholestrol to ultraviolet light and proximal renal tubules in
the kidneys through 1,25-dihydroxyvitamin D3 hydroxylase
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(94). Studies have shown that 25-hydroxyvitamin D1α hydroxylase, the enzyme that synthesizes 1α,25 dihydroxyD3,
is also expressed in cultured prostate cells (95). Recent studies have provided evidence that residential sunlight exposure
is associated with a decreased risk of prostate cancer that
may be linked with vitamin D synthesis (96). Epidemiological studies have further suggested that an increased prostate
cancer risk is associated with decreased production of vitamin D (97,98). Studies in cell culture systems and preclinical
models of prostate cancer have shown that the biologically
active form of vitamin D (1α,25-D3) inhibits proliferation of
human prostate cancer cells through mechanisms that include cell cycle arrest, induction of apoptosis, and altered activation of growth factor signaling (99,100). Consistent with
tumor suppressor activity, vitamin D compounds and
retinoids have been shown to act synergistically with
genistein in inhibiting the growth of human prostate epithelial cells (101). Genistein is the component in soy that has
been employed in chemoprevention strategies with other putative chemopreventive agents. The combination of vitamin
D compounds and retinoids has emerged as an attractive tool
for use in controlling prostate cancer progression (98). However, hypercalcemia induced by 1α,25-D3 in vivo limits its
use clinically as a therapeutic agent. Population-based studies with vitamin D as well as plasma 1,25-dihydroxyvitamin
and 25-hydroxyvitamin D levels have not provided any significant data on protective effects in prostate carcinogenesis
(102–104).
Vitamin E is a family of naturally occurring, essential,
fat-soluble vitamin compounds that constitutes at least eight
structurally related molecules as four tocopherols and four
tocotrienols (105). Vitamin E functions as the major lipidsoluble antioxidant in cell membranes; it is a chain-breaking
free-radical scavenger and specifically inhibits lipid peroxidation, a biological activity relevant to carcinogen-induced DNA damage (106). The most active form of vitamin
E is α-tocopherol, a compound that is abundant and widely
distributed in nature and present in most types of human tissue and plasma (107,108). Epidemiological studies have
shown that supplementation of vitamin E in the diet lowers
the incidence of prostate carcinoma (109). However, some
epidemiological studies did not support the role of vitamin E
in prostate cancer (110,111). Further studies have observed
that men with lower plasma levels of vitamin E had an increased risk of developing prostate cancer (112). Tocopherols have inherent antioxidant affinity for highly reactive
and genotoxic electrophiles, such as hydroxyl, superoxide,
lipid peroxyl, lipid hydroperoxyl, and nitrogen radicals
(113). Consequently, tocopherols prevent free-radical damage in biological membranes and decrease mutagenesis and
carcinogenesis (113). Animal studies have shown that dietary supplementation of vitamin E slows prostate cancer
growth due to its ability to inhibit androgen signaling (114).
The mechanisms through which tocopherols inhibit cell proliferation include inhibition of protein kinase C activity, induction of NADPH detoxification enzyme, and reduction of
arachidonic acid and prostaglandin metabolism (115). Vita21
min E has been shown to inhibit the growth of chemically and
hormonally induced prostate cancer cells via modulation of
cell cycle regulatory machinery and induction of apoptosis
(116). Other putative mechanisms through which vitamin E
may inhibit proliferation of human prostate cancer cells include inhibition of androgen receptor (AR) function, inhibition of PSA production, and inhibition of the production of
vascular endothelial growth factor (117). The Alpha
Tocopherol Beta Carotene (ATBC) cancer prevention trial, in
which 29,133 male smokers were studied for prevention of
lung cancer using vitamin E (50 mg/day) and/or β-carotene
(20 mg/day), demonstrated that, although there was an increase in lung cancer risk, the incidence of prostate cancer
was reduced by 32% in men receiving α-tocopherol compared with the control group, which did not receive it. Additionally, 41% lower mortality rates were observed in men receiving α-tocopherol. Among subjects receiving β-carotene,
the incidence of prostate cancer was 23% higher and mortality rate was up by 15% compared with subjects who did not
receive β-carotene supplementation (118). More recent studies have shown that α-tocopherol has a stronger association
with the lower risk of prostate cancer, and higher circulating
concentration of major vitamin E fractions α- and γ-tocopherol was similarly associated with lower prostate cancer
risk (119). These studies suggest that vitamin E may perhaps
be used in prevention of prostate cancer.
