[41]Hormesis and synergy pathways and mechanisms of quercetin in cancer prevention and management, studia, ...
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Emerging Science
Hormesis and synergy: pathways and mechanisms of quercetin
in cancer prevention and management
Ashley J Vargas and Randy Burd
nure_301 418..428
Quercetin is a unique dietary polyphenol because it can exert biphasic
dose-responses on cells depending on its concentration. Cancer preventative effects
ofquercetinareobservedatconcentrationsofapproximately1–40
m
Mandarelikely
mediated by quercetin's antioxidant properties. Pro-oxidant effects are present at
cellular concentrations of 40–100
m
M. However, at higher concentrations, many
novel pathways in addition to ROS contribute to its effects. The potent bioactivity of
quercetin has led to vigorous study of this compound and revealed numerous
pathways that could interact synergistically to prevent or treat cancer. The effect of
intake and concentration on emerging pathways and how they may interact are
discussed in this review.
© 2010 International Life Sciences Institute
INTRODUCTION
effects,which again rely on the concentration of quercetin
at the tissue site. Quercetin’s hormetic nature makes it
well-suited to use in cancer prevention efforts; these
efforts would likely involve lower and long-term con-
sumption of quercertin-containing foods, and/or supple-
mentation or therapeutic administration in combination
with conventional therapies.Although this review focuses
on quercetin in relation to cancer, it is generally under-
stood that the same pathways could be applied to other
disease states as well.
Quercetin is a dietary polyphenol that is readily found in
a variety of foods and is consumed daily.The tremendous
growth in the study of this bioactive compound has
revealed numerous pathways that could possibly interact
to prevent or treat diseases such as cancer, so a review of
the recent literature utilizing this compound is pertinent.
Quercetin also has a unique ability to act as an antioxi-
dant or a pro-oxidant depending on its concentration,
which is indicative of its hormetic properties.
1
For the
purpose of this review, hormesis is defined as a biphasic
dose-response whereby low doses of quercetin result in a
given effect (antioxidant properties) and higher doses
result in another effect (pro-oxidant properties). Given
this assumption, there are two fundamental factors that
impact quercetin’s bioactivity as either an oxidant or an
antioxidant. First, and arguably most important, is quer-
cetin’s tissue bioavailability and digestion process.Second
is the concentration and isoform or conjugate form of
quercetin in the target tissue. In this review, multiple
effects of quercetin are proposed that are concentration
dependent; this implies a dependence on the entire meta-
bolic process of this flavonoid. It is also proposed that
multiple pathways could interact to produce synergistic
CENTRAL ROLE OF REACTIVE OXYGEN SPECIES IN
QUERCETIN ACTIVITY IN CANCER
The biphasic oxidation properties of quercetin are likely
beneficial in cancer prevention and therapy because dif-
ferent concentrations of quercetin counter the transfor-
mation and growth processes of cancer.
1
Malignant
tumors result from uncontrolled cell growth due to muta-
tions. Mutations are a result of DNA damage, which is
commonly incurred through exposure to reactive oxygen
species (ROS). Quercetin is able to donate electrons
to ROS
2
and thereby reduce their ability to damage cellu-
lar DNA.
3
This is the primary mechanism by which
A
liation:
AJ Vargas
and
R Burd
are with the Department of Nutritional Sciences at the University of Arizona, Tucson, Arizona, USA.
Correspondence:
R Burd
, Department of Nutritional Science, University of Arizona, Shantz Building, Room 301, 117 E. 4th Street, Tucson,
AZ 85721, USA. E-mail: rburd@u.arizona.edu, Phone:
+
1-520-626-1863; Fax:
+
1-520-621-9446.
Key words: estrogen receptor, HSPs, P53, quercetin, ROS
doi:10.1111/j.1753-4887.2010.00301.x
Nutrition Reviews® Vol. 68(7):418–428
418
quercetin exerts antioxidant and chemopreventive effects
on the cell.
3
Typically, this effect is seen at cellular quer-
cetin concentrations in the range of 1–40 mM, which
could likely be achieved by diet.
