1. health and fitness
2. disease
3. 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.
References
1. American Cancer Society, www.cancer.org: Overview: Prostate Cancer: How many men get prostate cancer? 2005.
2. Penson DF and Albertsen PC: Lessons learnt about early prostate cancer from large scale databases: population-based pearls of wisdom.
Surg Oncol 11, 3–11, 2002.
3. Dijkman GA and Debruyne FM: Epidemiology of prostate cancer. Eur
Urol 30, 281–295, 1996.
4. Denis L, Morton MS, and Griffiths K: Diet and its preventive role in
prostatic disease. Eur Urol 35, 377–378, 1999.
5. Donaldson MS: Nutrition and cancer: a review of the evidence for an
anti-cancer diet. Nutr J 3, 1–21, 2004.
6. Moyad MA and Carroll PR: Lifestyle recommendations to prevent
prostate cancer. I. Time to redirect our attention? Urol Clin North Am
31, 289–300, 2004.
7. Shirai T, Asamoto M, Takahashi S, and Imaida K: Diet and prostate
cancer. Toxicology 181–182, 89–94, 2002.
8. Kolonel LN, Altshuler D, and Henderson BE: The multiethnic cohort
study: exploring genes, lifestyle and cancer risk. Nat Rev Cancer 4,
519–527, 2004.
9. Sporn MB: Approaches to prevention of epithelial cancer during the
preneoplastic period. Cancer Res 36, 2699–2702, 1976.
10. Sporn MB and Suh N: Chemoprevention: an essential approach to controlling cancer. Nat Rev Cancer 2, 537–543, 2002.
11. Ansari MS, Gupta NP, and Hemal AK: Chemoprevention of carcinoma prostate: a review. Int Urol Nephrol 34, 207–214, 2002.
12. Montironi R, Barbisan F, and Mazzucchelli R: Target populations,
pathological biomarkers and chemopreventive agents in prostate cancer prevention. Arch Ital Urol Androl 75, 127–134, 2003.
13. Lieberman R: Chemoprevention of prostate cancer: current status and
future directions. Cancer Metastasis Rev 21, 297–309, 2002.
14. Surh YJ: Cancer chemoprevention with dietary phytochemicals. Nat
Rev Cancer 3, 768–780, 2003.
15. Schuurman AG, Goldbohm RA, Dorant E, and van den Brandt PA:
Vegetable and fruit consumption and prostate cancer risk: a cohort
study in The Netherlands. Cancer Epidemiol Biomarkers Prev 7,
673–680, 1998.
16. Riboli E and Norat T: Epidemiologic evidence of the protective effect
of fruit and vegetables on cancer risk. Am J Clin Nutr 78, 559–569,
2003.
17. Gupta S: Prostate cancer chemoprevention: models, limitations and
potential (review). Int J Oncol 25, 1133–1148, 2004.
18. Djavan B, Zlotta A, Schulman C, Teillac P, Iversen P, et al.:
Chemotherapeutic prevention studies of prostate cancer. J Urol 171,
10–13, 2004.
19. Tsao AS, Kim ES, and Hong WK: Chemoprevention of cancer. CA
Cancer J Clin 54, 150–180, 2004.
20. National Cancer Institute: Cancer facts: “chemoprevention.”
Bethesda, MD: National Cancer Institute, 2002.
21. Greenwald P, Clifford CK, and Milner JA: Diet and cancer prevention.
Eur J Cancer 37, 948–965, 2001.
22. Sarkar FH and Li Y: Cell signaling pathways altered by natural
chemopreventive agents. Mutat Res 555, 53–64, 2004.
23. Thompson IM: Pharmacologic agents in complementary medicine in
prostatic disease. Drugs Today 37, 427–433, 2001.
24. Go VL, Wong DA, Resnick MS, and Heber D: Evaluation of botanicals and dietary supplements therapy in cancer patients. J Nutr 131,
179–180, 2001.
Vol. 53, No. 1
25. Katz AE: Flavonoid and botanical approaches to prostate health. J
Altern Complement Med 8, 813–821, 2002.
26. Park EJ and Pezzuto JM: Botanicals in cancer chemoprevention. Cancer Metastasis Rev 21, 231–255, 2002.
27. Kroes R and Walker R: Safety issues of botanicals and botanical preparations in functional foods. Toxicology 198, 213–220, 2004.
28. Kumar NB, Hopkins K, Allen K, Riccardi D, Besterman-Dahan K, et
al.: Use of complementary/integrative nutritional therapies during cancer treatment: implications in clinical practice. Cancer Control 9,
236–243, 2002.
29. Karan D, Lin MF, Johansson SL, and Batra SK: Current status of the
molecular genetics of human prostatic adenocarcinomas. Int J Cancer
103, 285–293, 2003.
30. Shukla S, MacLennan GT, Marengo SR, Seftel AD, Resnick MI, et al.:
Genetic abnormalities in prostate cancer. Curr Genom 5, 67–83, 2004.
31. Abate-Shen C and Shen MM: Molecular genetics of prostate cancer.
Genes Dev 14, 2410–2434, 2000.
32. El Sheikh SS, Domin J, Abel P, Stamp G, and Lalani el-N: Androgen-independent prostate cancer: potential role of androgen and ErbB
receptor signal transduction crosstalk. Neoplasia 5, 99–109, 2003.
33. Thompson TC: Growth factors and oncogenes in prostate cancer. Cancer Cells 2, 345–354, 1990.
34. Giovannucci E: Insulin-like growth factor-I and binding protein-3 and
risk of cancer. Horm Res 51, 34–41, 1999.
35. De Marzo AM, Coffey DS, and Nelson WG: New concepts in tissue
specificity for prostate cancer and benign prostatic hyperplasia. Urology 53, 29–39, 1999.
36. Billis A and Magna LA: Inflammatory atrophy of the prostate. Prevalence and significance. Arch Pathol Lab Med 127, 840–844, 2003.
37. Konig JE, Senge T, Allhoff EP, and Konig W: Analysis of the inflammatory network in benign prostate hyperplasia and prostate cancer.
Prostate 58, 121–129, 2004.
38. Lucia MS and Torkko KC: Inflammation as a target for prostate cancer
chemoprevention: pathological and laboratory rationale. J Urol 171,
30–40, 2004.
39. De Marzo AM, Meeker AK, Zha S, Luo J, Nakayama M, et al.: Human
prostate cancer precursors and pathobiology. Urology 62, 55–62,
2003.
40. Urban T, Hurbain I, Urban M, Clement A, and Housset B: Oxidants
and antioxidants. Biological effects and therapeutic perspectives. Ann
Chir 49, 427–434, 1995.