Although much progress has been made with studies of
the effects of vitamins on prostate cancer, additional studies
are required to determine their potential use as chemopreventive agents for prostate cancer. The Selenium and Vitamin E Cancer Prevention Trial (SELECT), an intergroup
phase III, randomized, double-blind, placebo-controlled,
population-based clinical trial designed to test the efficacy of
selenium and vitamin E alone and in combination in the prevention of prostate cancer, is an example of the ongoing interest in this area of research (120).
Minerals and Prostate Cancer
Chemoprevention
Minerals that appear to play important roles in the
chemoprevention of prostate cancer are selenium and zinc.
Selenium is an essential dietary trace element; its concentration in various foods, such as fruits and vegetables, is dependent on the soil content of selenium in the region where
these foodstuffs are grown (121). As a constituent of
selenoproteins, selenium has several structural and enzymatic roles (122). A number of natural and synthetic
organoselenium compounds have been examined as chemopreventive agents in several animal tumor bioassay systems.
Selenium in the form of sodium selenite or selenomethionine
functions as an essential micronutrient at levels of about 0.1
ppm in the animal diet and acts as a chemopreventive agent at
3–5 ppm and is toxic at levels higher than 5 ppm (123). Most
of the selenium chemoprevention studies have used either sodium selenite, selenomethionine, or methylseleninic acid as a
test agent. Epidemiological studies, preclinical investiga22
tions, and clinical intervention trials support the role of
selenium compounds as potent chemopreventive agents for
prostate cancer (123). A randomized trial on selenium
supplementation from the National Prevention of Cancer
Study in 974 men with 200-µg/day doses of selenium in 0.5 g
high-selenium yeast demonstrated 63% reduction in incidence of prostate cancer (124). However, no significant associations were observed between baseline serum α-tocopherol, dietary vitamin E, or selenium and prostate cancer in
the ATBC trial, a randomized, double-blind, placebo-controlled, primary prevention study of lung cancer, upon secondary analysis (125). The compelling findings in the ATBC
trial prompted the establishment of a large prospective study,
the SELECT trial for prostate cancer chemoprevention (120).
Selenium appears to exert its cancer chemopreventive effects through induction of cell cycle arrest and apoptosis and
reduction of angiogenesis (126). Selenium compounds have
been shown to alter the expression and/or activities of a number of cell cycle regulatory proteins, signaling molecules,
proteases, mitochondrial associated factors, transcription
factors, tumor suppressor genes, polyamines, and glutathione levels (123,127). Selenium compounds have also been
shown to decrease PSA expression by inducing protein degradation and suppressing androgen-stimulated gene transcription (128). Combination studies with selenium and vitamin E have shown decreased prostate cancer cell
proliferation via distinct mechanistic pathways (114,129).
Although selenium appears to hold significant promise as a
chemopreventive agent, more detailed in vivo studies elucidating the molecular mechanisms of selenium-mediated effects on prostate cancer are warranted. The ongoing
SELECT clinical trial with selenium (200 µg/day from
L-selenomethionine) and vitamin E (400 IU/day of all-rac-αtocopheryl acetate) alone and in combination for a planned
minimum of 7 yr (maximum of 12 yr) on 32,400 American
men will determine the chemopreventive potential of selenium against prostate cancer (120).
