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Introduction
In recent years there has been increasing interest in the
use of biologically active phytochemicals in cancer
prevention. In particular, many in vitro studies using a wide
range of natural products have demonstrated a preferential
induction of cell cycle arrest or apoptosis in tumor cell lines
compared to lines derived from non-tumor tissue. On further
investigation, phytochemicals have been found to modulate
the expression or activity of a large number of cellular
proteins which are key for cell survival and the transformed
phenotype. However, there is also much concern that many
of these effects[1_3] are irrelevant
in vivo, since the concentrations used are often orders of magnitude greater than
appear to be achievable in the human body.
In this review, we have attempted to address this
concern for a few of the most studied diet-derived compounds.
For each agent, we have assimilated reported in
vivo concen-trations, based where possible on human data. We have
then surveyed the in vitro biological effects at these or lower
doses. For the indoles only, we have included data on phase
I drug metabolizing activity relating to altered estrogen
metabolism. Encouragingly, a significant amount of
published data validates some of these changes in
vivo.
For a number of reasons, some guesswork was involved
in deciding on the most relevant in vitro doses for
considera-tion. First, adding a compound directly to a cell culture may
deliver a much higher local dose than occurs following
ingestion in the body. Second, some if not all of the
compounds may undergo metabolism in vivo to other more or
less active derivatives and such metabolism may not be
possible in culture. Third, higher in vivo doses than those so far
reported may be achievable by administration of a pure
compound rather than a dietary source, or an optimized
formulation of a pure compound. Fourth, some target tissues may
receive a higher (or more prolonged) dose than the reported
peak levels in plasma. Fifth, some target tissues, such as
skin, oral cavity, gastrointestinal tract, and bladder, may
receive higher doses because they are not dependent on
circulating levels. The colon, for example, can be exposed to
significant amounts of (unabsorbed) excreted material and
the lining of the bladder may be exposed for substantial
periods of time to any compounds concentrated in urine.
Finally, where diet is concerned, any one compound may be
poorly bioavailable, but with dozens, even hundreds, of
active molecules being ingested together, the cumulative
dose of similar acting compounds may be significantly higher.
It should not be forgotten that some natural products
have exhibited toxicity in vivo when given in high doses, so
there is also an argument for the use of higher
concentrations in vitro to indicate the full range of activity of these
molecules.
Indole-3-carbinol and diindolylmethane
Indole-3-carbinol (I3C) is derived from glucobrassicin,
found in cruciferous vegetables. Diindolylmethane (DIM) is
an acid condensation product formed from 2 molecules of
I3C. In vivo, this is thought to occur in the acid conditions of
the stomach. Data for mammals only are considered here.
Bioavailability of I3C and DIM in humans
Information on the bioavailability and tissue distribution of I3C or DIM
in humans is very limited[4_6]. However, there are a number
of studies in which oral administration of I3C resulted in a
biochemically or clinically measurable outcome, indicating
that the absorption of I3C and/or its acid-condensation
products does occur. Administered doses of I3C have ranged
from 200 to 500 mg/d (~ 6_7 mg/kg), typically for periods of
1_6 months, although treatments up to 82 months have also
been reported[7_14]. A dose-dependent effect (placebo, 200
and 400 mg/d for 3 months) was observed in the treatment of
cervical intraepithelial neoplasia[7], and 200 or 400 mg/d were
similarly effective against vulval intraepithelial
neoplasia[14]. In dose-escalation studies for breast cancer prevention, 300
mg/d (minimum) increased the urinary estrogen metabolite
ratio of 2-hydroxyestrone to 16 alpha-hydroxyestrone; 800
mg/d did not provide additional benefits over 400 mg/d in
adult women[15,16]. Elevated cytochrome P450 activity was
responsible for an increase in 2-hydroxylation of estrogen,
increasing the ratio of 2-OH:16-OH
estrone[16], which is
regarded as favorable for the prevention of breast cancer
and human papilloma virus (HPV)-related
neoplasias[7_14].
Two studies detected DIM in plasma (2.5 µmol/L
maximum at 2 h, gradually decreasing by 12 h) or in urine
following oral administration of I3C (Table 1). I3C was not detected
in plasma or serum following oral doses of 400_1200
mg[4,5]. DIM was also detected in the urine of a patient receiving
DIM[4]. In a pilot study using a formulation of enhanced
absorption DIM (BioResponse DIM, 108 mg/d for 30 d),
increased 2-hydroxylation of estrogen was also
reported[6].
Bioavailability of I3C and DIM in animals
Radio-labeled I3C was used to follow distribution and tissue content in
several studies, although this method did not differentiate
between I3C and related products. In rats receiving 50 mg
14C-I3C by gavage, I3C equivalents peaked at 28 µmol/L in
the blood and 121 µmol/L in the liver after 30 min. The
labeled product was detectable in the 100 µmol/L range from
10 min to 2 h following dosing[17]. High maximal
concentrations of the I3C equivalent, but not I3C itself, were detected
in the liver (1154 µmol/L), kidney, lung (436 µmol/L), blood
(320 µmol/L), and tongue of the rats given
3H-I3C in the diet for 1 week (0.88+/_0.074
mmol/kg/d)[18]. Once a steady state had been reached, excretion in feces and urine accounted for
75% dose/d, the majority of this being present in the feces
by 110 h, indicating that either the dose was not absorbed or
that a major excretory route was via bile. When
14C-I3C was given to pregnant mice, it was detected in the fetal liver,
stomach, kidney, intestine, and lung (100_300 µmol/L) after
8 h of maternal exposure[19].