41. Wang W, Bergh A, and Damber JE: Chronic inflammation in benign
prostate hyperplasia is associated with focal upregulation of
cyclooxygenase-2, Bcl-2, and cell proliferation in the glandular epithelium. Prostate 61, 60–72, 2004.
42. Gupta S, Shukla S, MacLenan GT, Jain S, Resnick MI, et al.: Chronic
inflammation as inductor of prostate carcinogenesis: a needle biopsy
study. Proc Am Assoc Cancer Res 45, 1773, 2004.
43. Shah R, Mucci NR, Amin A, Macoska JA, and Rubin MA:
Postatrophic hyperplasia of the prostate gland: neoplastic precursor or
innocent bystander? Am J Pathol 158, 1767–1773, 2001.
44. Gonzalgo ML and Isaacs WB: Molecular pathways to prostate cancer.
J Urol 170, 2444–2452, 2003.
45. Malins DC, Johnson PM, Wheeler TM, Barker EA, Polissar NL, et al.:
Age-related radical-induced DNA damage is linked to prostate cancer.
Cancer Res 15, 6025–6028, 2001.
46. Morton MS, Griffiths K, and Blacklock N: The preventive role of diet
in prostatic disease. Br J Urol 77, 481–493, 1996.
47. Chan JM and Giovannucci EL: Vegetables, fruits, associated micronutrients, and risk of prostate cancer. Epidemiol Rev 23, 82–86, 2001.
48. Pathak SK, Sharma RA, and Mellon JK: Chemoprevention of prostate
cancer by diet-derived antioxidant agents and hormonal manipulation.
Int J Oncol 22, 5–13, 2003.
49. Cohen LA: Nutrition and prostate cancer: a review. Ann NY Acad Sci
963, 148–155, 2002.
50. Willis MS and Wians FH: The role of nutrition in preventing prostate
cancer: a review of the proposed mechanism of action of various dietary substances. Clin Chim Acta 330, 57–83, 2003.
27
51. Stahl W, Ale-Agha N, and Polidori MC: Non-antioxidant properties of
carotenoids. Biol Chem 383, 553–558, 2002.
52. Lieberman R: Evolving strategies for prostate cancer
chemoprevention trials. World J Urol 21, 3–8, 2003.
53. Moyad MA: The use of complementary/preventive medicine to prevent prostate cancer recurrence/progression following definitive therapy. II. Rapid review of dietary supplements. Curr Opin Urol 13,
147–151, 2003.
54. Shureiqi I and Brenner DE: Chemoprevention of epithelial cancers.
Curr Opin Oncol 11, 408–413, 1999.
55. Greenwald P, Milner JA, Anderson DE, and McDonald SS: Micronutrients in cancer chemoprevention. Cancer Metastasis Rev 21, 217–
230, 2002.
56. Vainio H: Chemoprevention of cancer: a controversial and instructive
story. Br Med Bull 55, 593–599, 1999.
57. Chung FL, Schwartz J, Herzog CR, and Yang YM: Tea and cancer prevention: studies in animals and humans. J Nutr 133, 3268–3274, 2003.
58. Kelly GE and Husband AJ: Flavonoid compounds in the prevention
and treatment of prostate cancer. Methods Mol Med 81, 377–394,
2003.
59. Kristal AR and Lampe JW: Brassica vegetables and prostate cancer
risk: a review of the epidemiological evidence. Nutr Cancer 42, 1–9,
2002.
60. Chinni SR, Li Y, Upadhyay S, Koppolu PK, and Sarkar FH:
Indole-3-carbinol (I3C) induced cell growth inhibition, G1 cell cycle
arrest and apoptosis in prostate cancer cells. Oncogene 20, 2927–2936,
2001.
61. Xiao D, Srivastava SK, Lew KL, Zeng Y, Hershberger P, et al.: Allyl
isothiocyanate, a constituent of cruciferous vegetables, inhibits proliferation of human prostate cancer cells by causing G2/M arrest and inducing apoptosis. Carcinogenesis 24, 891–897, 2003.
62. Barnes S. Soy isoflavones—phytoestrogens and what else? J Nutr 134,
1225–1228, 2004.
63. Vayalil PK, Mittal A, and Katiyar SK: Proanthocyanidins from grape
seeds inhibit expression of matrix metalloproteinases in human prostate carcinoma cells, which is associated with the inhibition of activation of MAPK and NF kappa B. Carcinogenesis 25, 987–995, 2004.
64. Kristal AR: Vitamin A, retinoids and carotenoids as chemopreventive
agents for prostate cancer. J Urol 171, S54–S58, 2004.
65. Cook NR, Le IM, Manson JE, Buring JE, and Hennekens CH: Effects
of beta-carotene supplementation on cancer incidence by baseline
characteristics in the Physicians’ Health Study (United States). Cancer
Causes Control 11, 617–626, 2000.
66. Goodman GE, Schaffer S, Omenn GS, Chen C, and King I: The association between lung and prostate cancer risk, and serum micronutrients:
results and lessons learned from beta-carotene and retinol efficacy
trial. Cancer Epidemiol Biomarkers Prev 12, 518–526, 2003.
67. Schuurman AG, Goldbohm RA, Brants HA, and van den Brandt PA: A
prospective cohort study on intake of retinol, vitamins C and E, and carotenoids and prostate cancer risk (Netherlands). Cancer Causes Control 13, 573–582, 2002.
68. Bosetti C, Talamini R, Montella M, Negri E, Conti E, et al.: Retinol,
carotenoids and the risk of prostate cancer: a case-control study from
Italy. Int J Cancer 112, 689–692, 2004.
69. Hwang ES and Bowen PE: Can the consumption of tomatoes or
lycopene reduce cancer risk? Integr Cancer Ther 1, 121–132, 2002.
70. Jian L, Du CJ, Lee AH, and Binns CW: Do dietary lycopene and other
carotenoids protect against prostate cancer? Int J Cancer 113,
1010–1014, 2005.
71. Etminan M, Takkouche B, and Caamano-Isorna F: The role of tomato
products and lycopene in the prevention of prostate cancer: a
meta-analysis of observational studies. Cancer Epidemiol Biomarkers
Prev 13, 340–345, 2004.
72. Giovannucci E: Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature. JNCI 91, 317–331, 1999.
73. Obermuller-Jevic UC, Olano-Martin E, Corbacho AM, Eiserich JP,
van der Vliet A, et al.: Lycopene inhibits the growth of normal human
prostate epithelial cells in vitro. J Nutr 133, 3356–3360, 2003.