Zinc is another essential trace element known to possess
antioxidant properties (130). Zinc is present in high concentrations in the prostate (130). In cell culture systems, zinc has
been shown to inhibit prostate cancer cell growth via inhibition of cell cycle and induction of apoptosis through disruption of mitochondrial function (131). More research is required to understand the essential role and mechanism of
zinc in the prostate and chronic zinc oversupply in prostate
cancer.
Flavonoids and Prostate Cancer
Chemoprevention
Flavonoids are polyphenolic compounds that are ubiquitously present in foods of plant origin (132). The flavonoid
family includes about 5,000 compounds that are defined
chemically as substances composed of a common phenylchromanone structure (C6–C3–C6), with one or more
hydroxyl substituents (132–134). These are mainly classified
into flavones, flavanols (catechins), isoflavones, flavonols,
Nutrition and Cancer 2005
flavanones, and anthocyanins (133,134). The dietary flavonoids possess antioxidative, anti-inflammatory, and possibly
anticarcinogenic properties and are receiving increasing attention (135). The plant flavonoids whose roles in prostate
carcinogenesis have been studied are soy isoflavones,
catechins from green and black tea, silymarin from milk thistle, resveratrol, apigenin, and proanthocynadins from grape
seed.
Soy isoflavones have been identified as dietary components that may play an important role in reducing the incidence of prostate cancer (136). The major soy isoflavones include genistein and daidzein. Genistein, the predominant
isoflavone found in soy, has been shown to reduce proliferation of prostate cancer cells (137). The antiproliferative effects of genistein are attributed to the modulation of genes related to control of cell cycle and apoptosis (137,138). The
pathways through which genistein exerts its antiproliferative
effects include inhibition of tyrosine kinase, proteasome activity, angiogenesis, metastasis, PI3K/Akt and NF-κB survival signaling pathways, and induction of glutathione
peroxidase in human prostate cancer cells (139,140). Genistein is also recognized as a phytoestrogen, which targets estrogen- and androgen-mediated signaling pathways in prostate carcinogenesis (141). Administration of a genisteinenriched diet to mice has been shown to correlate positively
with changes in prostate DNA methylation at CpG islands
(142). This study demonstrates that epigenetic alterations
may influence prostate cancer risk. Recent studies have
shown that dietary genistein feeding improves survival and
reduces expression of osteopontin, which may delay progression of prostate cancer from benign to malignant tumors in a
transgenic adenocarcinoma of the mouse prostate (TRAMP)
model (143). Further studies have shown that dietary
genistein feeding inhibits bone metastasis in SCID mice by
regulating metastasis-related genes (144). Epidemiological
and case-control studies are supportive of a chemopreventive
action for these compounds; however, clinical studies with
soy isoflavones have not been encouraging (145). Various
soy isoflavone supplementation regimens in prostate cancer
patients have shown no statistically significant changes in serum PSA levels (146). A randomized controlled trial demonstrated that soy isoflavone did not modulate PSA concentrations in men between 50 and 80 yr of age (147). It is possible
that soy isoflavones may be more beneficial in preventing
prostate cancer when used in combination with other compounds. Additional studies are needed to ascertain this.
Tea, the most widely consumed beverage in the world, has
been shown to possess strong antioxidant potential (148).
The major catechins present in green tea are (–)-epicatechin,
(–)-epicatechin-3-gallate, (–)-epigallocatechin, and (–)-epigallocatechin-3-gallate. Epigallocatechin-3-gallate accounts
for approximately 40% of the total polyphenolic mixture in
green tea (148). The major constituents of black tea are
theaflavins and thearubigins (148,149). Epidemiological
studies show that, in Asian countries, where tea is very popular, the incidence of all types of cancer, including prostate
cancer, is low compared with that in the West (150). The JapVol. 53, No. 1
anese and Chinese people, who regularly consume green tea,
have the lowest prostate cancer incidence in the world (Ref.