Anderton et al detected I3C and DIM in tissues
following the dosing of mice with 250 mg/kg I3C (Table 2) using an
HPLC method allowing the simultaneous identification and
quantification of I3C and its
derivatives[20]. The maximum level of 28 µmol/L I3C was observed at 15 min, falling below
the level of detection by 1 h after dosing. I3C was detected
in the liver (170 µmol/L)>kidney (116 µmol/L)>lung and
heart>plasma>brain. The levels of DIM peaked at around 2 h in the
liver (16 µmol/L)>lung and kidney>heart>brain>plasma (4
μmol/L), and by 24 h, were still detectable at
approximately 0.5 µg/g in the brain and liver. The presence of linear trimer,
1-(3-hydroxymethyl)-indolyl-3-indolylmethane and
indolo(3,2b)carbazole, together with oxidative metabolites of I3C, was
also documented. In a further study, Anderton et
al compared concentrations of DIM in tissues of mice dosed with
either pure DIM (250 mg/kg; Table 2) or an equivalent dose
of the enhanced absorption BioResponse
DIM[21]. The tissue distribution of DIM was similar to that reported
previously following the administration of I3C with maximal
concentrations around 160 µmol/L in the
liver[20]. The BioRes-ponse DIM resulted in levels approximately 50% higher than
those obtained with unformulated DIM.
Thus, following the oral administration of I3C, both I3C
and DIM were detectable at µmol/L concentrations in the
blood and multiple organs. I3C was rapidly absorbed and
cleared from the blood and tissues within 1 h, while DIM
peaked slightly later and was more persistent. The
observation of I3C in the blood and tissues at these very early time
points belies previous assumptions that I3C is not absorbed,
but undergoes complete acid condensation in the stomach.
Several studies have revealed distinct responses to I3C and
DIM in animal models[22_26]. Therefore, the
in vivo activity of dietary I3C cannot be attributed completely to the
production of DIM, although response due partially to DIM
conversion is probable.
Physiologically relevant concentrations of I3C and DIM
As no data are available for achievable levels of I3C in
humans, we extrapolated from animal
studies[20,21]. The maximum plasma and tissue concentrations attained in mice for
I3C were 28 and 170 µmol/L (15 min) and for DIM, 4 and 16
µmol/L (2 h), respectively (Table 2). By allometric scaling,
the I3C dose given to mice would equate to a 20 mg/kg dose
in humans (1200 mg/d), which yielded the maximal serum
concentration 2.5 µmol/L DIM (2 h), with no I3C detectable
after 1 h[5]. Therefore, maximal detectable DIM
concentrations following I3C administration are similar in mice and
humans, and the discrepancy in I3C detection is likely to be
caused by the sensitivity of methods and selection of time
points.
The maximum levels of DIM achieved in animals
following a dose of a pure compound range from 24_200 µmol/L
(Table 2), with BioResponse DIM resulting in 50% higher
bioavailability. The dose of BioResponse DIM used in
humans was 108 mg (~1.3_1.9 mg/kg)[6], which might be
expected to give levels in the range 3_30 µmol/L.
For the purposes of this review, the effects of the
physiological concentrations up to 150 µmol/L I3C and 50 µmol/L
DIM in vitro have been considered.
In vitro mechanistic studies using low doses of I3C or
DIM Several mechanisms are responsible for the
chemo-preventive activities of I3C and DIM, as summarized in Tables
3 and 4. Both agents induce activity of phase I and II
enzymes involved in the biotransformation and elimination
of carcinogens and steroid hormones. While detailed
molecular interactions involved have not been completely
elucidated, DIM interacts with the aryl hydrocarbon
receptor (AhR), resulting in its nuclear translocation and
induction of the genes encoding phase1 and II
enzymes[27]. Several lines of evidence suggest that DIM exerts agonist
and/or modulator activity on the
AhR[28,29]. I3C can activate the NF-E2-related factor-2 (Nrf2) transcription factor which
interacts with the antioxidant response element in the
promoter of many cytoprotective enzymes, as described later.
The induction of cytochrome P450 (CYP450) by
physiological concentrations of I3C and DIM was observed in cancer
cells[30] and confirmed by an analysis of mRNA expression
profiles[31]. Increased CYP450 activity led to increased
estrogen metabolism and the degradation of estradiol
(E2)[27], which is required for the growth of estrogen
receptor-alpha (ERα)-positive cancer cells. I3C (50 µmol/L)
inhibited the estradiol-stimulated growth of estrogen-responsive
MCF7, T47D and ZR75.1 breast and cervical cells. It
inhibited receptor phosphorylation and DNA binding as well as
estrogen-dependent reporter gene activity in breast tumor
cells and cervical cancer cell
lines[32,33]. DIM (10 µmol/L) also
inhibited the estradiol-stimulated growth of MCF7, but in the
absence of 17β-estradiol it appeared to stimulate
growth[34].
DIM also exerted other estrogenic effects in these and
endometrial cells[34_36]. Conversely, earlier data indicated an
inhibitory effect of DIM on E2-regulated reporter activity
and ER DNA binding[27]. Both I3C (75_100 µmol/L) and DIM
(1_25 µmol/L) reduced the expression of ERα mRNA in
MCF7 cells[33,37]. DIM also interfered with androgen
receptor expression, DNA binding, and
signaling[38,39].
Both compounds are growth inhibitory to a wide range
of tumor cell lines, including ER-negative cancer cells. The
increased loss of viability of several breast cancer cell lines
when grown in a 3-D environment in the presence of I3C
implied greater susceptibility in vivo than in a monolayer cell
culture[40]. Recent studies have shown that I3C decreases
proliferation and induces apoptosis by reducing the
expression and signaling of the genes essential for tumor cell
viability, such as ER and epidermal growth factor receptor
(EGFR) in breast cells of luminal A and basal-like
subtypes[33,41]. I3C (50 µmol/L) can also inhibit phosphoinositide-3-kinase
(PI3K)[42], resulting in the inhibition of protein kinase B (Akt)
phosphorylation and decreased survival in cancer cells
dependent on this pathway. A mechanism dependent on breast
cancer-related protein (BRCA)1/2 upregulation has also been
proposed[43].
DIM, which is considerably more potent than I3C, also
inhibits the growth of a range of cells (Table 4). Topoisomerase
II-alpha and mitochondrial H+-ATP synthase were identified
as direct targets of DIM. The inhibition of the latter enzyme
results in increased mitochondrial reactive oxygen species
(ROS) production and signaling via the p38 stress activation
pathway[44,45]. Apoptosis via the activation of the
endoplasmic reticulum stress pathway has also been
reported[46,47].