28
74. Aust O, Ale-Agha N, Zhang L, Wollersen H, Sies H, et al.: Lycopene
oxidation product enhances gap junctional communication. Food
Chem Toxicol 41, 1399–1407, 2003.
75. Boileau TW, Liao Z, Kim S, Lemeshow S, Erdman JW Jr, et al.: Prostate carcinogenesis in N-methyl-N-nitrosourea (NMU)-testosterone-treated rats fed tomato powder, lycopene, or energy-restricted diets. JNCI 95, 1578–1586, 2003.
76. Bowen P, Chen L, Stacewicz-Sapuntzakis M, Duncan C, Sharifi R, et
al.: Tomato sauce supplementation and prostate cancer: lycopene accumulation and modulation of biomarkers of carcinogenesis. Exp Biol
Med 227, 886–893, 2002.
77. Campbell JK, Canene-Adams K, Lindshield BL, Boileau TW, Clinton
SK, et al.: Tomato phytochemicals and prostate cancer risk. J Nutr 134,
S3486–S3492, 2004.
78. Kucuk O, Sarkar FH, Sakr W, Djuric Z, Pollak MN, et al.: Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy. Cancer Epidemiol Biomarkers Prev 10, 861–868, 2001.
79. Kucuk O, Sarkar FH, Djuric Z, Sakr W, Pollak MN, et al.: Effects of
lycopene supplementation in patients with localized prostate cancer.
Exp Biol Med 227, 881–885, 2002.
80. Ansari MS and Gupta NP: Lycopene: a novel drug therapy in hormone
refractory metastatic prostate cancer. Urol Oncol 22, 415–420, 2004.
81. Blomhoff R, Green MH, and Norum KR: Vitamin A: physiological
and biochemical processing. Annu Rev Nutr 12, 37–57, 1992.
82. Richter F, Joyce A, Fromowitz F, Wang S, Watson J, et al.:
Immunohistochemical localization of the retinoic acid receptors in human prostate. J Androl 23, 830–838, 2002.
83. Igawa M, Tanabe T, Chodak GW, and Rukstalis DB: N-(4-Hydroxyphenyl) retinamide induces cell cycle specific growth inhibition in
PC3 cells. Prostate 24, 299–305, 1994.
84. Liang JY, Fontana JA, Rao JN, Ordonez JV, Dawson MI, et al.: Synthetic retinoid CD437 induces S-phase arrest and apoptosis in human
prostate cancer cells LNCaP and PC-3. Prostate 38, 228–236, 1999.
85. Webber MM and Waghray A: Urokinase-mediated extracellular matrix degradation by human prostatic carcinoma cells and its inhibition
by retinoic acid. Clin Cancer Res 1, 755–761, 1995.
86. Giovannucci E, Ascherio A, Rimm EB, Stampfer MJ, Colditz GA, et
al.: Intake of carotenoids and retinol in relation to risk of prostate cancer. JNCI 87, 1767–1776, 1995.
87. Ohno Y, Yoshida O, Oishi K, Okada K, Yamabe H, et al.: Dietary
beta-carotene and cancer of the prostate: a case-control study in Kyoto,
Japan. Cancer Res 48, 1331–1336, 1988.
88. Hu ML and Shih MK: Ascorbic acid inhibits lipid peroxidation but enhances DNA damage in rat liver nuclei incubated with iron ions. Free
Radic Res 26, 585–592, 1997.
89. Menon M, Maramag C, Malhotra RK, and Seethalakshmi L: Effect of
vitamin C on androgen independent prostate cancer cells (PC3 and
Mat-Ly-Lu) in vitro: involvement of reactive oxygen species-effect on
cell number, viability and DNA synthesis. Cancer Biochem Biophys
16, 17–30, 1998.
90. Weisburger JH: Mechanisms of action of antioxidants as exemplified
in vegetables, tomatoes and tea. Food Chem Toxicol 37, 943–948,
1999.
91. Taper HS, Jamison JM, Gilloteaux J, Gwin CA, Gordon T, et al.: In
vivo reactivation of DNases in implanted human prostate tumors after
administration of a vitamin C/K(3) combination. J Histochem
Cytochem 49, 109–120, 2001.
92. Agus DB, Vera JC, and Golde DW: Stromal cell oxidation: a mechanism
by which tumors obtain vitamin C. Cancer Res 59, 4555–4558, 1999.
93. Gunawardena K, Campbell LD, and Meikle AW: Combination therapy
with vitamins C plus E inhibits survivin and human prostate cancer cell
growth. Prostate 59, 319–327, 2004.
94. Favus MJ and Langman CB: Evidence for calcium-dependent control
of 1,25-dihydroxyvitamin D3 production by rat kidney proximal tubules. J Biol Chem 261, 11224–11229, 1986.
95. Chen TC, Wang L, Whitlatch LW, Flanagan JN, and Holick MF: Prostatic 25-hydroxyvitamin D-1alpha-hydroxylase and its implication in
prostate cancer. J Cell Biochem 88, 315–322, 2003.
Nutrition and Cancer 2005
96. John EM, Dreon DM, Koo J, and Schwartz GG: Residential sunlight
exposure is associated with a decreased risk of prostate cancer. J Steroid Biochem Mol Biol 89–90, 549–552, 2004.
97. Schwartz GG, Whitlatch LW, Chen TC, Lokeshwar BL, and Holick
MF: Human prostate cells synthesize 1,25-dihydroxyvitamin D3 from
25-hydroxyvitamin D3. Cancer Epidemiol Biomarkers Prev 7, 391–
395, 1998.
98. Stewart LV and Weigel NL: Vitamin D and prostate cancer. Exp Biol
Med 229, 277–284, 2004.
99. Blutt SE, Allegretto EA, Pike JW, and Weigel NL: 1,25Dihydroxyvitamin D3 and 9-cis-retinoic acid act synergistically to inhibit the growth of LNCaP prostate cells and cause accumulation of
cells in G1. Endocrinology 138, 1491–1497, 1997.
100. Polek TC, Stewart LV, Ryu EJ, Cohen MB, Allegretto EA, et al.: p53 is
required for 1,25-dihydroxyvitamin D3-induced G0 arrest but is not
required for G1 accumulation or apoptosis of LNCaP prostate cancer
cells. Endocrinology 144, 50–60, 2003.
101. Rao A, Woodruff RD, Wade WN, Kute TE, and Cramer SD: Genistein
and vitamin D synergistically inhibit human prostatic epithelial cell
growth. J Nutr 132, 3191–3194, 2002.
