Resveratrol and Quercetin - Anti Heart and Anti Cancer Dynamic 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 thrombosis).
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.
HROMBI 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 less common.
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 stimuli.'(15).
In a classic 1992 article about the 'French paradox for heart disease, 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 'opposing' pathology.
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 1990's 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 flavenoids... [including] compounds such as quercetin, rutin, catechin and epicatechin...." (5). Goldberg points out that 'flavenoids' 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 flavenoids, so 'why the fuss about red wine?' (Indeed, the Zutphen Elderly study showed that even the modest amount of flavenoids, 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 (RSV) possesses a powerful ability to inhibit eicosanoid production.
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 (RSV) concentration needed to reduce by 50% (IC50) the AA-LOX product 5-HETE was only 2.72 micromoles RSV (=62mcg RSV/100cc!), while the IC50 to reduce thromboxane B2 production from AA by COX required only 0.81 micromoles RSV (=18.5 mcg RSV/100cc!). Kimura et al also reported RSV 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-RSV and quercetin of the aggregation of platelets prepared from healthy human subjects. The IC50 concentrations for both RSV and quercetin (QRC) 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-RSV strongly inhibited the COX-catalyzed thromboxane synthesis by platelets, with approximately 60% inhibition at 10 micromoles RSV. Neither QRC or any of the other wine phenolics or antioxidants tested had any major effect at that concentration. At a concentration of 10 micromoles, QRC inhibited the platelet LOX pathway by 70%, while only RSV 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 RSV and QRC], commonly found in wine, are potent antioxidants.... DeWhalley et al (1990) reported that flavenoids 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 RSV and QRC 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 RSV, QRC, 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 atherogenesis).
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 RSV 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 RSV's anti-cox activity and antioxidant/antimutagenic activity in preventing tumor promotion and initiation.
QRC has also shown potent anti-cancer activity. QRC has "been shown to inhibit the growth of cells derived from human and animal cancers, such as leukaemia 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 RSV 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 QRC'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 QRC "...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 RSV 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 RSV as premier COX-inhibitor and QRC 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 RSV and QRc, 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 QRC absorption in healthy ileostomy patients with complete small intestines. They found a 100mg dose of pure QRC 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: RSV, QRC, vitamin E, vitamin C and selenium. Recommended dosages: 1-10mg trans-RSV, 3 times daily. 100-500mg QRC, 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 RSV researcher D. Goldberg remarks that both cis and trans-isomers of RSV appear to be biologically active, 5 most of the studies mentioned in this article used either plant-extracted or synthetic trans-RSV. Caveat emptor!
IAS offers the trans-Resveratrol as used in clinical studies. Caution: Anyone who suffers from platelet deficiency or blood-clotting difficulties should use this program only under medical supervision, if at all. Similarly, anyone taking medical blood-thinning drugs (e.g. aspirin, coumadin) should use this program only under medical supervision, if at all.
Quercetin is available from health food stores - note absorption can be improved when taken with bromelain.
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