4
However, after a tumor
has formed, quercetin could continue to have beneficial
anti-tumor effects at higher doses by exerting cytotoxic
effects. Quercetin is able to increase oxidative stress and
cytotoxicity in tumor cells, usually at concentrations
greater than 40 mM; it is able to do this by becoming an
ROS itself and by increasing damage or apoptotic path-
ways in the transformed cell.
2,3
These benefits rely on ROS
and the quercetin concentration to produce either anti-
or pro-oxidant effects. There are various pathways and
mechanisms that can interact and these are described in
more detail below. In addition, because biomedical
research must be translatable to real-life situations, this
review begins with an assessment of the bioavailability
and metabolism of quercetin. Since much of the research
discussed in this review has only been conducted in vitro
or in cell culture, an attempt is made here to link these
studies with biologically relevant concentrations in
humans.
other hypotheses, including the idea that some hydrolysis
occurs in the small intestines, via both b-glycosidase and
lactase phlorizen hydrolase (LPH).
9
Despite differences of
opinion, it is generally accepted that bioavailability
depends on the location and type of sugar group attached
to quercetin.
8
Most likely, the digestion and absorption
of quercetin occurs through a combination of the pro-
posed pathways, depending on which form the quercetin
is in at a given point in time.
Hydrolysis of quercetin by b-glycosidase results in
different metabolites of quercetin depending on what
the original glycoside was (i.e., where the glycosidic bond
was located and what type of sugar was attached). These
metabolites include not only free quercetin, but also con-
jugates such as glucuronides,
O
-methylated products,and
sulfate forms.
8
This conjugation of quercetin is reported
to occur throughout the processes of digestion and
absorption.
8
In animals, it appears that quercetin and its
metabolites are transported unevenly throughout the
body.
10
Animal studies have also shown that blood con-
tains mostly quercetin metabolites after quercetin inges-
tion,
8,10
whereas only the organs involved in quercetin
metabolism (i.e.,kidney,liver,and intestines) can contain
significant amounts of free quercetin in addition to
methylated forms.
10
However, few studies have focused
on detecting quercetin concentrations at target tissues
and further research is greatly needed in this area. The
findings of one study conducted in pigs indicated that the
kidney, liver, and jejunum had concentrations of querce-
tin between approximately 2.0 and 6.0 mM/L.
10
Human
studies are not available to confirm this finding
4
;however,
both human and animal studies suggest that quercetin’s
distribution and absorption depend on its form.
4,10
Further, studies have shown that both the bioavailability
and other intestinal contents can affect absorption of
quercetin and its derivatives.
8
The reduction-oxidation potential of a quercetin
molecule is also dependent on quercetin’s form. For
example, non-catechol containing structures do not
chelate oxidative metals as well as those that do contain
catechol.
8
Given the immense variability in quercetin
metabolism, it is tremendously complicated to assess
quercetin’s direct ability to exert pro-oxidant and antioxi-
dant affects in the body.Additionally, there are too many
factors to provide a complete comprehensive review of
the literature involving quercetin metabolism. Thus, this
review focuses on studies that have examined oral supple-
mentation and/or dietary intake of quercetin versus
blood concentrations or tissue concentrations. Since it is
conceivable that long-term consumption and chronic
quercetin blood concentrations will eventually infiltrate
tissues, a general assumption is made that it may be pos-
sible to achieve levels of quercetin in tissues and tumors
that are somewhat near those measured in blood. Also,
ABSORPTION AND METABOLISM OF QUERCETIN
Quercetin is consumed daily by millions of people
through nuts, teas, vegetables, and herbs in the diet.
3
It is
also available as a commercial dietary supplement, and it
is now being included in functional foods. Quercetin is
generally recognized as safe in oral dosages of 1,000 mg/
day or in intravenously administered dosages of 756 mg/
day.
5
Up to 60% of orally ingested quercetin is absorbed,
5
and the average dietary intake of quercetin is somewhere
between 6 and 31 mg daily (not including supplement/
intravenous use).
