& Quercetin - Anti Heart & Anti Cancer Duo
by James South MA
Heart disease and cancer are the two main causes of death in America and
Europe, eventually killing about 2/3 of all adults. For the past 40
years, it has been virtually a dogma of Western medicine that a diet
high in saturated fat/cholesterol, and/or a high blood cholesterol
level, is the primary cause of heart disease.
The high blood cholesterol so typical of Western peoples is alleged to
cause atherosclerotic plagues to develop over a lifetime, eventually
"plugging up" heart arteries and leading to death by
"heart attack" (i.e. myocardial infarction (MI) or coronary
The so-called "fatty/cholesterol plague" that can occlude
arteries is called "atheroma"; the gradual development of
atheroma in heart arteries is referred to as "coronary
atherogenesis"; and the chief culprit in the process of
atherogenesis is alleged to be cholesterol/saturated fat. More recent
refinements of the atherogenesis dogma posit high LDL cholesterol and/or
low HDL cholesterol as the chief culprit in atherogenesis.
THROMBI VS. ATHEROMA
Yet there has been a mass of evidence dating back 40 years that clearly
points to atheroma/atherogenesis as being secondary phenomena in the
20th century epidemic of heart attacks. In a 1984 review article summing
up the case against atheroma as the primary cause of MI, Wayne Martin
noted that 'Keely and Higginson in 1957 reported [widespread] atheroma
among the Bantus, even though they seemed to be free from MI. They
suggested that thrombi [abnormal blood clots] rather than atheroma may
be the major cause of MI. In 1959 Gore et al found the same degree of
atheroma in Japan and in the United States.... In 1968 Strong et al
reported on a world-wide study showing that atheroma is as prevalent
among women as it is among men, and further, that all populations of the
world suffer from atheroma to about the same degree, even among
populations such as the Bantus, who are known to suffer little from MI.
In 1960 Thomas et al reported on a study in pathology, showing the black
population of Uganda to be free from MI; however they did note that
these blacks had atheroma.
They, like Keeley and Higginson, said that it was high time more concern
should be shown over the danger of thrombi and less concern about
atheroma. Strong et al are continuing a study comparing atheroma in New
Orleans, USA and Tokyo, Japan, finding that in New Orleans, USA, where
the death rate from MI was very high as of 1978, there was very little
difference in atheroma as compared with Tokyo men, among whom MI is much
In 1980 Sinclair noted that in Jamaica, where there is severe atheroma
caused presumably by coconut oil in diet, atheroma does not seem to
cause coronary thrombosis. Sinclair stated that thrombosis and not
atheroma is the major causal factor in MI.
There is now abundant evidence that man, world-wide, is afflicted with
atheroma, but that many populations in Africa and Asia co-exist with
atheroma without being afflicted with MI.' (1).
Kinsella et al also highlight the importance of platelet aggregation/thrombogenesis
in MI deaths: '... the antioxidative agents in plant foods and wine may
also be very effective in reducing thrombosis and blockage of narrowed
arteries, which is a fatal event in more than 90% of deaths from CHD
[coronary heart disease].... Thus, the partially occluded [by atheroma]
artery is easily blocked by thrombi formed mostly from aggregated blood
cells that rapidly aggregate and clump in response to specific
In a classic 1992 article about the 'French paradox for heart disease,
Õ Renaud and de Lorgeril present evidence that dietary fat and blood
cholesterol are not primary MI villains, at least among the French. They
note that the annual mortality rate per 100,000 population from coronary
heart disease (CHD) is 78 in Toulouse, France, and 105 in Lille, France
(for men), compared to 182 in Stanford, USA, 348 in Belfast, UK, and 380
in Glasgow, UK. Yet the saturated fat intake is about the same for these
groups - 15% of total calories. The mean serum cholesterol is notably
lower for men in Stanford (209 mg%) than in France (230 in Toulouse, 252
in Lille), while Belfast (232) and Glasgow (244) levels are similar to
France, yet all three have higher MI mortality rates than France. Renaud
and de Lorgeril report that 'Stepwise multivariate analysis ... shows
that in the 17 countries that report wine consumption, wine is the only
foodstuff in addition to dairy fat that correlates significantly with
mortality.... wine has a negative sign indicating a protective effect
that accords with previous reports.'(2). Renaud and de Lorgeril then
present evidence that it is not through inhibitory effects on
atherosclerotic lesions (atheroma) that wine provides MI protection, but
rather through a decrease in the tendency of platelets to pathologically
aggregate and 'plug up' heart arteries. They note "... we have
compared farmers from Var, Southern France (low in CHD mortality), with
farmers from south-west Scotland for [platelet aggregation tendencies].