102. Chan JM and Giovannucci EL: Dairy products, calcium, and vitamin
D and risk of prostate cancer. Epidemiol Rev 23, 87–92, 2001.
103. Platz EA, Leitzmann MF, Hollis BW, Willett WC, and Giovannucci E:
Plasma 1,25-dihydroxy- and 25-hydroxyvitamin D and subsequent
risk of prostate cancer. Cancer Causes Control 15, 255–265, 2004.
104. Tavani A, Bertuccio P, Bosetti C, Talamini R, Negri E, et al.: Dietary
intake of calcium, vitamin d, phosphorus and the risk of prostate cancer. Eur Urol 48, 27–33, 2005.
105. Argao EA and Heubi JE: Fat-soluble vitamin deficiency in infants and
children. Curr Opin Pediatr 5, 562–566, 1993.
106. McCall MR and Frei B: Can antioxidant vitamins materially reduce
oxidative damage in humans? Free Radic Biol Med 26, 1034–1053,
1999.
107. Blatt DH, Leonard SW, and Traber MG: Vitamin E kinetics and the
function of tocopherol regulatory proteins. Nutrition 17, 799–805,
2001.
108. Eichholzer M, Stahelin HB, Gey KF, Ludin E, and Bernasconi F: Prediction of male cancer mortality by plasma levels of interacting vitamins: 17-year follow-up of the prospective Basel study. Int J Cancer
66, 145–150, 1996.
109. Brawley OW, Barnes S, and Parnes H: The future of prostate cancer
prevention. Ann NY Acad Sci 952, 145–152, 2001.
110. Vlajinac HD, Marinkovic JM, Ilic MD, and Kocev NI: Diet and prostate cancer: a case-control study. Eur J Cancer 33, 101–107, 1997.
111. Rodriguez C, Jacobs EJ, Mondul AM, Calle EE, McCullough ML, et
al.: Vitamin E supplements and risk of prostate cancer in U.S. men.
Cancer Epidemiol Biomarkers Prev 13, 378–382, 2004.
112. Eichholzer M, Stahelin HB, Ludin E, and Bernasconi F: Smoking,
plasma vitamins C, E, retinol, and carotene, and fatal prostate cancer:
seventeen-year follow-up of the prospective Basal study. Prostate 38,
189–198, 1999.
113. Wang X and Quinn PJ: Vitamin E and its function in membranes. Prog
Lipid Res 38, 309–336, 1999.
114. Siler U, Barella L, Spitzer V, Schnorr J, Lein M, et al.: Lycopene and
vitamin E interfere with autocrine/paracrine loops in the Dunning
prostate cancer model. FASEB J 18, 1019–1021, 2004.
115. Fazzio A, Marilley D, and Azzi A: The effect of alpha-tocopherol and
beta-tocopherol on proliferation, protein kinase C activity and gene expression in different cell lines. Biochem Mol Biol Int 41, 93–101, 1997.
116. Gunawardena K, Murray DK, and Meikle AW: Vitamin E and other
antioxidants inhibit human prostate cancer cells through apoptosis.
Prostate 44, 287–295, 2000.
117. Zhang Y, Ni J, Messing EM, Chang E, Yang CR, et al.: Vitamin E
succinate inhibits the function of androgen receptor and the expression
of prostate-specific antigen in prostate cancer cells. Proc Natl Acad Sci
USA 99, 7408–7413, 2002.
118. Heinonen OP, Albanes D, Virtamo J, Taylor PR, Huttunen JK, et al.:
Prostate cancer and supplementation with alpha-tocopherol and
Vol. 53, No. 1
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
beta-carotene: incidence and mortality in a controlled trial. JNCI 90,
440–446, 1998.
Weinstein SJ, Wright ME, Pietinen P, King I, Tan C, et al.: Serum alpha-tocopherol and gamma-tocopherol in relation to prostate cancer
risk in a prospective study. JNCI 97, 396–399, 2005.
Lippman SM, Goodman PJ, Klein EA, Parnes HL, Thompson IM Jr, et
al.: Designing the Selenium and Vitamin E Cancer Prevention Trial
(SELECT). JNCI 97, 94–102, 2005.
Ferguson LR, Philpott M, and Karunasinghe N: Dietary cancer and
prevention using antimutagens. Toxicology 198, 147–159, 2004.
Soriano-Garcia M: Organoselenium compounds as potential therapeutic and chemopreventive agents: a review. Curr Med Chem 11, 1657–
1669, 2004.
Sinha R and El-Bayoumy K: Apoptosis is a critical cellular event in
cancer chemoprevention and chemotherapy by selenium compounds.
Curr Cancer Drug Targets 4, 13–28, 2004.
Clark LC, Dalkin B, Krongrad A, Combs GF Jr, Turnbull BW, et al.:
Decreased incidence of prostate cancer with selenium
supplementation: results of a double-blind cancer prevention trial. Br J
Urol 81, 730–734, 1998.
Hartman TJ, Albanes D, Pietinen P, Hartman AM, Rautalahti M, et al.:
The association between baseline vitamin E, selenium, and prostate
cancer in the alpha-tocopherol, beta-carotene cancer prevention study.
Cancer Epidemiol Biomarkers Prev 7, 335–340, 1998.
Jiang C, Ganther H, and Lu J: Monomethyl selenium-specific inhibition of MMP-2 and VEGF expression: implications for angiogenic
switch regulation. Mol Carcinog 29, 236–250, 2000.
Krishnan K, Campbell S, Abdel-Rahman F, Whaley S, and Stone WL:
Cancer chemoprevention drug targets. Curr Drug Targets 4, 45–54,
2003.
Cho SD, Jiang C, Malewicz B, Dong Y, Young CY, et al.: Methyl selenium metabolites decrease prostate-specific antigen expression by inducing protein degradation and suppressing androgen-stimulated transcription. Mol Cancer Ther 3, 605–611, 2004.
Venkateswaran V, Fleshner NE, and Klotz LH: Synergistic effect of vitamin E and selenium in human prostate cancer cell lines. Prostate
Cancer Prostatic Dis 7, 54–56, 2004.
Powell SR: The antioxidant properties of zinc. J Nutr 130, S1447–
S1454, 2000.
Liang JY, Liu YY, Zou J, Franklin RB, Costello LC, et al.: Inhibitory
effect of zinc on human prostatic carcinoma cell growth. Prostate 40,
200–207, 1999.
Williams CA and Grayer RJ: Anthocyanins and other flavonoids. Nat
Prod Rep 21, 539–573, 2004.