Both agents have a significant effect on several other
signaling pathways, such as those involving
p38[45,48] and NF-κB
signaling[49_53]. They modulate a variety of growth-,
cell cycle-, and apoptotic-regulatory proteins at the mRNA
or protein level, including EGFR, PI3K, transforming growth
factor (TGF)-β2, fibroblast growth factor (FGF), cyclin E2,
activating transcription factor (ATF), B cell lymphoma Bcl2,
BclXL, Bad, and Bax.
In vitro effects of I3C or DIM observed
in vivo Both I3C and DIM clearly inhibit tumor cell growth
in vivo in a range of animal
models[54]. The reduced incidence and multiplicity
of mammary tumors was concurrent with increased phase I
and II drug metabolizing enzymes in I3C-treated
animals[55_57]. An analysis of transgenic
Nrf2_/_ mice indicated that the I3C-induced upregulation of phase II enzymes required the Nrf2
transcription factor[58,59]. The upregulation of CYP450
activity by DIM in vivo has been proposed to occur via a
mechanism involving the AhR[30], as reported in MCF7 cells
in
vitro[27]. The induction of phase I and II enzymes has been
reported in liver, small intestine, and lungs of rodents
receiving I3C (in the diet or by
gavage)[30,54,57,60_63]. DIM also induced P450 activity and flavin-containing monooxygenase
1 in the rat liver[30,60].
Apoptosis in response to I3C was observed in
vivo in initiated mammary glands with activation of caspases-8, -9,
and -3[25] and in cervical epithelium of transgenic mice
(HPV16), developing cervical cancer in response to
estrogen[56]. Few studies have investigated the effect of either
agent on signal transduction intermediates in
vivo, but in one study, dietary I3C (0.5%) caused a significant decrease
in total tyrosine phosphorylation and ornithine
decarboxylase activity in the rat
liver[62]. Many of the signaling events
modulated by I3C in vitro involve tyrosine
phosphoryla-tion[41], but interestingly, changes in ornithine
decarboxylase activity in breast and colon cells
in vitro were only observed at relatively high concentrations (>100
µmol/L)[62,64]. The downregulation of
NF-κB-regulated genes by I3C
occurring in a variety of cancer cells in
vitro, was also observed in mouse xenografts of MDA-MB231
cells[52,65].
Evidence for I3C or DIM acting synergistically/
antagonistically In rats, I3C (5 mg/kg) reversed vinblastine- or
vincristine-induced P-glycoprotein
levels[66]. This group also showed that a very high dose of I3C (10 mmol/L) decreased
P-glycoprotein levels in vitro in the multidrug resistant cell
line K562/R 10, sensitizing it to vinblastine, but had no
growth-inhibitory effect on the parent K562 cell
line[67]. I3C (333 or 500 mg/kg per day) also reversed the MDR phenotype of the
B16/hMDR1 (drug-resistant MDR1-expressing murine melanoma) tumor
in vivo, and in combination with vinblastine,
actually reduced the tumor mass[68]. In the same study, an
I3C acid-condensation mixture (12.5 µmol/L) sensitized the
B16/hMDR1 cell line in vitro to vinblastine, while DIM (45
µmol/L) increased the drug content of cells by
50%[68]. Combined treatments using I3C (50_125 µmol/L) in combination
with Src or/and EGFR inhibitors reduced the viability of breast
cancer cells MDA-MB468 and MCF7[41].
DIM (25 µmol/L) plus genistein (5 µmol/L)
synergistically induced growth arrest and DNA damage-inducible
(GADD)34 protein levels and apoptosis, and at higher
concentrations induced estrogen receptor response element
(ERE)-driven reporter gene activity[69]. I3C (50 or 100
µmol/L) has been shown to cooperate with tamoxifen (1
µmol/L) in vitro to increase cell growth inhibition and
G0/G1 cell cycle arrest of MCF7
cells[70]; in vivo, it reduces tumor mass and
increases latency of mammary
cancers[71]. An I3C acid condensation mixture also enhanced the efficacy of
vinblastine in mouse melanoma cells, while I3C itself had no
effect[68].
In vivo, dietary I3C, together with crambene (1-cyano
2-hydroxy 3-butene), another glucosinolate from vegetables,
showed a greater than additive induction of
glutathione-S-transferase (GST) and quinone reductase
activity[72].
Curcumin
Curcumin (diferuloylmethane) is a major constituent of
the spice turmeric, derived from the roots of Curcuma
longa. The major dietary source is curry, but it is also used as a
food coloring and in some medicines.
Bioavailability of curcumin in humans Curcumin
exhibits poor gastrointestinal absorption, with much of an oral
dose passing unchanged through the gastrointestinal tract,
and a further proportion undergoing conjugation, without
absorption, prior to fecal loss. Absorbed curcumin
undergoes sequential reduction and conjugation (glucuronidation
and/or sulfation) within the gastrointestinal tract and liver,
with the resultant formation of metabolites and low systemic
levels of the parent compound[73,74].
Studies in humans have demonstrated that the oral
administration of curcumin furnishes very low systemic levels,
mostly in the low nanomolar range (Table 5). An exception is
the study by Cheng et al, which reported serum levels in the
low micromolar range using the maximum tenable dose (8
g/d)[75]. Other groups have failed to replicate this finding,
with Sharma et al, for example, administering up to 3.6 g/d of
curcumin to patients for up to 4 months, yet only achieving
levels in the 10 nmol/L range[76]. The discrepancy between
these studies remains to be explained, but may have resulted
from the use of different formulations of curcumin.
Due to its poor bioavailability, curcumin levels in tissues
beyond the gastrointestinal tract are also in the low nanomolar
range or below. Garcea et al were unable to detect curcumin
in normal liver or colorectal liver metastases in patients who
had received 3.6 g/d for 1 week. In the only human study to
examine colorectal tissue to date, this oral dose resulted in
levels in the 10 µmol/L range[77].
Bioavailability of curcumin in animals A number of
groups have examined the bioavailability of curcumin in
animals, following oral, intragastric (ig) or intraperitoneal (ip)
dosing (Table 6). Studies suggest that oral dosing may give
rise to significant levels of curcumin within the
gastrointestinal tract. In a rat model, approximately 1.8
μmol curcumin/g of tissue was demonstrated in colonic mucosa following
the dietary administration of 1200 mg/kg
daily[78]. Perkins et al reported 750 mg/kg of curcumin/d to result in ~100
nmol/g in mouse small intestine mucosa and 500 nmol/g within
colonic mucosa[79]. Following oral dosing of 400 mg per rat,
liver and kidney levels were less than 20 μg per
tissue[80]. Significant levels of curcumin may also be achieved locally
when administered topically to the skin or within the oral
cavity, but the exact dose achieved in these scenarios
remains to be confirmed.