6
Quercetin is part of the flavanol family
and it is normally found in the glycosylated form.
7
Diges-
tion of most dietary quercetin, in the form of quercetin
glycosides, begins in the oral cavity with some cleavage of
the glycosides catalyzed by b-glycosidases (Figure 1).
7
Some of quercetin’s aglycoside form is absorbed in the
mouth as well.
7
There is some disagreement as to the exact post-oral
cavity metabolism of this substrate; however, a few pos-
sibilities exist (Figure 1).It is likely that the colonic micro-
flora hydrolyze the glycoside-form of quercetin to the
more active aglycone quercetin. Once aglycosylated, the
molecule becomes more lipophillic and can then be
absorbed into the epithelial cells of the colon.
8
Another
possibility is that some of the glycosidic quercetins are
absorbed directly, particularly those that are bound with
glucose.
8
It is also probable that colonic microflora
ferment quercetin into phenolic compounds and carbon
dioxide.
5
Both the carbon dioxide and the phenolic com-
pounds are then expelled from the body.
5
There are yet
Nutrition Reviews® Vol. 68(7):418–428
419
Figure 1
Schematic of possible pathways by which quercetin is digested, absorbed, metabolized, and excreted in the
human body.
Typically, quercetin glycoside is ingested orally and is then probably partially digested in the oral cavity. Surplus
quercetin is then digested and absorbed at multiple sites along the gastrointestinal tract. During absorption, or shortly
thereafter,quercetinundergoesmodificationandthenentersthecirculatorysysteminaconjugateform.Thecirculatorysystem
delivers quercetin to other tissues in mostly conjugated forms, and once quercetin reaches the target tissues it can likely be
converted back into the parental compound.
given that limited data are available on quercetin concen-
tration and form in human organs or tissue and that
many of the conjugate forms of quercetin are converted
back to the parental compound by cellular processes,only
those mechanisms involved in free quercetin action at the
target tissue will be examined.
11
It should be noted that
when discussing the high concentrations of quercetin
that would be required for therapeutic effect, it is likely
that high-dose supplementation or more direct forms of
administration would be required. While this is an over-
simplification, the diverse nature of the polyphenols
makes it necessary to focus on the mechanisms of the
parental compound in order to to further understanding
of its conjugates and how all factors combined will ulti-
mately impact the outcome of using quercetin for cancer
prevention and treatment in humans.
There are very few human studies that have evalu-
ated the absorption of quercetin, and most of them were
performed with low doses that could be achieved through
diet.Egert et al.
4
supplemented 18 men and 18 women for
2 weeks with various levels of the oral quercetin aglycone.
The study participants had no diculty absorbing
dosages of up to 150 mg/day but the researchers did find
variations in individual blood serum concentrations that
were independent of fat mass or sex.
4
The blood plasma
measurements for average total quercetin levels from
50 mg/day, 100 mg/day, and 150 mg/day supplementa-
tion were 145 nmol/L, 217 nmol/L, and 380 nmol/L,
respectively, after only 2 weeks of daily ingestion.
4
Two
well-known, specific quercetin metabolites (isorham-
metin and tamarixetin) were increased to between 9 and
23 nmol/L after treatment with the various dosages of the
oral quercetin aglycone.
4
These findings agree with those
from other human quercetin absorption studies.
4,12
It
should be noted, however, that the measurement of total
quercetin includes all detectable conjugates, which can
then be converted to free quercetin in the cell.
11
Because
the preventative effects of free quercetin are seen in vitro
420
Nutrition Reviews® Vol. 68(7):418–428
at approximately 1,000–40,000 nmol/L (1–40 mM), for
antioxidant effects, it is likely that these concentrations
could be achieved through diet or, more likely, dietary
supplementation of quercetin.
4
However, the cancer-
treating pro-oxidant effects are not commonly seen
until cellular concentrations reach 40,000 to above
100,000 nmol/L (40–
quercetin is able to prevent oxidative DNA damage and
increase DNA repair at lower dosages.
Quercetin also has the ability to work synergistically
with other antioxidant systems in the body in order to
decrease oxidative stress.