Platelet aggregation was strikingly lower in Var. Secondary aggregation
to ADP, the test that undergoes the greatest decrease with alcohol, was
55% lower in Var than in Scotland, whereas mean HDL [allegedly
MI-protective] cholesterol was 69 mg/dl in Girvan, Scotland, 66 mg/dl in
Stranraer, Scotland, and 63 mg/dl in Var. Consumption of alcohol was
greatest in Var (45g per day vs 20g per day in Scotland), mostly in the
form of wine." (2).
Lest anyone derive from this the moral that alcohol per se is beneficial
for heart health, several points should be noted. As Goldberg et al
state, "...ethanol or a metabolite impairs the platelet function as
a consequence of... platelet injury." (3). It is not sound
nutritional or medical practice (although it is the essence of
allopathic medicine) to try to oppose pathology by creating a new
THE RED WINE CONNECTION
Goldberg et al also note that "...Klatsky and Armstrong recorded
the lowest risk of CHD mortality among those who drank wine compared
with those preferring [other alcoholic] beverages, especially at higher
rates of consumption." (3). And, when "...16 healthy subjects
were given [pure] alcohol, white wine and red wine [for 15 days for each
beverage], alcohol enhanced [i.e. increased] ... platelet
aggregation.... Red wine led to a fall in ADP-induced [platelet]
aggregation and increased HDL-cholesterol, clearly the most favourable
response to the three beverages tested." (3).
Klurfield and Kritchevsky reported that "Rabbits were fed on
atherogenic diet together with water (controls), or one of five
different beverages containing equal amounts of ethanol. After 3 months,
all the control rabbits had developed atherosclerotic lesions in the
coronary arteries. The alcoholic beverages, except beer, reduced the
incidence of such lesions, but the most dramatic reduction (to 40% of
controls) occured in the rabbits receiving red wine." (3). This is
just a sampling of the evidence that it is primarily red wine, not
spirits or beer, that is 'heart-friendly.' Yet even red wine contains
alcohol, and alcohol, especially through its chief metabolite,
acetaldehyde, is a powerful and broad-acting metabolic toxin, with liver
damage being just the 'tip of the iceberg' of alcohol's destructive
side. (for more detail on the dark side of alcohol/acetaldehyde, see my
article 'Acetaldehyde: A common and potent neurotoxin.') (4).
As it became clear by the early 1990Õs that something relatively unique
to red wine provided significant heart protection, nutritional
scientists began searching to find the 'active ingredient(s).'
In a 1995 article, researcher David Goldberg rhetorically asked
"What on earth has the color of the wine got to do with it all? A
great deal it seems. The only consistent difference between the red and
white wines is that the red contains more phenolic compounds; among
these phenols, the major difference is in the flavonoids... [including]
compounds such as quercetin, rutin, catechin and epicatechin...."
(5). Goldberg points out that 'flavonoids' have been demonstrated to
have powerful biological effects, including the ability to inhibit
eicosanoid synthesis and pathological platelet aggregation, as well as
the ability to inhibit cancer growth and development. Goldberg also
notes these red wine-phenolics are individually and collectively 10 to
20 times more potent than vitamin E in protecting low-density
lipoproteins (LDL) against oxidation, (oxidized LDL is now considered to
be a powerful initiating mechanism of atherogenesis). Yet Goldberg also
points out that people who eat a decent amount of fruits and vegetables
will already ingest a fairly healthy dose of flavonoids, so 'why the
fuss about red wine?' (Indeed, the Zutphen Elderly study showed that
even the modest amount of flavonoids, primarily quercetin, found in tea,
onions and apples, seemed to provide significant protection against
death from MI among elderly men consuming these 3 foods, compared to
those not consuming them. (6).
Goldberg then asked the rhetorical question "Does [red] wine
contain a biological component that is present only in limited amounts
in a typical diet?" Indeed, it does: resveratrol. This
trihydroxystilbene is synthesized by [grapes], being present in the
canes, leaves and the skins of the berries. Because these are present
during the fermentation of red wines, but not white wines, only the
former contain significant amounts of resveratrol in the finished
product.... Apart from peanuts, no other human-consumed foodstuff
contains significant amounts." (5).
The resveratrol story does not begin with its (recent) discovery in
wine. It actually started in the early 1980's among Japanese scientific
researchers. Reporting in 1982, Arichi et al noted that the dried roots
of Polygonum cuspidatum have been used in traditional Japanese and
Chinese medicine in a product called 'Kojo-kon,' used to treat a wide
range of afflictions, including fungal diseases, various skin
inflammations and diseases of the heart, liver and blood vessels.