It is neither practicable nor desirable to increase the oral
dose of curcumin above that already investigated. Recent
animal studies, however, have demonstrated that the
reformulation of curcumin may enable further improvements in
bioavailability. It has previously been shown that the
formulation of drugs with phosphatidylcholine increases their
plasma bioavailability. Such a formulation led to significantly
higher levels of curcumin within plasma and the liver
compared with the parent compound, although lower levels within
the intestinal mucosa[81]. Several other animal studies have
also found curcumin bioavailability to be significantly
increased by its administration as a phospholipid
complex[82,83]. These increases in bioavailability now require confirmation
in human studies. Although the bioavailability data are
lacking, in vitro and animal studies have also shown
promising anticancer potential for a liposomal preparation of
curcumin[84,85]. In addition, nanoparticle-encapsulated
curcumin may provide an alternative means to increase the
bioavailability of this agent[86].
Physiologically relevant concentrations of curcumin
The bioavailability data suggest that in
vitro studies with curcumin in the 10 µmol/L range or below might have human
physiological relevance, but that its role as a chemopreventive
agent may lie primarily within the gastrointestinal tract.
In vitro mechanistic studies using low doses of curcumin
The anticancer effects of curcumin have been demonstrated
in multiple cell types, at concentrations between 5 and 50
µmol/L[87]. Selected studies demonstrating the anticancer
activity of curcumin at or below the 10 µmol/L level
achievable in the human colon in vivo are summarized in Table 7.
Where available, data are presented from studies using
colorectal cell lines; results from other cell types using a
maximal dose of 10 µmol/L are also included. In addition to
these studies, curcumin also inhibited the proliferation of
squamous carcinoma SCC-25 cells[88] and the proliferation
and invasion of HBL100 breast cells[89].
In vitro effects of curcumin observed
in vivo In a rat model, dietary curcumin significantly increased the apoptotic
index in azoxymethane-induced colonic
tumors[90]. Rao et al demonstrated the effect of a curcumin-containing diet on
azoxymethane-induced rat
carcinogenesis[91]. Curcumin significantly reduced tumor volume, as well as colonic mucosa
and tumor prostaglandin (PGE)2 expression by over 38%.
Similarly, it enhanced
2-amino-1-methyl-6-phenylimidazol(4,5-b)pyridine-induced apoptosis in Min/+ mice and inhibited
tumorigenesis in the proximal small intestine. Also in mice,
Mahmoud et al found dietary curcumin to normalize
enterocyte proliferation and restore the level of enterocyte
apoptosis to that of wild-type
animals[92]. In rats, a gavage administration of curcumin (200 or 600 mg/kg) inhibited
diethylnitrosamine (DEN)-induced hepatic hyperplasia and
inflammation. Specifically, the increased expression of p21ras
and p53 in the liver was prevented. The decreased
expression of proliferating cell nuclear antigen, cyclin E, and cdc2
was also observed, along with the inhibition of DEN-induced
NF-κB activation[93].
While there are no in vitro studies for comparison, there
is evidence from both animal and human studies showing
that curcumin suppresses malondialdehyde-deoxyguanosine
adduct (M1dG) adduct formation in
DNA[77,78]. However, Garcea et
al, while noting decreased M1dG adduct formation
in the colorectum following curcumin treatment, found no
alteration in cyclooxygenase 2 (COX2) protein
levels[77].
Despite the low bioavailability of curcumin, there are
examples in animal studies of its biological activity at sites
distant from the locus of absorption, where levels are
expected to be inefficacious based upon the results of
in vitro studies. Sharma et al, for example, demonstrated
increased hepatic GST expression and the attenuation of
hepatotoxin-induced adduct formation following curcumin
treatment[78]. Oral curcumin also led to the complete
suppression of tumor NF-κB activation in an orthotopic mouse
model of pancreatic cancer[94]. Anticancer activity has also
been reported at a number of other sites distant from the
gastrointestinal tract, including the
breast[95], prostate[96],
lung[97], and liver[98].
Evidence for curcumin acting
synergistically/antagonistically The treatment of MCF7 breast cells with curcumin
(10 µmol/L) and genistein (25 µmol/L) demonstrated a
synergistic effect, leading to the total inhibition of proliferation
induced by an endosulfane/chlordane/DDT
mixture[99]. Curcumin also synergistically potentiated the inhibitory
effect of celecoxib on pancreatic carcinoma
cells[100] and additively inhibited the growth of colorectal cancer with celecoxib
in the 1,2-dimethylhydrazine rat
model[101].
In an in vitro model of oral cancer, EGCG blocked cells in
the G0/G1 phase, while curcumin blocked in the
G2/M phase of the cell cycle. The combination showed synergistic
interactions in growth inhibition[102]. While tea or curcumin
individually decreased the number and volume of
dimethylben-zanthracene (DMBA)-induced oral tumors in hamsters, only
the combination decreased the proliferation index of
squamous cell carcinoma[103].
LNCaP prostate cancer cells are relatively insensitive to
tumor necrosis factor related, apoptosis-inducing ligand
(TRAIL). At low concentrations, neither TRAIL (20 ng/mL)
nor curcumin (10 µmol/L) produced significant cytotoxicity,
whereas cell death was markedly enhanced by the
combina-tion. Both agents together induced the cleavage of
procas-pases-8, -9, and -3, the truncation of Bid, the release of
cytochrome c, and apoptosis[104].