Cuyckens F and Claeys M: Mass spectrometry in the structural analysis of flavonoids. J Mass Spectrom 39, 1–15, 2004.
Ross JA and Kasum CM: Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu Rev Nutr 22, 19–34, 2002.
Robak J and Gryglewski RJ: Bioactivity of flavonoids. Pol J
Pharmacol 48, 555–564, 1996.
Moyad MA: Soy, disease prevention, and prostate cancer. Semin Urol
Oncol 17, 97–102, 1999.
Santibanez JF, Navarro A, and Martinez J: Genistein inhibits proliferation and in vitro invasive potential of human prostatic cancer cell lines.
Anticancer Res 17, 1199–1204, 1997.
Davis JN, Singh B, Bhuiyan M, and Sarkar FH: Genistein-induced
upregulation of p21WAF1, downregulation of cyclin B, and induction of apoptosis in prostate cancer cells. Nutr Cancer 32, 123–131,
1998.
Li Y and Sarkar FH: Inhibition of nuclear factor kappaB activation in
PC3 cells by genistein is mediated via Akt signaling pathway. Clin
Cancer Res 8, 2369–2377, 2002.
Li Y and Sarkar FH: Down-regulation of invasion and angiogenesis-related genes identified by cDNA microarray analysis of PC3
prostate cancer cells treated with genistein. Cancer Lett 186, 157–164,
2002.
Bektic J, Berger AP, Pfeil K, Dobler G, Bartsch G, et al.: Androgen receptor regulation by physiological concentrations of the isoflavonoid
29
142.
143.
144.
145.
146.
147.
148.
149.
150.
151.
152.
153.
154.
155.
156.
157.
158.
159.
160.
161.
30
genistein in androgen-dependent LNCaP cells is mediated by estrogen
receptor beta. Eur Urol 45, 245–251, 2004.
Day JK, Bauer AM, DesBordes C, Zhuang Y, Kim BE, et al.: Genistein
alters methylation patterns in mice. J Nutr 132, S2419–S2423, 2002.
Mentor-Marcel R, Lamartiniere CA, Eltoum IA, Greenberg NM, and
Elgavish A: Dietary genistein improves survival and reduces expression of osteopontin in the prostate of transgenic mice with prostatic
adenocarcinoma (TRAMP). J Nutr 135, 989–995, 2005.
Li Y, Che M, Bhagat S, Ellis KL, Kucuk O, et al.: Regulation of gene
expression and inhibition of experimental prostate cancer bone metastasis by dietary genistein. Neoplasia 6, 354–363, 2004.
Fischer L, Mahoney C, Jeffcoat AR, Koch MA, Thomas BE, et al.:
Clinical characteristics and pharmacokinetics of purified soy
isoflavones: multiple-dose administration to men with prostate neoplasia. Nutr Cancer 48, 160–170, 2004.
deVere White RW, Hackman RM, Soares SE, Beckett LA, Li Y, et al.:
Effects of a genistein-rich extract on PSA levels in men with a history
of prostate cancer. Urology 63, 259–263, 2004.
Adams KF, Chen C, Newton KM, Potter JD, and Lampe JW: Soy
isoflavones do not modulate prostate-specific antigen concentrations
in older men in a randomized controlled trial. Cancer Epidemiol
Biomarkers Prev 13, 644–648, 2004.
Saleem M, Adhami VM, Siddiqui IA, and Mukhtar H: Tea beverage in
chemoprevention of prostate cancer: a mini-review. Nutr Cancer 47,
13–23, 2003.
Frei B and Higdon JV: Antioxidant activity of tea polyphenols in vivo:
evidence from animal studies. J Nutr 133, 3275–3284, 2003.
Gupta S, Saha B, and Giri AK: Comparative antimutagenic and
anticlastogenic effects of green tea and black tea: a review. Mutat Res
512, 37–65, 2002.
Gupta S, Ahmad N, and Mukhtar H: Prostate cancer chemoprevention
by green tea. Semin Urol Oncol 17, 70–76, 1999.
Klein RD and Fischer SM: Black tea polyphenols inhibit IGF-I-induced signaling through Akt in normal prostate epithelial cells and
DU145 prostate carcinoma cells. Carcinogenesis 23, 217–221, 2002.
Adhami VM, Ahmad N, and Mukhtar H: Molecular targets for green
tea in prostate cancer prevention. J Nutr 133, 2417–2424, 2003.
Siddiqui IA, Adhami VM, Afaq F, Ahmad N, and Mukhtar H: Modulation of phosphatidylinositol-3-kinase/protein kinase B- and
mitogen-activated protein kinase-pathways by tea polyphenols in human prostate cancer cells. J Cell Biochem 91, 232–242, 2004.
Gupta S, Hastak K, Afaq F, Ahmad N, and Mukhtar H: Essential role
of caspases in epigallocatechin-3-gallate-mediated inhibition of nuclear factor kappa B and induction of apoptosis. Oncogene 23,
2507–2522, 2004.
Nam S, Smith DM, and Dou QP: Ester bond-containing tea polyphenols potently inhibit proteasome activity in vitro and in vivo. J Biol
Chem 276, 13322–13330, 2001.
Fang MZ, Wang Y, Ai N, Hou Z, Sun Y, et al.: Tea polyphenol
(–)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Re.s
63, 7563–7570, 2003.
Gupta S, Hastak K, Ahmad N, Lewin JS, and Mukhtar H: Inhibition of
prostate carcinogenesis in TRAMP mice by oral infusion of green tea
polyphenols. Proc Natl Acad Sci USA 98, 10350–10355, 2001.
Adhami VM, Siddiqui IA, Ahmad N, Gupta S, and Mukhtar H: Oral
consumption of green tea polyphenols inhibits insulin-like growth factor-I-induced signaling in an autochthonous mouse model of prostate
cancer. Cancer Res 64, 8715–8722, 2004.
Saleem M, Adhami VM, Ahmad N, Gupta S, and Mukhtar H:
Prognostic significance of metastasis-associated protein S100A4
(Mts1) in prostate cancer progression and chemoprevention regimens
in an autochthonous mouse model. Clin Cancer Res 11, 147–153,
2005.
Jian L, Xie LP, Lee AH, and Binns CW: Protective effect of green tea
against prostate cancer: a case-control study in southeast China. Int J
Cancer 108, 130–135, 2004.
162. Jatoi A, Ellison N, Burch PA, Sloan JA, Dakhil SR, et al.: A phase II
trial of green tea in the treatment of patients with androgen independent metastatic prostate carcinoma. Cancer 97, 1442–1446, 2003.