Resveratrol and its glycoside 'polydatin' have been shown to be the
primary active ingredients of Kojo-kon. (7).
In 1985 Kimura et al discovered the key to resveratrol's metabolic
activity. Working with rat leukocytes (white blood cells), they showed
that resveratrol possesses a powerful ability to inhibit
EICOSANOSIS THE QUASI-HORMONES
Eicosanoids are powerful 'quasi-hormones,' extremely short-lived,
generated from three 20-carbon fatty acids: dihomogamma-linolenic acid (DGLA),
arachidonic acid (AA) and eicosapentaenoic acid (EPA, common in fish
oils). AA predominates in mammalian cells, being stored in cell
membranes. Through the cyclooxygenase (COX) enzymes AA is transformed
into the powerful pro-inflammatory and platelet-aggregating thromboxanes,
as well as inflammatory prostaglindins. Through the lipoxygenase (LOX)
enzymes AA becomes the powerful inflammatory and white cell stimulating
agents known as leukotrienes, hepoxillins and lipoxins. (8).
Kimura et al found that the resveratrol concentration needed to
reduce by 50% (IC50) the AA-LOX product 5-HETE was only 2.72 micromoles resveratrol
(=62mcg resveratrol /100cc!), while the IC50 to reduce thromboxane B2
production from AA by COX required only 0.81 micromoles resveratrol (=18.5 mcg resveratrol
/100cc!). Kimura et al also reported resveratrol to inhibit platelet
aggregation induced by AA, thrombin and ADP. (9).
As Soleas et al noted, "Platelets were the next biological system
to be tested, and a series of papers from Chinese laboratories...
described the ability of resveratrol... to inhibit the aggregation of
rabbit platelets as well as their formation of thromboxane B2 from
arachidonate. Finally, resveratrol was shown to inhibit the antigen
induced contraction of isolated trachea from guinea pigs rendered
sensitive to albumin... inhibition of arachidonate metabolism was the
like; y mechanism." (10).
In 1995 Pace-Asciak et al reported a dose-dependent inhibition by both
trans-resveratrol and quercetin of the aggregation of platelets prepared from
healthy human subjects. The IC50 concentrations for both resveratrol and
quercetin were approximately 100 micromoles, while ethanol
required 1000 times higher concentrations to achieve the same effect.
The standard antioxidants BHT and vitamin E were ineffective at
inhibiting platelet aggregation, as were the major wine phenolics
catechin and epicatechin. (11).
Pace-Asciak et al also found that trans-resveratrol strongly inhibited the
COX-catalyzed thromboxane synthesis by platelets, with approximately 60%
inhibition at 10 micromoles resveratrol. Neither Quercetin or any of the other wine
phenolics or antioxidants tested had any major effect at that
concentration. At a concentration of 10 micromoles, Quercetin inhibited the
platelet LOX pathway by 70%, while only resveratrol of the other phenolics and
antioxidants tested exerted modest LOX inhibition at higher levels.
Platelet LOX activity generates hepoxillins from AA, which induce
vascular permeability and neutrophil activity, two partial causes of
atherogenesis. (8,11). As Soleas et al note, "...resveratrol at
micromolar concentrations is able to inhibit thromboxane A2 production,
and quercetin can likewise inhibit the formation of hepoxillins. Between
them, these two red wine phenolics can virtually shut down eicosanoid
synthesis of human platelets in vitro [and excessive platelet eicosanoid
synthesis is the basis of thrombogenesis]. (10). And in 1997 Soleas et
al reported that "...by applying information obtained from
dose-response curves, the [platelet] antiaggregatory effect of
dealcoholized red wines could be computed as approximately that expected
from its concentrations of resveratrol and quercetin." (12).
BLOOD VESSEL BIOLOGY
To more fully grasp the importance of eicosanoids in platelet
aggregation, it is necessary to understand a simple fact about blood
vessel biology. Healthy, smooth, intact blood vessel linings (the
endothelium, a layer only one cell thick) "...synthesize and
secrete prostacyclin [PGI2] is a strong vasodilator and the most potent
inhibitor of platelet aggregation known." (13). "...the
platelet thromboxane pathway is activated markedly in acute coronary
syndromes.... PGI2...contributes to the non-thrombogenic properties of
the endothelium.... PGI2 and TXA2 [thromboxane A2] represent
biologically opposite poles of a mechanism for regulating
platelet-vessel wall interaction and the formation of hemostatic plugs
and intraarterial thrombi." (8). In other words, PGI2 prevents
clots from plugging up heart arteries, keeps the arteries dilated (wide
open), and promotes healthy endothelial lining. TXA2, however, promotes
pathological clotting, constricts arteries, and can damage the blood
vessel endothelial lining-i.e. promote atheroma. (8).