Recent studies have also demonstrated promising
interactions between curcumin and established
chemotherapeutic agents. In colorectal carcinoma lines, the antiproliferative
and pro-apoptotic effects of curcumin and oxaliplatin
increased markedly when cells were treated with both
agents[84,105]. Similarly, curcumin potentiated the
pro-apoptotic effects of gemcitabine and paclitaxel in bladder
cancer cell lines[106] and the antitumor activity of gemcitabine
in an orthotopic model of pancreatic cancer. Antagonistic
interactions have also been demonstrated, however, with
curcumin shown to inhibit chemotherapy-induced apoptosis
in breast tumor lines. Camptothecin-, mechlorethamine-, and
doxorubicin-induced apoptosis in MCF7, MDA-MB231 and
BT474 cells was inhibited by as much as 70%, following 3 h
exposure to as little as 1 μmol/L curcumin. The inhibition of
both c-jun N-terminal kinase (JNK) activation and cytochrome
c release occurred[107]. The same authors, using an
in vivo xenograft model, found dietary curcumin (25 g/kg) decreased
the level of cyclophosphamide-induced tumor regression,
again with decreased JNK activation and less apoptosis.
Epigallocatechin-3-gallate (EGCG)
Green tea and its constituent molecules, including EGCG,
have been found to prevent tumor formation in a wide range
of tissues in animal models. However, the possible
influence of green tea on cancer in humans has been difficult to
interpret due to confounding factors, such as diversity in
types of tea used, preparation methods, including
temperature of infusion, and frequency of tea drinking.
The relevance of in vitro studies with EGCG has been
reviewed by Lambert and Yang[108], who concluded that the
effectiveness of tea consumption in cancer prevention
remained unclear and required a better understanding of
bioavailability and fundamental mechanisms.
Bioavailability of EGCG in humans A number of studies
have reported the bioavailability of EGCG in various human
body fluids (Table 8) following the administration of green
tea or EGCG. Levels in plasma up to a maximum of 7.3
µmol/L (±3.6) have been reported, but more often are in the
submicro-molar range. Bioavailability in two early studies found plasma
levels at 0.2%_2% of the ingested amount of EGCG (up to 4
µmol/L), but higher plasma concentrations have since been
reported in fasting patients compared to those who
consumed catechins with food[109_111]. The oral administration
in human patients resulted in high plasma clearance levels
and volume distribution, suggesting that the bioavailability
of EGCG in the blood may be low, similar to the situation
found in rodents[109,112]. Dvorakova
et al suggested that topical application to skin of an ointment containing 10%
EGCG was likely to result in substantial intradermal uptake,
but very poor systemic absorption[113].
It has been found that holding a green tea solution (1.2
g/200 mL water) in the mouth for 1 min resulted in salivary
EGCG concentrations (mean) of 27 µmol/L, with values up to
48 µmol/L recorded, several fold higher than that achieved
through normal drinking, and many more times greater than
plasma concentrations[114,115]. However, holding the tea in
the mouth for 5 min resulted in salivary concentrations 4_5
times higher, whilst taking tea solids in capsules resulted in
no detectable salivary catechin levels. Thus, drinking tea
slowly may be an effective way of delivering relatively high
concentrations to the oral cavity and esophagus.
EGCG can undergo metabolism through glucuronidation,
sulfation, methylation, or ring
fission[108], processes which are subject to interindividual variation.
Bioavailability of EGCG in animals Surprisingly, few
studies have documented the bioavailability of EGCG in
animals. Most have shown a maximum plasma
concentration in the nmol/L to low µmol/L range, similar to the human
situation, although 1 study using a large dose of EGCG in
rats reported plasma concentrations up to 20 µmol/L (Table
9). No animal studies have examined the effect of fasting on
bioavailability. Fang et al, using liposomes for the local
(injection) delivery of EGCG, found that a liposomal cocktail
containing deoxycholic acid and ethanol greatly increased
the tumor uptake of EGCG in both melanoma and colon
murine tumor models[116,117]. However, liposomal delivery
was not superior following topical application.
Lambert and colleagues[118] reported that piperine from
black pepper enhanced the bioavailability of EGCG in mice.
Small intestinal levels following EGCG administration alone
resulted in a Cmax of 37.5±2.5 nmol/g at 60 min, decreasing to
5.1±1.7 nmol/g at 90 min. Following cotreatment with piperine,
the Cmax was 31.6±15.1 nmol/g at 90 min, with levels still
above 20 nmol/g at 180 min. The appearance of EGCG in the
colon and feces was slower in the cotreated mice.
In rats and mice 24 h after the intragastric administration
of radiolabeled EGCG, 10% of the dose was present in the
blood, with around 1% in tissues, such as liver, kidney, heart,
lung, and prostate[119]. Major elimination occurred in the
feces. In line with these findings, another study suggested
that the transporter-mediated intestinal efflux of catechins
may play a role in the systemic elimination of these
compounds[120]. Following an intravenous (iv) dose in rats,
>70% was eliminated in bile and 2% in
urine[119,121]. A study in rats, in which different green tea catechins were
administered by iv or ip, suggested that first-pass hepatic
elimination did not play a major role in the metabolism of
orally-administered epigallocatechin, epicatechin, and
EGCG[122].
Physiologically relevant concentrations of EGCG
The plasma bioavailability of EGCG, whether administered as tea
or a pure compound, is in the range of 0.1_7 µmol/L in humans,
with concentrations over 100 µmol/L observed in saliva. No
significant excretion occurred in urine (generally <0.1% of
dose). Rodent data indicate levels up to 20 µmol/L may be
achievable. Based on these data, we chose 20 µmol/L as the
maximum concentration at which to consider in
vitro findings.
In vitro mechanistic studies using low doses of EGCG
Many in vitro studies show that EGCG, at concentrations
£20 μmol/L, inhibits growth and induces cell cycle arrest or
apoptosis in a variety of cell types (Table 10). A wide range
of signaling molecules is affected, including growth factor
receptors [EGFR, platelet derived (PDGFR), fibroblast (FGFR),
vascular endothelial (VEGFR)], survival signaling pathway
components [extracellular signal regulated kinase (ERK), p38,
activating protein-1 (AP-1), signal transducer and activator
of transcription (STAT), PI3K, Akt, and NF-κB], cell cycle
regulators [cyclin D1, p21, p27, phosphorylated
retinoblastoma (pRb), cyclin-dependent kinases (cdk)2/4/6], and
regulators of apoptosis [Bcl2, Bax, Bad, caspases-3/7/8/9, and
poly (ADP ribose) polymerase (PARP)]. One interesting
effect of EGCG at the lowest doses (0.01_0.1 µmol/L) is the
inhibition of VEGF-dependent phosphorylation of the VEGFR
(Table 10), an anti-angiogenesis effect which also occurs
in vivo, as discussed later.