163. Choan E, Segal R, Jonker D, Malone S, Reaume N, et al.: A prospective clinical trial of green tea for hormone refractory prostate cancer:
an evaluation of the complementary/alternative therapy approach.
Urol Oncol 23, 108–113, 2005.
164. Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, et al.: Cancer
chemopreventive activity of resveratrol, a natural product derived from
grapes. Science 275, 218–220, 1997.
165. Aziz MH, Kumar R, and Ahmad N: Cancer chemoprevention by
resveratrol: in vitro and in vivo studies and the underlying mechanisms
(review). Int J Oncol 23, 17–28, 2003.
166. Hsieh TC and Wu JM: Differential effects on growth, cell cycle arrest,
and induction of apoptosis by resveratrol in human prostate cancer cell
lines. Exp Cell Res 249, 109–115, 1999.
167. Narayanan BA, Narayanan NK, Re GG, Nixon DW, Narayanan BA, et
al.: Differential expression of genes induced by resveratrol in LNCaP
cells: P53-mediated molecular targets. Int J Cancer 104, 204–212,
2003.
168. Narayanan BA, Narayanan NK, Stoner GD, and Bullock BP: Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci 70, 1821–1839, 2002.
169. Shih A, Zhang S, Cao HJ, Boswell S, Wu YH, et al.: Inhibitory effect
of epidermal growth factor on resveratrol-induced apoptosis in prostate cancer cells is mediated by protein kinase C-alpha. Mol Cancer
Ther 3, 1355–1364, 2004.
170. Cardile V, Scifo C, Russo A, Falsaperla M, Morgia G, et al.: Involvement of HSP70 in resveratrol-induced apoptosis of human prostate
cancer. Anticancer Res 23, 4921–4926, 2003.
171. Hsieh TC and Wu JM: Grape-derived chemopreventive agent
resveratrol decreases prostate-specific antigen (PSA) expression in
LNCaP cells by an androgen receptor (AR)-independent mechanism.
Anticancer Res 20, 225–228, 2000.
172. Singh RP and Agarwal R: Flavonoid antioxidant silymarin and skin
cancer. Antioxid Redox Signal 4, 655–663, 2002.
173. Chlopcikova S, Psotova J, Miketova P, and Simanek V: Chemoprotective effect of plant phenolics against anthracycline-induced toxicity on rat cardiomyocytes. I. Silymarin and its flavonolignans.
Phytother Res 18, 107–110, 2004.
174. Zhu W, Zhang JS, and Young CY: Silymarin inhibits function of the
androgen receptor by reducing nuclear localization of the receptor in
the human prostate cancer cell line LNCaP. Carcinogenesis 22,
1399–1403, 2001.
175. Zi X and Agarwal R: Silibinin decreases prostate-specific antigen with
cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention.
Proc Natl Acad Sci USA 96, 7490–7495, 1999.
176. Singh RP and Agarwal R: Prostate cancer prevention by silibinin. Curr
Cancer Drug Targets 4, 1–11, 2004.
177. Thelen P, Wuttke W, Jarry H, Grzmil M, and Ringert RH: Inhibition of
telomerase activity and secretion of prostate specific antigen by
silibinin in prostate cancer cells. J Urol 171, 1934–1938, 2004.
178. Tyagi AK, Singh RP, Agarwal C, Chan DC, and Agarwal R: Silibinin
strongly synergizes human prostate carcinoma DU145 cells to
doxorubicin-induced growth inhibition, G2-M arrest, and apoptosis.
Clin Cancer Res 8, 3512–3519, 2002.
179. Singh RP, Sharma G, Dhanalakshmi S, Agarwal C, and Agarwal R:
Suppression of advanced human prostate tumor growth in athymic
mice by silibinin feeding is associated with reduced cell proliferation,
increased apoptosis, and inhibition of angiogenesis. Cancer Epidemiol
Biomarkers Prev 12, 933–939, 2003.
180. Shi J, Yu J, Pohorly JE, and Kakuda Y: Polyphenolics in grape seeds—
biochemistry and functionality. J Med Food 4, 291–299, 2003.
181. Zhao J, Wang J, Chen Y, and Agarwal R: Anti-tumor-promoting activity of a polyphenolic fraction isolated from grape seeds in the mouse
skin two-stage initiation-promotion protocol and identification of
Nutrition and Cancer 2005
182.
183.
184.
185.
186.
187.
188.
189.
190.
191.
192.
193.
194.
195.
196.
197.
198.
procyanidin B5–3′-gallate as the most effective antioxidant constituent. Carcinogenesis 20, 1737–1745, 1999.
Agarwal C, Singh RP, and Agarwal R: Grape seed extract induces
apoptotic death of human prostate carcinoma DU145 cells via
caspases activation accompanied by dissipation of mitochondrial
membrane potential and cytochrome c release. Carcinogenesis 23,
1869–1876, 2002.
Dhanalakshmi S, Agarwal R, and Agarwal C: Inhibition of
NF-kappaB pathway in grape seed extract-induced apoptotic death of
human prostate carcinoma DU145 cells. Int J Oncol 23, 721–727,
2003.
Agarwal C, Singh RP, Dhanalakshmi S, and Agarwal R:
Anti-angiogenic efficacy of grape seed extract in endothelial cells.
Oncol Rep 11, 681–685, 2004.
Singh RP, Tyagi AK, Dhanalakshmi S, Agarwal R, and Agarwal C:
Grape seed extract inhibits advanced human prostate tumor growth
and angiogenesis and upregulates insulin-like growth factor binding
protein-3. Int J Cancer 108, 733–740, 2004.
O’Prey J, Brown J, Fleming J, and Harrison PR: Effects of dietary
flavonoids on major signal transduction pathways in human epithelial
cells. Biochem Pharmacol 66, 2075–2088, 2003.
Yin F, Giuliano AE, Law RE, and Van Herle AJ: Apigenin inhibits
growth and induces G2/M arrest by modulating cyclin-CDK regulators
and ERK MAP kinase activation in breast carcinoma cells. Anticancer
Res 21, 413–420, 2001.
Gupta S, Afaq F, and Mukhtar H: Selective growth-inhibitory, cell-cycle deregulatory and apoptotic response of apigenin in normal versus
human prostate carcinoma cells. Biochem Biophys Res Commun 287,
914–920, 2001.
Shukla S and Gupta S: Molecular mechanisms for apigenin-induced
cell-cycle arrest and apoptosis of hormone refractory human prostate
carcinoma DU145 cells. Mol Carcinog 39, 114–126, 2004.