151 and references therein). Consequently, researchers have
developed considerable interest in tea, and especially in
green tea polyphenols (GTPs), as a cancer chemopreventive
agent. Tea catechins have been shown to modulate a number
of cellular signaling pathways that have relevance to prostate
cancer (152–156). These include proteins related to cell cycle progression, inflammation, angiogenesis, metastasis, tyrosine kinases, PI3K/Akt and NF-κB survival signaling pathways, AR, 5-α reductase, protein kinase C, proteasome
inhibition, and apoptosis (153–156). A recent study has
shown that GTPs inhibit DNA methyltransferase and have
potential to reactivate methylation-silenced genes in prostate
cancer cells (157). Studies on the TRAMP model have shown
that oral infusion of GTPs in drinking water for 24 wk resulted in approximately 44% reduction in tumor volume and
70% increase in overall survival compared with the control
group, which did not receive GTP (158). More recent studies
employing a similar protocol for GTP infusion to TRAMP
mice have shown significant reduction in IGF-1 levels with
concomitant increase in IGFBP-3 expression in dorsolateral
prostate of these mice (159). Further, GTP infusion has been
reported to inhibit protein expression of the S100A4 gene
(Mts1) and restored the expression of E-cadherin in TRAMP
mice (160). These studies indicate that GTPs may prove useful as chemopreventive agents for prostate cancer. Epidemiological and case-control studies have further supported the
chemopreventive properties of green tea; however, clinical
studies with green tea have not been encouraging (161,162).
A phase II study, in which 6 g/day of tea was administered to
42 patients with asymptomatic, androgen-independent prostate cancer, demonstrated that a single patient achieved a
PSA response of >50% that lasted for approximately 1 mo
(162). These patients suffered with side effects that include
diarrhea, nausea, and fatigue. Another recent clinical study
used a 250-mg dose of GTPs twice daily. In this study, 6 of 19
patients had disease control for 3–5 mo and only 1 patient
whose PSA rise was affected by green tea supplementation.
The dose used in this study did not discernibly alter the
course of hormone-refractory prostate cancer (163). These
results suggest that green tea possesses minimal antineoplastic activity against advanced-stage prostate cancer.
Well-designed clinical studies are further required to test the
validity of GTPs in prevention-based trials.
Resveratrol, a dietary stilbene, is another plant product
derivative that has been proposed as a chemopreventive agent
based on safety and efficacy studies in cell culture and animal
models (164). Resveratrol has been shown to possess strong
anti-inflammatory, antioxidant, and anticarcinogenic properties (165). Resveratrol has shown growth-inhibitory effects
on both androgen-sensitive and -insensitive human prostate
cancer cells; its effects are mediated through inhibition of the
cell cycle and induction of apoptosis (166). Interactive gene
expression patterns in prostate cancer LNCaP cells exposed
to resveratrol have shown alterations in multiple signaling
pathways that include p53-responsive genes, the PPAR fam23
ily, tyrosine kinase family members, Rel/NF-κB family
members, heat-shock proteins, cell cycle regulatory genes,
and apoptosis-related genes (167–170). Resveratrol has also
been shown to modulate AR function and inhibits PSA expression in prostate cancer cells (171). Based on cell culture
studies, evaluation of resveratrol as a chemopreventive agent
in preclinical models of prostate cancer may be warranted.
Silymarin is a plant flavonoid that has been shown to possess exceptionally high anti-inflammatory, antioxidant, and
anticarcinogenic properties (172). The major active constituent of silymarin is silibinin; other minor constituents include
dehydrosilibinin, silychristin, and silydianin (173). Silymarin and silibinin have shown remarkable antiproliferative
effects on both androgen-sensitive and -insensitive human
prostate cancer cells (174,175). The underlying mechanisms
of silibinin activity against prostate cancer involve alterations in cell cycle progression and inhibition of mitogenic
and cell survival signaling, including modulation of epidermal growth factor receptor, IGF-1, and NF-κB signaling
(176). Silibinin has been shown to modulate AR function and
to inhibit telomerase activity and PSA expression in prostate
cancer cells (176). Silibinin has also been shown to inhibit
prostate cancer progression through reduced secretion of
pro-angiogenic factors from prostate cancer cells (177).