In vitro effects of EGCG observed in
vivo There is substantial evidence that the effects of EGCG or green tea
recorded in vitro have also been observed in animal models
or humans. Green tea polyphenols inhibited the growth of
4T1 breast cancer cells and their metastasis to lungs in
BALB/c mice. A reduction in tumor weight, increased survival time,
and later tumor appearance were observed. The ratio of
Bax/Bcl2 was altered in favor of apoptosis, along with a decrease
in proliferating cell nuclear antigen and the activation of
caspase-3[123]. The topical application of EGCG to SKH-1
hairless mice that had been pretreated twice weekly with
UVB light decreased the multiplicity of skin tumors by
44%_72% and increased the apoptotic index by 56%_92%, again
measured by increased caspase-3
activity[124]. Fang and colleagues, who demonstrated that the liposomal delivery of
EGCG resulted in increased tumor uptake, also found that
this delivery system led to increased antiproliferative
activity in basal carcinoma cells in
vitro, where the EGCG concentration in the liposomes was 21.3
μmol/L[117].
A study investigating the effect of EGCG in murine colon
26-L5 cells found that, using in vitro assays,
1,1-diphenyl-2-picryl-hydrazyl free radicals were reduced with an
ED50 of
2.9 µmol/L, and cell growth was inhibited with an
IC50 of 41.8 µmol/L. Following the injection of these colon cells into
female BALB/c mice to analyze the effect on lung metastases,
they found that EGCG, administered ip, reduced the number
of tumor nodules in a dose-dependent
manner[125].
When green tea extract (400_500 mg/cup, 5 cups/d) was
administered for 4 weeks to 3 heavy
smokers[126], smoking-induced DNA damage was decreased, cell growth
(keratino-cytes) was inhibited, and the percentage of cells in S phase
was reduced, with accumulation in the
G0/G1 phase. DNA content became less aneuploid and p53 and caspase-3 were
increased. Li and colleagues found that in hamsters,
0.6% green tea inhibited DMBA-induced oral tumor number
and volume, with increased apoptosis and a decreased
proliferation index and microvessel
density[103]. In vitro EGCG inhibits AP-1 transcriptional activation, and this was also
observed in vivo in UVB-treated transgenic mice carrying a
luciferase reporter gene with an AP-1 binding
sequence[127].
EGCG (10 or 50 µg/mL) significantly decreased
the proliferation of bovine capillary endothelial cells, and at 1_100 µg
per disc, it also inhibited neovascularization in the chick
chorioallantoic membrane assay[128]. These authors also
showed that green tea in drinking water (1.25% containing
708 µg/mL EGCG, giving plasma levels of 0.1_0.3 µmol/L)
could significantly suppress VEGF-induced corneal neovascularization. Such results suggest that EGCG may be
a useful in vivo inhibitor of angiogenesis.
Green tea consumption in two study groups, one in China
and one in the USA, decreased oxidative DNA damage
(8-hydroxy-deoxyguanosine in white blood cells and urine),
lipid peroxidation (malondialdehyde in urine), and free
radical generation (2,3-dihydroxy benzoic acid in urine) in
smokers. Non-smokers (USA group) also exhibited a
decrease in overall oxidative stress, which was correlated to
decreased levels of free radicals[129].
A recent clinical trial involving 60 volunteers with
(premalignant) prostate intraepithelial neoplasia, conducted
by Bettuzzi et al, showed that after 1 year, only 1 man (3%) in
the group receiving 600 mg/d green tea compounds in (oral)
capsule form, presented with cancer compared to 9 (30%)
from the placebo group[130]. No significant side-effects were
reported. Therefore, despite the apparent poor bioavailability
of green tea catechins in many studies, they appear to have
great promise as chemopreventive agents.
Evidence for EGCG acting synergistically/
antagonistically There are a number of reports documenting an
enhanced chemopreventive effect when EGCG or green tea is
used in combination with another chemopreventive agent or
a therapeutic drug.
Suganuma et al found that epicatechin significantly
enhanced the uptake of labeled EGCG into human lung PC-9
cells and suggested that whole green tea was a better
preventive agent than EGCG alone[131]. In this study, the
pro-apoptotic effects of EGCG were also increased by tamoxifen
or sulindac. Another study using the prostate cancer cell
lines PC-3, LNCaP, and CWR22Rv1 showed that while 10
μmol/L EGCG only resulted in a 12%_21% inhibition in cell
viability, the addition of 10 μmol/L NS-398 (a COX2 inhibitor),
resulted in a 44%_49% inhibition, greater than the additive
effect of either agent alone. These results corresponded to
decreases in Bcl-2, procaspases-6 and -9, phospho-p65 and
peroxisome proliferator-activated receptor (PPAR)g, and
increases in Bax and PARP[132].
EGCG at 0.1 µg/mL (equivalent to serum concentrations)
markedly enhanced the growth inhibitory effects of
5-fluorouracil in head and neck squamous carcinoma
cells[133]. The IC50 values for 2 different cell lines were reduced by ~4-fold
(sensitive line) and 45-fold (resistant line). EGCG on its own
at this concentration had no effect. The same group also
found that EGCG enhanced the sensitivity of HNSCC (0.1
µg/mL) and breast (1.0 µg/mL) cells to
Taxol[134].
Min/+ mice treated with a combination of white tea
(1.5%) and sulindac (80 ppm) had significantly fewer
intestinal tumors than mice treated with either agent alone. While
β-catenin and β-catenin/T cell factor-4-regulated genes,
cyclin D1, and c-jun were detected in polyps, the expression
of these proteins was markedly reduced in the normal
intestine[135]. A combination of EGCG and sulindac was also found
to be efficacious in preventing azoxymethane-induced
colon cancer in rat, where the combination synergistically
enhanced apoptosis[136].
Resveratrol
The phytoalexin resveratrol is found largely in grape
products and peanuts, with red wine a major source of human
consumption. Its potential role in disease prevention is well
documented, as it exhibits vasorelaxing, anti-inflammatory,
antilipidemic, anti-estrogenic, antioxidant, antifungal, and
antibacterial properties[137_139].