Lee SC, Kuan CY, Yang CC, and Yang SD: Bioflavonoids commonly
and potently induce tyrosine dephosphorylation/inactivation of
oncogenic proline-directed protein kinase FA in human prostate carcinoma cells. Anticancer Res 18, 1117–1121, 1998.
Makela S, Poutanen M, Kostian ML, Lehtimaki N, Strauss L, et al.: Inhibition of 17beta-hydroxysteroid oxidoreductase by flavonoids in
breast and prostate cancer cells. Proc Soc Exp Biol Med 217, 310–316,
1998.
Gupta S, Afaq F, and Mukhtar H: Involvement of nuclear factor-kappa
B, Bax and Bcl-2 in induction of cell cycle arrest and apoptosis by
apigenin in human prostate carcinoma cells. Oncogene 21,
3727–3738, 2002.
Shukla S and Gupta S: Suppression of constitutive and tumor necrosis
factor alpha-induced nuclear factor (NF)-kappaB activation and induction of apoptosis by apigenin in human prostate carcinoma PC-3 cells:
correlation with down-regulation of NF-kappaB-responsive genes.
Clin Cancer Res 10, 3169–3178, 2004.
Nachshon-Kedmi M, Yannai S, Haj A, and Fares FA:
Indole-3-carbinol and 3,3′-diindolylmethane induce apoptosis in human prostate cancer cells. Food Chem Toxicol 41, 745–752, 2003.
Howells LM, Gallacher-Horley B, Houghton CE, Manson MM, and
Hudson EA: Indole-3-carbinol inhibits protein kinase B/Akt and induces apoptosis in the human breast tumor cell line MDA MB468 but
not in the nontumorigenic HBL100 line. Mol Cancer Ther 1, 1161–
1172, 2002.
Li Y, Li X, and Sarkar FH: Gene expression profiles of I3C- and
DIM-treated PC3 human prostate cancer cells determined by cDNA
microarray analysis. J Nutr 133, 1011–1019, 2003.
Zhang J, Hsu JC, Kinseth MA, Bjeldanes LF, and Firestone GL:
Indole-3-carbinol induces a G1 cell cycle arrest and inhibits prostate-specific antigen production in human LNCaP prostate carcinoma
cells. Cancer 98, 2511–2520, 2003.
Nachshon-Kedmi M, Fares FA, and Yannai S: Therapeutic activity of
3,3′-diindolylmethane on prostate cancer in an in vivo model. Prostate
61, 153–160, 2004.
Vol. 53, No. 1
199. Garikapaty VP, Ashok BT, Chen YG, Mittelman A, Iatropoulos M, et
al.: Anti-carcinogenic and anti-metastatic properties of indole3-carbinol in prostate cancer. Oncol Rep 13, 89–93, 2005.
200. Chiao JW, Chung F, Krzeminski J, Amin S, Arshad R, et al.: Modulation of growth of human prostate cancer cells by the N-acetylcysteine
conjugate of phenethyl isothiocyanate. Int J Oncol 16, 1215–1219,
2000.
201. Kolonel LN, Hankin JH, Whittemore AS, Wu AH, Gallagher RP, et al.:
Vegetables, fruits, legumes and prostate cancer: a multiethnic
case-control study. Cancer Epidemiol Biomarkers Prev 9, 795–804,
2000.
202. Cohen JH, Kristal AR, and Stanford JL: Fruit and vegetable intakes
and prostate cancer risk. JNCI 92, 61–68, 2000.
203. Wang L, Liu D, Ahmed T, Chung FL, Conaway C, et al.: Targeting cell
cycle machinery as a molecular mechanism of sulforaphane in prostate
cancer prevention. Int J Oncol 24, 187–192, 2004.
204. Brooks JD, Paton VG, and Vidanes G: Potent induction of phase 2 enzymes in human prostate cells by sulforaphane. Cancer Epidemiol
Biomarkers Prev 10, 949–954, 2001.
205. Kong AN, Yu R, Hebbar V, Chen C, Owuor E, et al.: Signal
transduction events elicited by cancer prevention compounds. Mutat
Res 480–481, 231–241, 2001.
206. Singh SV, Herman-Antosiewicz A, Singh AV, Lew KL, Srivastava SK,
et al.: Sulforaphane-induced G2/M phase cell cycle arrest involves
checkpoint kinase 2-mediated phosphorylation of cell division cycle
25C. J Biol Chem 279, 25813–25822, 2004.
207. Singh AV, Xiao D, Lew KL, Dhir R, and Singh SV: Sulforaphane induces caspase-mediated apoptosis in cultured PC-3 human prostate
cancer cells and retards growth of PC-3 xenografts in vivo.
Carcinogenesis 25, 83–90, 2004.
208. Xu C, Shen G, Chen C, Gelinas C, and Kong AN: Suppression of
NF-kappaB and NF-kappaB-regulated gene expression by
sulforaphane and PEITC through IkappaBalpha, IKK pathway in human prostate cancer PC-3 cells. Oncogene 24, 4486–4495, 2005.
209. Robbins RJ: Phenolic acids in foods: an overview of analytical methodology. J Agric Food Chem 51, 2866–2887, 2003.
210. Lopez-Velez M, Martinez-Martinez F, and Del Valle-Ribes C: The
study of phenolic compounds as natural antioxidants in wine. Crit Rev
Food Sci Nutr 43, 233–244, 2003.
211. Mukhopadhyay A, Banerjee S, Stafford LJ, Xia C, Liu M, et al.:
Curcumin-induced suppression of cell proliferation correlates with
down-regulation of cyclin D1 expression and CDK4-mediated retinoblastoma protein phosphorylation. Oncogene 21, 8852–8861,
2002.
212. Dorai T, Cao YC, Dorai B, Buttyan R, and Katz AE: Therapeutic potential of curcumin in human prostate cancer. III. Curcumin inhibits
proliferation, induces apoptosis, and inhibits angiogenesis of LNCaP
prostate cancer cells in vivo. Prostate 47, 293–303, 2001.
213. Gopalakrishna R and Gundimeda U: Antioxidant regulation of protein
kinase C in cancer prevention. J Nutr 132, S3819–S3823, 2002.
214. Nakamura K, Yasunaga Y, Segawa T, Ko D, Moul JW, et al.: Curcumin
down-regulates AR gene expression and activation in prostate cancer
cell lines. Int J Oncol 21, 825–830, 2002.
215. Kumar AP, Garcia GE, Ghosh R, Rajnarayanan RV, Alworth WL, et
al.: 4-Hydroxy-3-methoxybenzoic acid methyl ester: a curcumin derivative targets Akt/NF kappa B cell survival signaling pathway: potential for prostate cancer management. Neoplasia 5, 255–266, 2003.