Silibinin has also been shown to synergize the therapeutic effects of doxorubicin in prostate cancer cells and to sensitize it
to TNFα-induced apoptosis (178). Translational studies with
silibinin on preclinical models of prostate cancer have demonstrated similar results with reduced tumor proliferation, induction of IGFBP-3 and apoptosis, and inhibition of
angiogenesis (179). These findings suggest a rationale for
clinical studies to be conducted in prostate cancer patients.
Proanthocyanidins and procynadins are flavonoids that
are found in high concentrations in grape seed extract, a popular dietary supplement (180). Grape seed extract has been
shown to possess significant anti-inflammatory, antioxidant,
antiviral, and anticarcinogenic properties (181). Grape seed
extract has been shown to induce apoptosis in prostate cancer
cells through activation of caspases and disruption of mitochondrial function (182). The pathways involved in the
chemopreventive activity of grape seed extract on prostate
cancer include inhibition of protein tyrosine kinase, matrix
metalloproteinases, and Rel/NF-κB family members
(183,184). Grape seed extract has recently been shown to inhibit prostate tumor growth and angiogenesis through
up-regulation of IGFBP-3 in an athymic nude mouse model
(185). More mechanistic studies on cell cultures and in vivo
models of prostate cancer are required to assess the possible
efficacy of grape seed extract as a chemopreventive agent for
prostate cancer.
Apigenin, a widely distributed plant flavonoid abundantly
present in fruits and vegetables, is a free-radical scavenger
that has been shown to possess anti-inflammatory and anticarcinogenic effects (186). Studies have shown that apigenin
possesses growth-inhibitory properties against many types of
human cancer cells, including prostate cancer (187,188). We
have shown that apigenin causes tumor cell growth inhibi24
tion, cell cycle deregulation, and apoptosis in both androgen-sensitive and -insensitive human prostate cancer cells
without affecting normal cells (188,189). The molecular
mechanisms underlying the activities of apigenin include inactivation of tyrosine phosphorylation, inhibition of 17βhydroxysteroid oxidoreductase, inhibition of AR function,
modulation in cell cycle regulatory proteins, disruption of
mitochondrial function, and NF-κB inhibition in prostate
cancer cells (190–192). More recently we have shown that
apigenin is capable of sensitizing human prostate cancer
PC-3 cells to TNFα-induced apoptosis, which correlates
with down-regulation of genes relevant for prostate cancer
progression (193). Additional mechanistic cell culture studies with apigenin are required, targeting other signaling pathways that have relevance to prostate cancer development and
progression. Further testing of apigenin in preclinical models
of prostate cancer is warranted.
Indoles and Prostate Cancer
Chemoprevention
A diet rich in fruits and vegetables provides a rich source
of indoles, which may be responsible for prevention of many
types of cancer (21,22). Indoles are naturally occurring constituents of Brassica vegetables. Cruciferous vegetables contain glucobrassicin, which during metabolism yields indole3-carbinol (I3C) and its in vivo dimeric product 3,3′diindolylmethane (DIM). These derivatives have been shown
to inhibit cell proliferation and induce apoptosis in prostate
cancer cells (194). The mechanisms through which indoles
exert their anticarcinogenic effects include modulations in
cell cycle regulatory proteins and inhibition of cell survival
pathways (PI3K/Akt) and NF-κB transcription factor (195).
Gene expression profiles have demonstrated that I3C and
DIM affect the expression of a large number of genes that
have relevance to cancer, cell survival, and physiological behavior (196). Further, it has been shown that indoles are
strong androgen antagonists and that they inhibit PSA production in human prostate cancer cells (197). These findings
suggest that dietary indoles may prove useful in the
chemoprevention of prostate cancer. Therapeutic studies
with plant indoles were performed on preclinical prostate
cancer models. Intraperitoneal administration of DIM to
C57BL/6 mice bearing TRAMP-C2 malignant cells has been
shown to inhibit tumor growth (198). Systemic administration of I3C to Copenhagen rats injected with MAT-LyLu cells
has been shown to inhibit prostate tumor growth and metastasis (199). More mechanistic in vivo studies are required to assess the potential of indoles in this capacity.