Whilst resveratrol appears to have great potential
in vitro, the relevance to in vivo effects in both humans and animals
is less clear, as its chemopreventive effect in
vivo depends greatly on its absorption, metabolism, and tissue distribution.
Bioavailability of resveratrol in humans Several
studies have looked at the rate of uptake in healthy human
volunteers via the oral administration of either resveratrol in its
pure form or when present in foodstuffs (Table 11).
Estimates of the amount of resveratrol in red wine (mainly trans),
vary from 0.3 to 10.6 mg/L (1.3_46
µmol/L)[140_142]. Recent studies by Boocock
et al[143,144] found peak resveratrol plasma
concentrations of 0.3_2.4 µmol/L following single oral doses
of 0.5_5 g in healthy human volunteers. Observed peak
plasma concentrations for resveratrol metabolites ranged
between 0.92 and 4.3 µmol/L (mono-glucuronides), and
3.7_14 µmol/L (resveratrol 3-sulfate). Plasma half-lives for the
parent compound and major conjugates were of a similar
order (2.9_10.6 h).
Subjects receiving a lower dose of 10_25 mg pure
resvera-trol/70 kg body mass were similarly found to have serum
resveratrol levels between 1.83 and 2.06 µmol/L at 30 min
post-dose, returning to baseline by 4
h[145]. Wang et
al[146] found both resveratrol and resveratrol glucuronide
present at up to 6 h following a dose of 1 g. It is likely that
conjugated resveratrol is the main component in the
circulation[147], and plasma concentrations around 2 µmol/L appear typical
(Table 11).
Several major metabolites of resveratrol are found in
human subjects, including the sulfate-glucuronide,
mono-glucuronides, and mono- and
di-sulfates[143,144], with sulfation thought to occur primarily via the sulfotransferase
1A1[148] and glucuronidation via the UDP-glucuronosyltransfera-
ses[149]. The rate of glucuronidation in the human liver ranges
between 0.23 and 1.2 nmol/min/mg and the rate of sulfation
is 80 pmol/min per mg[141,150]. The presence of sulfated
products in vivo may vary depending upon whether pure
resveratrol is administered, as quercetin (also present in red
wine) is known to inhibit its sulfation. Resveratrol
glucuronide has been assumed to be pharmacologically inactive,
although it has been suggested that glycosylation of
polyphenols is an important step in protecting them from
enzymatic oxidation, so extending their half-life and
biological properties[151]. However, it is possible that the
glucuronide may be converted back to resveratrol
in vivo by the action of
beta-glucuronidases[152]. The aqueous solubility
of resveratrol is low, and it is thought that albumin is the
main carrier in plasma, with little free
resveratrol[153]. The presence of fatty acids increases binding to serum albumin,
which may have important consequences for the delivery of
resveratrol to cell membranes and thus signaling events.
Bioavailability of resveratrol in animals
Marier et al[154] observed that resveratrol was absorbed within minutes
following an oral dose of 50 mg/kg to rats. Resveratrol
aglycone (parent compound) plasma concentrations dropped from
10 µmol/L to levels at the limit of detection by 12 h. The
glucuronide, however, was present at ~100 µmol/L, falling to
3 µmol/L after 12 h, again suggesting that resveratrol is
absorbed from the intestine mainly in this form. A lower dose
of 20 mg/kg gave a maximal resveratrol plasma content of 3
μmol/L, falling to <0.1 µmol/L after 1
h[140], with a 5 mg/kg dose showing maximal plasma levels of 1.5 µmol/L
[155].
The disposition of resveratrol revealed far higher levels
in tissues involved in absorption and excretion, such as the
intestine, liver, and kidney, than in plasma. In mice, the
highest accumulation was in intestinal
mucosa[156], brain[157], kidneys, and liver, reaching 25_30 µmol/L following a dose
of 5 mg/kg[155]. The major tissue metabolites were
resveratrol-3,4'-disulfate, -3,4',5-trisulfate and
β-D-glucuronide[158]. Following a 20 mg/kg dose, the rat lung contained 0.8 nmol/g
resveratrol, the mouse liver 1.03 nmol/g, and the mouse
kidney 0.17 nmol/g[140].
Physiologically relevant concentrations of resveratrol
Animal and human studies consistently indicate resveratrol
levels of 1_2 µmol/L in plasma (Tables 11, 12).
Concentrations 10_20 times higher than this have been achieved
through ig or iv dosing in animal studies. An examination of
tissue distribution revealed that concentrations in some
tissues can be significantly higher than those in plasma.
Therefore, in considering the relevance of in
vitro studies, we have focused on those which have reported effects at
concentrations of 10 µmol/L or less.
In vitro mechanistic studies using low doses of
resveratrol Cell culture studies with resveratrol indicate
anticancer potential over a range of doses and in a wide
variety of tissues, including breast, colon, pancreas, stomach,
prostate, head and neck, ovary, liver, lung, and
cervix[137] (Table 13). At physiological concentrations of 10 µmol/L or
less, resveratrol exhibits a range of activities which
modulate signal transduction. These include the downregulation
of growth factors (EGF and VEGF), alterations to survival
signaling (ERK, JNK, AP-1, and NF-κB), cell cycle regulators
(cyclinD1, cdk4/6, p21, and p53) and apoptosis regulators
(PARP, ceramide, and caspases). In U937 monocytes,
concentrations as low as 0.1 µmol/L effectively inhibited the
production of ROS, with the inhibition of Akt
phosphorylation at 10 µmol/L [159].
In vitro effects of resveratrol observed
in vivo Whether or not the IC50
values in vitro are achievable in
vivo depends to some extent on the target tissue. It is likely that the
highest concentration of resveratrol and its metabolites
following ingestion would be achieved in colorectal mucosal
tissue and in the liver. Several studies administering resveratrol
via ingestion of red wine have used the mean serum
antioxidant capacity as a marker of efficacy. In healthy volunteers
consuming 300 mL red wine over a 30 min period, blood taken
up to 2 h post-dose showed significantly raised serum
antioxidant capacity[160].