216. Sah NK, Munshi A, Kurland JF, McDonnell TJ, Su B, et al.: Translation inhibitors sensitize prostate cancer cells to apoptosis induced by
tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by
activating c-Jun N-terminal kinase. J Biol Chem 278, 20593–20602,
2003.
217. Chendil D, Ranga RS, Meigooni D, Sathishkumar S, and Ahmed MM:
Curcumin confers radiosensitizing effect in prostate cancer cell line
PC-3. Oncogene 23, 1599–1607, 2004.
218. Sigounas G, Hooker J, Anagnostou A, and Steiner M:
S-Allylmercaptocysteine inhibits cell proliferation and reduces the vi-
31
219.
220.
221.
222.
223.
224.
225.
226.
227.
228.
229.
230.
231.
232.
32
ability of erythroleukemia, breast, and prostate cancer cell lines. Nutr
Cancer 27, 186–191, 1997.
Amagase H, Petesch BL, Matsuura H, Kasuga S, and Itakura Y: Intake
of garlic and its bioactive components. J Nutr 131, 955–962, 2001.
Herman-Antosiewicz A and Singh SV: Signal transduction pathways
leading to cell cycle arrest and apoptosis induction in cancer cells by
Allium vegetable-derived organosulfur compounds: a review. Mutat
Res 555, 121–131, 2004.
Pinto JT, Qiao C, Xing J, Suffoletto BP, Schubert KB, et al.: Alterations of prostate biomarker expression and testosterone utilization in
human LNCaP prostatic carcinoma cells by garlic-derived
S-allylmercaptocysteine. Prostate 45, 304–314, 2000.
Grayson DH: Monoterpenoids. Nat Prod Rep 11, 225–247, 1994.
Crowell PL: Prevention and therapy of cancer by dietary
monoterpenes. J Nutr 129, S775–S778, 1999.
Karlson J, Borg-Karlson AK, Unelius R, Shoshan MC, Wilking N, et
al.: Inhibition of tumor cell growth by monoterpenes in vitro: evidence
of a Ras-independent mechanism of action. Anticancer Drugs 7,
422–429, 1996.
Liu G, Oettel K, Bailey H, Ummersen LV, Tutsch K, et al.: Phase II
trial of perillyl alcohol (NSC 641066) administered daily in patients
with metastatic androgen independent prostate cancer. Invest New
Drugs 21, 367–372, 2003.
Broitman SA, Wilkinson J IV, Cerda S, and Branch SK: Effects of
monoterpenes and mevinolin on murine colon tumor CT-26 in vitro
and its hepatic “metastases” in vivo. Adv Exp Med Biol 401, 111–130,
1996.
Rajesh D and Howard SP: Perillyl alcohol mediated radiosensitization
via augmentation of the Fas pathway in prostate cancer cells. Prostate
57, 14–23, 2003.
Nelson PS and Montgomery B: Unconventional therapy for prostate
cancer: good, bad or questionable? Nat Rev Cancer 3, 845–858, 2003.
Wilkinson S and Chodak GW: Critical review of complementary therapies for prostate cancer. J Clin Oncol 21, 2199–2210, 2003.
Meyer JP and Gillatt DA: PC-SPES: A herbal therapy for the treatment
of hormone refractory prostate cancer. Prostate Cancer Prostatic Dis
5, 13–15, 2002.
Yip I, Cudiamat M, and Chim D: PC-SPES for treatment of prostate
cancer: herbal medicine. Curr Urol Rep 4, 253–257, 2003.
de la Taille A: PC SPES in prostatic cancer: critical review of the literature. Prog Urol 11, 428–432, 2001.
233. Tiwari RK, Geliebter J, Garikapaty VP, Yedavelli SP, Chen S, et al.:
Anti-tumor effects of PC-SPES, an herbal formulation in prostate cancer. Int J Oncol 14, 713–719, 1999.
234. Kubota T, Hisatake J, Hisatake Y, Said JW, Chen SS, et al.: PC-SPES: a
unique inhibitor of proliferation of prostate cancer cells in vitro and in
vivo. Prostate 42, 163–171, 2000.
235. Chenn S: In vitro mechanism of PC SPES. Urology 58, 28–35, 2001.
236. Bonham M, Arnold H, Montgomery B, and Nelson PS: Molecular effects of the herbal compound PC-SPES: identification of activity pathways in prostate carcinoma. Cancer Res 62, 3920–3924, 2002.
237. Oh WK, George DJ, Hackmann K, Manola J, and Kantoff PW: Activity of the herbal combination, PC-SPES, in the treatment of patients
with androgen-independent prostate cancer. Urology 57, 122–126,
2001.
238. Small EJ, Frohlich MW, Bok R, Shinohara K, Grossfeld G, et al.: Prospective trial of the herbal supplement PC-SPES in patients with progressive prostate cancer. J Clin Oncol 18, 3595–3603, 2000.
239. Oh WK, Kantoff PW, Weinberg V, Jones G, Rini BI, et al.: Prospective,
multicenter, randomized phase II trial of the herbal supplement,
PC-SPES, and diethylstilbestrol in patients with androgen-independent prostate cancer. J Clin Oncol 22, 3705–3712, 2004.
240. Ranga RS, Girija R, Nur-e-Alam M, Sathishkumar S, Akbarsha MA, et
al.: Rasagenthi lehyam (RL) a novel complementary and alternative
medicine for prostate cancer. Cancer Chemother Pharmacol 54, 7–15,
2004.
241. Habib FK, Ross M, Ho CK, Lyons V, and Chapman K: Serenoa repens
(Permixon) inhibits the 5alpha-reductase activity of human prostate
cancer cell lines without interfering with PSA expression. Int J Cancer
114, 190–194, 2005.
242. Al-Shukri SH, Deschaseaux P, Kuzmin IV, and Amdiy RR: Early
urodynamic effects of the lipido-sterolic extract of Serenoa repens
(Permixon®) in patients with lower urinary tract symptoms due to benign prostatic hyperplasia. Prostate Cancer Prostatic Dis 3, 195–199,
2000.
243. Lu X, Guo J, Hsieh TC, and Wu JM: Inhibition of proliferation and expression of AR/PSA by herbal supplement Equiguard in LNCaP cells
cultured in androgen-proficient FBS and androgen-deficient charcoal-stripped FBS is correlated with increased serine-15
phosphorylation of the tumor suppressor gene p53. Anticancer Res 23,
2489–2498, 2003.
Nutrition and Cancer 2005