Isothiocyanates and Prostate Cancer
Chemoprevention
There is evidence to suggest that thiol conjugates of
isothiocyanates present in cruciferous vegetables are effective cancer chemopreventive agents (200). At least two population-based, case-controlled studies have documented reNutrition and Cancer 2005
duced risk of prostate cancer in men consuming cruciferous
vegetables (201,202). These salutary effects have been attributed to 2-phenylethyl isothiocyanate, allyl isothiocyanate,
and sulforaphane (203). These agents exert their anticarcinogenic activities in cell culture system through mechanisms that include cell cycle inhibition, induction of phase II
enzymes, inhibition of extracellular signal-regulated kinases,
suppression of NF-κB and its regulated genes, proteasome
degradation, caspase activation, and induction of apoptosis
(204–208). Phenylethyl isothiocyanate and allyl isothiocyanate have been shown to inhibit the growth of human
prostate cancer PC-3 xenografts through cell cycle perturbation and induction of apoptosis (207). More detailed mechanistic studies are required to assess the potential of isothiocyanates in the chemoprevention of prostate cancer.
Phenolic Acids and Prostate Cancer
Chemoprevention
Phenolic acids are aromatic secondary plant metabolites,
widely present throughout the plant kingdom (209). Phenolic
acids are well recognized for their antioxidant potential
(210). Curcumin, a phenolic acid and active component of
turmeric, has received a great deal of attention as a possible
chemopreventive agent against prostate cancer (210).
Curcumin has been shown to inhibit proliferation of both androgen-sensitive and -insensitive human prostate carcinoma
cells via inhibition of the cell cycle and induction of
apoptosis (211). Diets containing 2% curcumin provided to
LNCaP tumor xenograft in nude mice for 6 wk have been
shown to induce apoptosis and inhibited proliferation and
angiogenesis (212). The molecular pathways that contribute
to its anticarcinogenic activity include tyrosine kinase and
protein kinase C inhibition, down-regulation of AR gene expression, inhibition of PI3K/Akt and NF-κB, and modulation
of the motility of prostate cancer cells through effects on their
microfilament organization (211,213–215). Curcumin has
been shown to enhance tumor necrosis factor-related
apoptosis-inducing ligand (TRAIL)–induced apoptosis; it
also radiosensitizes prostate carcinoma cells (216).
Curcumin in combination with radiation showed significant
enhancement to radiation-induced clonogenic inhibition and
apoptosis in PC-3 cells (217). These findings suggest that
curcumin may have some potential as a chemopreventive
agent for prostate cancer, which needs further evaluation.
Organosulfur Compounds and Prostate
Cancer Chemoprevention
Organosulfur compounds are the biologically active components of allium vegetables (218). The primary sulfurcontaining constituents in garlic are the γ-glutamylS-alk(en)yl-L-cysteines and S-alk(en)yl-L-cysteine; the odor
of garlic is attributable to allicin and other oil-soluble sulfur
components (219,220). Once garlic undergoes cutting or
crushing, hundreds of organosulfur compounds are released
in a short period of time. The transiently formed compound,
Vol. 53, No. 1
allicin, comprises 70–80% of the thiosulfinates and quickly
decomposes to other compounds, such as diallyl sulfide,
diallyl disulfide, diallyl trisulfide, dithiine, and ajoene (219).
Many health benefits have been ascribed to organosulfur
compounds including inhibition of carcinogenesis. Two
studies have shown that S-allylmercaptocysteine inhibits
prostate cancer cell proliferation (118,221). More studies of
the potential of organosulfur compounds in prostate cancer
chemoprevention appear to be warranted.