MDA-MB231 xenografts in nude mice exhibited an
increase in the apoptotic index and decreased angiogenesis
when treated daily with 25 mg/kg resveratrol for 3 weeks,
while the same cell line in the culture did not undergo
apoptosis at concentrations less than 100
µmol/L[161]. Conversely, when B16M tumor cells were inoculated into
mice, 20 mg/kg resveratrol did not affect tumor growth (tumor
concentration of 0.04 nmol/g), even though in the culture
the cells underwent 60% apoptosis following a 5 µmol/L
treatment for 24 h[140]. The rats inoculated with the Yoshida
ascites hepatoma receiving daily ip injections (1 mg/kg) of
resveratrol exhibited decreased tumor growth due to the
induction of apoptosis and a G2/M cell cycle arrest. This
effect was not seen in vitro using resveratrol in the range of
15_30 µmol/L over 24 h[162]. Daily ip injections of 40 mg/kg
resveratrol (estimated serum level of 25 µmol/L) reduced
neuroblastoma growth in rats and increased survival by 70%. In
culture, resveratrol was also cytotoxic to
neuroblastoma cells in a range from 10 to 100 µmol/L
[163]. Resveratrol at 100 mg/kg per day prolonged the survival time for rats with
intracerebral tumors generated from RT-2 glioma cell
xenografts. The IC50 for RT-2 cells in the culture equated to
12.8 µmol/L following a 48 h treatment, with 39% cells
undergoing apoptosis at the higher concentration of 25
µmol/L[164].
A number of reports have shown that resveratrol can
inhibit NF-κB activation in vitro. Banerjee
et al found that in rats, 10 ppm produced striking reductions in DMBA-
induced breast tumor incidence and multiplicity, while
extending tumor latency[165]. They reported that resveratrol
suppressed DMBA-induced COX2 and matrix
metallopro-teinase (MMP)-9 expressions through the downregulation
of NF-κB activation.
Resveratrol treatment may also inhibit preneoplastic
conditions. In both an experimentally induced model of
colitis[166] and the Min/+
mouse[167], resveratrol was able to
reduce damage/adenoma load and COX2 protein expression.
The spontaneous development of mammary tumors in
HER2/neu mice was delayed with the reduction in both size and
number of tumors following resveratrol
treatment[168]. In rats, azoxymethane treatment caused the formation of aberrant
crypt foci, the number of which was significantly reduced in
the presence of resveratrol (200 µg/kg per day for 100 d),
with decreased bax and increased p21 expression in the
crypts[169]. The treatment of dimethylhydrazine-induced
aberrant crypt foci with resveratrol (8 mg/kg per day)
resulted in a marked reduction in tumor incidence and
degree of histological lesions[170]. Similarly, rats fed a diet
containing 15% grape extract showed a decrease in the
number and area of GST-P+ve
foci[171].
Evidence for resveratrol acting
synergistically/antagonistically Resveratrol sensitized colon cancer cells to CD95
and the TRAIL-mediated induction of apoptosis, and at 10
µmol/L, sensitized HT29 cells to cisplatin-induced
apopto-sis[172]. Fulda and Debatin found that pretreatment with
resveratrol cooperatively enhanced doxorubicin, cytarabine,
actinomycin D, Taxol, and methotrexate-induced apoptosis
and cell cycle arrest in neuroblastoma
cells[173], and enhanced TRAIL-mediated apoptosis in neuroblastoma and Jurkat T
cells[174]. Resveratrol (10 μmol/L) also enhanced the apoptotic
effects of paclitaxel in A549, EBC-1, and Lu65 lung cancer
cell lines[175], and of cisplatin and doxorubicin in OVCAR-3
and Ishikawa cells, respectively[176].
Resveratrol has been used in combination with other
phytochemicals, such as beta-siterol, resulting in enhanced
growth inhibition due to an arrest at both the
G1 and G2/M phases of the cell cycle in PC-3
cells[177]. The combination of quercetin/ellagic acid with resveratrol resulted in a
synergistic effect on caspase-3 activation leading to
apoptosis[178]. Lee et
al[179] found individual concentrations of resveratrol
(0.5 µmol/L) or I3C (50 µmol/L) to induce the non-steroidal,
anti-inflammatory, drug-activated gene (NAG)-1, a
TGF-β superfamily gene associated with pro-apoptotic and
anti-tumorigenic activity. However, when used in combination,
the doses could be reduced to 0.025 and 1 µmol/L,
respec-tively.
Conclusion
Plasma concentrations in humans, following normal
dietary intake or administration of supplements or
formula-tions, have been measured or can be estimated from animal
studies for each of the agents reviewed. In general,
achievable plasma concentrations were in the low micromolar range,
although animal studies revealed the possibility of
considerably higher concentrations in some tissues. In
summarizing data from many cell culture studies, which have been
carried out using the low concentrations achievable
in vivo, it is apparent that all the compounds still exhibit biological
activity. However, the range of activities is more limited,
compared to that using a much wider dose range. While this
may reflect genuine lack of activity at low doses, it is partly
due to the fact that many studies have chosen to use only
higher doses and shorter time points. There may therefore
be many more useful preventive possibilities to be identified
using lower doses.
Two very encouraging themes emerge from the data
reviewed here. First, while not all in
vitro findings are matched in vivo, many observations have been validated in
animals or humans, giving credibility to the value of cell
cultures for screening and more detailed mechanistic studies.
However, some caution is required in extrapolation, as in
many cases it is not known whether exactly the same
signaling mechanisms are operational in
vivo. There can also be significant discrepancies in the effective doses, even to the
extent that where low levels are active in
vivo, much higher concentrations are required to achieve the same
effect in vitro.
Second, there is a growing body of evidence to suggest
that even if single agents are inactive at low concentrations,
combinations of 2 or more compounds might be much more
efficacious. Combinations with chemotherapeutic drugs also
offer the possibility of lowering the dose of the latter, with a
consequent reduction of unwanted side-effects.
Thus, studies in cell culture have provided valuable
insights into chemopreventive mechanisms of action, and
there is now a need to pursue these at physiological doses
and in novel combinations. One further aspect, which has
not been tackled in any detail here, is the need to address
more rigorously the question of tissue specificity and
cancer subtype.
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