16
When quercetin exerts its anti-
oxidant power,it can advance to the semiquinone or even
the 0-quinone state.
16,17
In these highly oxidized states,
quercetin is potentially damaging to the cell and activates
another antioxidant pathway involving glutathione
(GSH).
17
Kim et al.
17
recently examined the relationship
between oxidized quercetin and GSH in a human
hepatoma cell line (HepG2).
17
Their findings indicate that
10 and 100 mM doses of quercetin led to antioxidant
affects, but that exposure to 100 mM quercetin for longer
than 30 min led to pro-oxidant/pro-apoptotic effects.
17
More specifically, the data indicated that quercetin is able
to chelate reactive metal ions that produce ROS, react
with hydrogen peroxide to reduce ROS, and use GSH-
mediated reduction in order to return ROS to their
reduced states.
17
This cooperativity with GSH is likely one
mechanism by which quercetin can protect the cell from
mutagenesis.On the other hand,quercetin may be able to
cause cellular damage when it is administered in a long-
term high dose.
Animal models are frequently the vehicle for mea-
suring overall antioxidant status after treatment with
quercetin. Santos et al.
18
fed mice 4.2 mg of quercetin
daily for 3 weeks and then measured blood values of
quercetin metabolites against control mice. The primary
metabolites found in the blood were glucuronide sulfate
conjugates of isorhamnetin at a concentration of
4.2 mM.
18
The chemical structures of these conjugates
inhibit some of the antioxidant capacity as compared to
the parent compound. Thus, the bioactivity of quercetin
conjugates is lower than that of the parent compound.
18
This decrease in bioactivity was supported by the
unchanged antioxidant activity when the experimental
and control blood samples were compared.
18
Similar null
results were found in humans when serum quercetin
metabolite concentrations reached 1.031 mM r
onion consumption.
19
Like in the murine study,
18
the
researchers in the human study also attributed their null
results to the blood concentration probably being lower
than the threshold needed to significantly change anti-
oxidant biomarkers.
19
However, different results were
obtained when higher dosages, approximately 20 mg
quercetin, were administered to mice intragastrically.
18,20
These acutely exposed mice achieved a 13.2 mM serum
concentration of quercetin metabolites, which was
expectantly higher than the concentration in the previ-
ously discussed lower-dose studies.
20
The higher concen-
tration was enough to increase the antioxidant capacity
of the treated mice, at 119 nmol Trolox equivalents/mL
plasma, relative to the control, at 48 nmol Trolox
100 mM). There are animal studies
that support the possibility of reaching higher concentra-
tions in vivo. Silberberg et al.
13
found that the combined
plasma concentration in rats, after oral consumption of
45–47 mg/day for 2 weeks, was approximately 60 mM.
Another possibility is to administer quercetin intrave-
nously.
14
A phase I clinical study found that individuals
with a cancer diagnosis could tolerate acute serum levels
of 200–400 mM.
14
Although more research is needed, it
appears to be physiologically possible to meet the ranges
required to both prevent and potentially treat carcino-
genesis with quercetin.
>
ANTIOXIDANT MECHANISMS OF QUERCETIN
QuercetinisabletoreactwithROSandchelateROS-
producing metal ions, both of which allow for decreased
oxidative DNA damage.
8
Preventing this DNA damage is
believed to be the general mechanism by which quercetin
is able to prevent tumorigenesis.
8
In particular, it is
known that quercetin’s hydroxyl groups have electron-
accepting capacity when they are in the semiquinone state
and that its catechol group is the structure that confers the
ability to chelate metal ions.
8
The addition of sugar mol-
ecules to form quercetin glycosides can obstruct both of
its antioxidant activities. Therefore, the aglycosylated
form is usually of higher antioxidant potency than the
glycoside form,depending on where the sugar molecule is
attached.
8
In this review, references to quercetin indicate
the free, aglyconated form.