Monoterpenes and Prostate Cancer
Chemoprevention
Monoterpenes are oils found in many plants including
members of the citrus family. Monoterpenes are commonly
used as flavoring agents and food additives and in various
fragrances (222). Monoterpenes, especially D-limonene and
perillyl alcohol, are recognized as chemopreventive agents
through their demonstrated ability to induce phase II carcinogen-metabolizing enzymes, inhibit posttranslational isoprenylation of small G-proteins including Ras oncogene, and
induce apoptosis in cancer cells (223,224). Only limited efficacy of perillyl alcohol has been observed in clinical studies
of patients with advanced prostate cancer (225). Other studies have shown that monoterpenes are more effective when
used in combination with chemotherapeutic agents (226). It
has also been suggested that monoterpenes are capable of
radiosensitizing prostate cancer cells (227). Additional studies of the potential usefulness of monoterpenes in the management of prostate cancer are needed.
Complementary Agents for Prostate Cancer
Chemoprevention
Complementary medical therapies often referred to as
“complementary and alternative medicine” (CAM) are used
alongside conventional medicine. The National Centre for
Complementary and Alternative Medicine (NCCAM) has
defined CAM as a group of diverse medical and health care
systems, practices, and products that are not normally considered to be conventional medicine (228). In 1994, the Dietary Supplements Health and Education Act opened the
market to many herbals, botanicals, and other food ingredients that would have otherwise needed safety testing before
being sold; these agents are being used with increasing frequency in men with prostate cancer (229). Little is known
about the efficacy of such agents in cancer. There are limited
prospective data supporting the chemopreventive or therapeutic value of such nutritional agents in prostate cancer. To
date, one of the most studied herbal agents for prostate cancer
is PC-SPES (230). PC-SPES is a mixture composed of extracts from eight herbs: Scutellaria baicalensis, Glycyrrhiza
glabra, Ganoderma lucidium, Isatis indigotica, Panax
pseudo-ginseng, Serenoa repens, Dendrantherma morifolium, and Rabdosia rubescens (230,231). All of these are
Chinese herbs except S. repens, an extract of the American
dwarf palm or saw palmetto. A proprietary herbal blend,
25
PC-SPES has been used since 1996 by thousands of men for
“prostate health” (232). PC-SPES contains flavonoids that
have antioxidant, anti-inflammatory, and anticarcinogenic
activity and also contains isoflavones that have some estrogen-like activity (233). PC-SPES has been shown to interfere
with testosterone metabolism and prevent testosterone from
binding to prostate cells (233). Because it is a mixture of
many herbs, it is possible that individual components act synergistically to provide opposition to prostate cancer progression, in part by blocking androgen-supported prostate cell
growth. In cell culture studies, PC-SPES has demonstrated
significant dose-dependent decreases in cell viability in both
androgen-sensitive and -insensitive human prostate cancer
cells (234). The mechanisms that account for its anticarcinogenic effects include induction of apoptosis; cell cycle modulation; down-regulation of Bcl-2, proliferating cell
nuclear antigen, and PSA proteins; down-regulation of AR;
and up-regulation of p53 and Bax proteins (235). Gene expression profiling on LNCaP prostate cancer cells exposed to
PC-SPES has shown alterations in the expression of transcripts encoding cell cycle regulatory proteins, α- and
β-tubulins, and AR (236). Studies on animal models of prostate cancer have confirmed a dose-dependent suppressive effect of PC-SPES on tumor volumes and tumor progression
(234). Clinical studies have suggested that PC-SPES may reduce PSA levels in patients with either androgen-dependent
or -independent prostate cancer (237,238). The clinical effects of PC-SPES appear to be more pronounced in advanced-stage prostate cancer. Additional testing became necessary to identify the active components of PC-SPES and to
define its role in the management of patients with prostate
cancer. However, these studies identified several synthetic
compounds that were present in varying doses in different
batches of PC-SPES, including DES, the synthetic estrogens;
ethinyl estradiol; warfarin, an anticoagulant; and indomethacin, an anti-inflammatory agent. The presence of these
drugs prompted the California Department of Health Services and, subsequently, the Food and Drug Administration
to issue warnings describing the adulteration of PC-SPES.