PGI2 is routinely made by healthy endothelial cells from AA, and then
secreted into the bloodstream. Prostacyclin synthase (PS) is the enzyme
that transforms AA into PGI2.
FREE RADICALS AND ANTI-OXIDANTS
And what impairs the activity of PS? Various free radicals and oxidants,
especially lipid peroxides and hydroperoxides- these are, essentially,
'rancid' fats. (14,18). Kinsella et al state that the prevailing
hydroperoxide 'tone' or concentration is a result of the balance of
pro-oxidants (e.g. free copper or iron ions, cigarette smoke),
antioxidants and oxidative substrates (i.e. the fatty acids in the
blood), and that this balance influences the propensity toward
oxidation/free radical production. (15). Thus, in order to maximise
production of heart-friendly PGI2, it is necessary to minimize the
'prevailing hydroperoxide tone' in the blood, since high hydroperoxide
tone = low PGI2 synthase activity = low PGI2. (It also helps PGI2 to
minimize or eliminate fried fats from the diet, too-these provide rich
sources of hydroperoxides/peroxides.) "Antioxidants inhibit lipid
peroxidation by reducing general [hydroperoxide] tone.... The
polyphenolics [including resveratrol and Quercetin], commonly found in wine, are
potent antioxidants.... DeWhalley et al (1990) reported that flavonoids
act by protecting (and perhaps regenerating) the primary antioxidant,
tocopherol [vitamin E], by direct antioxidant effects, and by scavenging
free radicals and peroxy radicals." (15). Frankel et al reported
both resveratrol and Quercetin to be more powerful antioxidants than vitamin E in
protecting human LDL against copper-catalyzed oxidation. (16).
In 1994, B. Stavric wrote that "It appears that a number of the
biological effects of quercetin and other flavonoids may be explained by
their antioxidative activity and ability to scavenge free radicals. The
antioxidative function of quercetin was enhanced by ascorbate [vitamin
C]. This enhancement is attributed to the ability of ascorbate to reduce
oxidized quercetin and of quercetin to inhibit ascorbate photoxidation.
Even more potent beneficial effects of quercetin, as a radical scavenger
and/or as inhibiting lipid peroxidation [key to enhancing PGI2
production] were found in its combination with alpha-tocopherol [vitamin
E] and ascorbic acid." (17).
It also turns out to be very important to minimize free radical/lipid
peroxide production in order to minimize pathological platelet
aggregation due to TXA2 excess. thus, "the synthesis of these
compounds [TXA2 and PGH2] by cyclo-oxygenase is enhanced by lipid
hydroperoxides." (15). "Free radical production is
intrinsically linked with the enzymatic generation of prostaglandins,
thromboxanes and leukotrienes from [AA]... Lipid-derived hydroperoxides
(HPETE's) are obligatory intermediates in the generation of
prostaglandin/ thromboxanes ... from AA .... Bryant et al reported that
GP [glutathione peroxidase] reduces the hydroperoxide compound 12-HPETE
derived from AA, to its [relatively harmless] derivative 12-HETE.... Any
impairment of GP (by lack of availability of [selenium]...) may lead to
abnormal accumulation of the HPETE peroxides, which are potent
inhibitors of the prostacyclin synthetase." (18).