A recent study looking at quercetin’s antioxidant
mechanism in colorectal adenocarcinoma cells (Caco2)
found that treatments consisting of 1 mM concentrations
of quercetin led to decreased double-stranded DNA
breaks, but that higher concentrations of quercetin
increased double-stranded DNA breakage.
15
Recall that
double-stranded DNA breakage is a major source of
mutagenesis and subsequent malignancies in cells.
15
However, increased double-stranded breaks can also lead
to increased apoptosis, as described later in this review.
Congruently, this group found decreased hydrogen
peroxide-induced single-strand DNA breakage in Caco2
cells pretreated with low-dose quercetin as compared to
cells that were untreated.
15
Additionally, it was deter-
mined that both low (1 mM) and high (100 mM) quercetin
treatments led to increased expression of human
8-oxyguanine DNA glycosylase (hOGG1). The hOGG1
protein is involved in repairing DNA.
15
This suggests that
Nutrition Reviews® Vol. 68(7):418–428
421
Figure 2
Map of several pro-apoptotic pathways triggered by quercetin concentrations greater than 40
m
M.
Quercetin
can generate increased cellular ROS, which then increases tumor suppressor proteins and leads to cell death via the mitochon-
drial pathway. Quercetin can also initiate cell death via the death domain pathways. Lastly, quercetin contributes to the
inhibition of proteins that encourage proliferation. Note: Arrows do not always indicate a direct mechanism of action.
equivalents/mL plasma.
20
These studies illustrate how
dependent quercetin’s antioxidant capacity is on both the
concentration and form of quercetin in the blood and,
presumably, target tissues.
MITOCHONDRIAL APOPTOTIC PATHWAY
(P53-DEPENDENT AND -INDEPENDENT)
The mitochondrial apoptotic pathway is initiated via Bcl-
2-associated X protein (Bax) and/or Bcl-2 homologous
antagonist/killer (Bak) proteins that bring about an
increase in the mitochondria outer-membrane pore
size. This allows for cytochrome C, among other pro-
apoptotic proteins, to leak out into the cytoplasm. When
cytochrome C is freed into the cytoplasm, it is able to
combine with apoptotic protease activating-factor 1
(APAF-1) and undergo a conformational change, thus
forming the apoptosome. The apoptosome then enlists
caspase-9 in order to activate the so-called executioner
proteins, caspase-7 and caspase-3. Cell death is subse-
quently carried out by these caspase proteins (Figure 2).
23
Quercetin is a known inducer of apoptosis in multiple
cancer cell lines when administered in doses of 40–50 mM
or greater concentrations.
24–26
Larger doses of quercetin
and longer exposure times lead to decreased cancer cell
viability. It has been proposed that the mitochondrial-
mediated cell-death pathway is a mechanism used by
quercetin in order to induce apoptosis.
25
Examples of quercetin’s antiproliferative effect are
largely documented as being mediated through the
induction of P53.
24–26
This tumor-suppressor protein can
activate Bax and initiate cell death.
27
Recently, Tan et al.
24
investigated protein expression and cell status of a human
PRO-OXIDANT MECHANISMS OF QUERCETIN
As described above, quercetin is not only an antioxi-
dant
1
; it can also become a pro-oxidant at high concen-
trations or for longer incubations at the greater
concentration. The present review of the literature indi-
cates that, in general, quercetin is able to act as a pro-
oxidant at concentrations greater than 40 mM, which is
in agreement with Watjen et al.
1
Although cytotoxicity
may not be a desirable outcome in healthy cells, it would
be greatly beneficial in tumor cells. Thus, if quercetin
was supplemented at high does or administered intrave-
nously, like other chemotherapeutic drugs, it may be
possible to use this pro-oxidative tendency in order to
initiate apoptosis in humans with cancer. Therefore,
quercetin could likely be used as an adjuvant to current
chemotherapies, and if quercetin is activated (oxidized)
by enzymes in tumor cells, the dose needed for the pro-
oxidant or anti-tumor responses could be considerably
lower.
21,22
Recently discovered mechanisms by which
quercetin is able to bring about advantageous cell death
are discussed below.
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Nutrition Reviews® Vol. 68(7):418–428
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