The product was recalled, production was subsequently
stopped, and studies supported by NCCAM were halted.
This incident raised important concern about clinical trials
utilizing herbal therapies that must account for issues of purity and consistency (239).
Another CAM used in southern India prescribed by
Siddha practitioners is rasagenthi lehyam (RL). RL is composed of 38 different botanicals as well as 8 inorganic compounds, all prepared in a paste form in palm sugar and hen’s
egg base. Preliminary studies with RL extract in different organic solvents have been shown to result in clonogenic inhibition and induction of apoptosis in human prostate cancer
PC-3 cells (240).
Permixon® is another CAM that is an extract from American dwarf palm fruit. S. repens is an effective dual inhibitor
of 5α-reductase isoenzyme activity in human prostate cancer
cells without interfering with PSA expression (241). Clinical
trials for symptomatic benign prostatic hyperplasia demon26
strated significant improvement in peak flow rate and
reduction in nocturia above placebo and five-point reduction
in International Prostate Symptom Score (242).
Equiguard is a composite supplement consisting of standardized extracts from nine Chinese herbs, originally formulated to correct physiological decline in kidney functions associated with age, and was fortuitously found to display
anti-prostate cancer properties. Ethanol extracts of Equiguard
significantly inhibited prostate cancer LNCaP cell growth, induced apoptosis, lowered expression of the AR, decreased
intracellular and secreted PSA levels, and completely abolished the colony-forming activities in these cells (243).
The number and brands of CAM are increasing in the
market and, until definitive evidence of chemopreventive or
antiproliferative effects of these agents is available, the safest, most affordable, and beneficial approach is to consume a
complex mixture in the diet.
Conclusions and Future Directions
Increasing knowledge of prostate carcinogenesis has led
to the widely held view that prostate cancer is a preventable
disease. Because of its long latency period, prostate cancer is
an important target for chemoprevention. 1) Continued efforts are needed to unravel the underlying molecular events
through which chemopreventive agents may exert their
anticarcinogenic effects. Identification of disease subtypes
based on etiological mechanisms may also help to formulate
better preventive approaches for individual patients with specific disease susceptibilities. 2) Novel chemopreventive strategies should be designed that could limit both exposure and
adverse health effects from dietary carcinogens and attenuate
the incidence of prostate tumorigenesis because the complete
elimination of exposure to these agents is not possible. 3) Additional studies are required to identify agents from complex
dietary mixtures, which could be developed for primary or
advanced therapy in the prevention and treatment of the disease. 4) An important future aspect of chemoprevention research should be identification of additional surrogate endpoint biomarkers for clinical disease that will advance this
area of investigation. 5) The development of “combination
chemoprevention” to study the synergistic effects of interactions between agents will be helpful in explaining epidemiological observations investigating prostate cancer risk. This
should be followed by clinical trials on pharmacokinetics and
mechanism-based markers to evaluate the efficacy of promising agents. Overall, more emphasis is needed on preventing
prostate cancer in its earliest stages rather than trying to treat
it in its terminal stages.
Acknowledgments and Notes
This research was sponsored by grants from the National Institutes of
Health RO1 CA108512, R21 CA109424, RO3 CA107806, RO3 CA094248,
and RO3 CA099049 and funds from the Cancer Research and Prevention
Nutrition and Cancer 2005
Foundation. Address correspondence to Sanjay Gupta, Ph.D., Department
of Urology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106. Phone: (216) 368 6162. FAX: (216) 368 0213. E-mail:
[email protected].
Submitted 9 November 2004; accepted in final form 18 August 2005.
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Nutrition and Cancer 2005