CONCLUSION FOR BLOOD
Thus, a combination of resveratrol, Quercetin, vitamin E, vitamin C, and the trace
mineral selenium may be expected to have a highly synergistic effect in
reducing pathological platelet aggregation (thrombogenesis), maximizing
PGI2/minimizing TXA2 (thus dilating arteries for healthy blood flow as
well as opposing platelet aggregation) and minimizing free radical
damage/disruption to blood vessel linings (i.e. preventing/minimizing
These same 5 compounds may also have a similarly beneficial effect in
preventing cancer, or even aiding in its cure. In 1997 Jang et al
reported the results of a series biochemical, cell culture, and animal
studies with resveratrol in the prestigious journal Science. They reported that
"Resveratrol inhibits cellular events associated with tumor
initiation, promotion and progression." (19). They also wrote that
"... we studied tumorigenesis in the two-stage mouse skin cancer
model in which DMBA was used as initiator and TPA as promoter. During an
18-week study mice treated with DMBA-plus TPA developed an average of
two tumors per mouse with 40% tumor incidence. Application of 1, 5, 10
or 25 [micromoles] of resveratrol together with TPA twice a week for 18
weeks reduced the number of skin tumors per mouse by 68, 81, 76 or 98%
respectively, and the percentage of mice with tumors was lowered by 50,
63, 63 or 88%, respectively. No overt signs of resveratrol induced
toxicity were observed...." (19). Jang et al also noted in their
paper the importance and potency of resveratrol's anti-cox activity and
antioxidant/antimutagenic activity in preventing tumor promotion and
Quercetin has also shown potent anti-cancer activity. Quercetin has "been shown
to inhibit the growth of cells derived from human and animal cancers,
such as leukemia and Ehrlich ascites tumors, the estrogen
receptor-positive breast carcinoma (MCF-7), squamous cell carcinoma of
head and neck origin, gastric cancer and colon cancer, as well as human
leukemia HL-60 cells in culture [Vang et al reported resveratrol to be active in
normalizing HL-60 cells in culture back into normal cells].... Quercetin
has antiproliferative activity against breast and stomach cancer cell
lines and human ovarian cancer primary cultures and can potentiate the
action of [the anti-cancer drug] cisplatin ex vivo....
Furthermore, in vivo synergy with cisplatin against Walker lung cancer
xenografts in nude mice has been described." (12).
Hoffman et al in 1988 related both Quercetin's direct anti-cancer activity, as
well as its synergistic effect with several standard anti-cancer drugs
to its ability to inhibit the enzyme protein kinase C. They also noted
that Quercetin "...is a licensed [anti-cancer] drug in many countries,
and is non-toxic at the required dose range." (20). It is
interesting to note that resveratrol was also reported by Jayatilake et al to be
a protein kinase inhibitor, also. (21).
In his textbook Cancer & Natural Medicine, J. Boik reports the
importance of platelet aggregation and eicosanoid issues in cancer. Thus
he writes: "The importance of platelet aggregation in cancer
metastasis is more widely accepted.... Activated platelets are sticky
and may enhance the adhesion of tumor cells to the endothelial lining.
Platelet-secreted factors... may stimulate the growth of tumor cells and
contribute to their survival within the blood circulation. Experimental
studies have shown that migrating cells from some cancers induce
platelet aggregation by modifying the eicosanoid balance.... Tumors
promote platelet aggregation by stimulating the production of PGI2....
Tumors synthesize eicosanoids through both the [COX and LOX] pathways.
The [LOX] pathway of [AA] is important, if not essential, to tumor
promotion." (23). Given the prior discussion in this article of resveratrol
as premier COX-inhibitor and Quercetin as premier LOX-inhibitor, and both as
excellent anti-platelet aggregators, their combined potential
anti-cancer benefit should be evident.
Garrison and Somer state that "Several studies report that vitamin
E reduces tumor growth and exerts an anti-cancer effect in both the
initiation and promotion stages because of its antioxidant and immuno-enhancing
actions.... vitamin E appears more effective in conjunction with other
nutrients, such as selenium and ascorbic acid, than by itself in the
prevention of tumor growth." (22).
Some question has been raised over the oral absorbability of both resveratrol
and Quercetin, but recent results clearly demonstrate their absorption. Thus
Soleas et al comment that "...the difference in thrombin-induced
platelet aggregation between the commercial and resveratrol-enriched
grape juices argues in favor of the absorption of this compound in
biologically active concentrations by human subjects...." (10).
Hollman et al recently completed a study of Quercetin absorption in healthy
ileostomy patients with complete small intestines. They found a 100mg
dose of pure Quercetin to be absorbed approximately 24%. (24).
USES AND DOSES
A simple yet elegant and potent anti-heart attack/anti-cancer program
may thus be constructed from the 5 synergistic nutrients: resveratrol, Quercetin,
vitamin E, vitamin C and selenium. Recommended dosages: 1-10mg
trans-resveratrol, 3 times daily. 100-500mg
Quercetin, 4 times daily. 100-400 IU
d-alpha tocopherol or d-alpha tocopheryl succinate (vitamin E), once
daily with a fat-containing meal. 250-1000mg ascorbate (vitamin C), 4
times daily. 100mcg once daily, or 50-100mcg twice daily, selenium as l-selenomethionine
and/or sodium selenate.
Although pioneer resveratrol researcher D. Goldberg remarks that both cis and
trans-isomers of resveratrol appear to be biologically active, (5) most of the
studies mentioned in this article used either plant-extracted or
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"Absorption of dietary quercetin glycosides and quercetin in
healthy ileostomy volunteers" Am J Clin Nutr 62, 1276-82.