Quercetin

Story at a glance

What is Quercetin

Flavonoids consist of a large group of “polyphenols” that are ubiquitously present in plants and serve to protect the plants and assist them in growing and thriving.

The polyphenols include flavonoids, phenolic acids, lignans, and stilbenes. There are more than 8,000 types of polyphenols that have been identified.

Their functions are necessary for plant growth, development, pigmentation, UV protection, defense, and as signaling molecules between plants and microorganisms. For example, the flavonoids in cotton play a significant role in cotton fiber production, and in defending against pathogens and herbivores.

One of the most interesting roles of flavonoids is regarding plant and bacterial interactions by controlling gene expression and infection of nitrogen-fixing microorganisms (rhizobia), living on the roots of certain plants. These microorganisms are capable of extracting nitrogen from the air and metabolizing it to ammonia, which plants can then use to produce the fundamental amino acids (protein).  Many microorganisms, including bacteria and archaea, can “fix nitrogen” from the air. Subsequently, when animals excrete waste containing nitrogen byproducts, such as urea, these microorganisms convert it back into N2, nitrogen gas, thus completing the cycle.

Chemically, flavonoids consist of a fifteen-carbon skeleton with two benzene rings on either side linked to a 3rd ring. They are a variety of classes such as flavones (e.g., flavone, apigenin, and luteolin), flavanols (e.g., quercetin, kaempferol, myricetin, and fisetin), flavanones (e.g., flavanone, hesperetin, and naringenin), and others, including flavanones, flavanonols, catechins, anthocyanins, and chalcones.

Basic Flavonoid is known as an Aglycone

Genistein (soy)

Quercetin

Sex Hormones

Flavonoids occur in all parts of plants including stems, roots, seeds, and flowers, and in higher concentrations in the cells that photosynthesize to produce oxygen and glucose. They are responsible for the beautiful coloring of flowers and are a fundamental and vital aspect of nutrition for both humans and animals. Not only do flavonoids impart the color and taste of plants and their fruits, but they are also essential to prevent fatty oxidation and provide protection for the vitamins, enzymes, and other vital elements in plants. Additionally, flavonoids protect plants from various stresses by filtering UV light, signaling molecules, allopathic compounds (drugs), phytoalexins (antimicrobial chemicals), and detoxifying agents, as well as other antimicrobial compounds.

Since these chemicals can only be produced by plants, they are known as phytochemicals. Clearly then, if flavonoids are found in animals, they originate from plants (as the animal consumed them).

Flavonoids provide several beneficial properties for humans who consume them. They act as powerful antioxidants, have anti-inflammatory effects, prevent mutations, interfere with CFC initiation, and regulate essential enzyme functions.

Certain classes of flavonoids are phytoestrogens since their structure resembles the skeleton of estrogens, which permits them to bind to the estrogen receptors and thereby modulate their activity. Depending on the receptor, flavonoids can produce an estrogenic or anti-estrogenic effect in many mammals, not just humans. Genistein is the predominant and most biologically active isoflavone in soy. Structurally, it is similar to 17β-estradiol however it has a higher affinity to ER-β than to ER-α, resulting in decreasing proliferation of tumors in both breast and prostate tissue.  The most abundant flavonoids in the human diet are soy isoflavones, flavanols, and flavones. Quercetin is a type of flavonoid called a flavanol.

In addition to their antioxidant function, they can stop CFC cells from dividing and inhibit topoisomerase II, the enzyme that blocks DNA repair leading to apoptosis or cell death. These effects play a significant role in preventing and treating breast and prostate cancers.

Flavanols, like quercetin (kaempferol, quercetin, myricetin, and fisetin) are found in onions, kale, lettuce, tomatoes, apples, grapes, and berries as well as tea and red wine.

Additionally, due to their estrogenic effects, flavonoids decrease osteoporosis, hence preventing bone loss and other symptoms of menopause.

CYP19, also known as aromatase, is a member of the cytochrome P450 enzyme in the liver that is inhibited by flavonoids. This enzyme converts C19 androgens (such as androstenedione and testosterone) to C18 estrogens (estrone and estradiol). Thereby, reducing the amount of estrogen in tissues. This is exactly what the pharmaceutical products, called aromatase inhibitors do except there are no unwanted side effects.

Orally, 1 g per day of quercetin is safe and 60% can be absorbed. So-called, “pharmacologic activities” for quercetin, include antioxidation, anti-diabetic, anti-inflammation, and as stated anti-proliferation, hence CFCs do not grow.

Quercetin has been found to inhibit CFCs in the breast, lung, nasopharyngeal (throat), kidney, colorectal, prostate, pancreas, as well as ovaries. Quercetin can interfere with every stage of CFC development from initiation to progression and metastases. Epidemiological studies have found a link between a high intake of quercetin from the diet and reduced risk of several types of CFCs.

However, the poor oral bioavailability may limit the medicinal use of quercetin as a supplement. Therefore, quercetin can be administered intravenously to ensure that therapeutic levels are achieved when treating active CFCs. Human studies have confirmed intravenous quercetin to be safe and selectively target CFCs without harming healthy cells.

In one study, Ferry, et.al. injected quercetin intravenously at doses of 60–2000 mg/m2, concluding that 945 mg/m2 was the safe dose. Higher doses were toxic, causing vomiting, high blood pressure, kidney damage, and decreased serum potassium.

There are multiple ways by which quercetin can benefit people with CFCs

Alleviates Symptoms Caused by CFCs and the Conventional Treatments

People going through chemotherapy are exposed to many adverse effects including nausea, fatigue, and muscle loss. These symptoms are caused by proinflammatory cytokines that are produced as a response to treatments. The effects of these cytokines can further enhance the progression of CFCs and the risk of CFCs coming back after the treatment.

In a study on people with colorectal CFCs, a high intake of quercetin from the diet was associated with lower levels of proinflammatory cytokine interleukin-6 (IL-6) in serum as well as reduced risk of CFC recurrence. In another study, quercetin helped to protect from the loss of muscle mass that was caused by chemotherapy.

People with CFCs usually have increased levels of platelets and blood clotting, which is one of the mechanisms CFCs use to hide from the immune system and spread throughout the body. This exposes a person also to a higher risk of fatal thrombosis or blood clots. Quercetin has shown anticoagulant activity and in people with advanced CFCs, quercetin treatment reduced the risk of blood clots without increasing the risk of bleeding.

Supports Antioxidative and Detoxification Processes

Quercetin can prevent CFC formation by supporting the body in the elimination of carcinogenic compounds and reactive oxygen species. Quercetin induces the expression of several phase II detoxifying and antioxidant enzymes such as glutathione-s-transferase (GST), NAD(P)H quinone reductase (NQO1), and heme oxygenase (HO-1) in cells by increasing the levels of nuclear factor-E2-related factor-2 (Nrf2) protein that regulates the production of these enzymes.

Prevents Tumor Growth and Metastases

Quercetin has been found to prevent the growth of CFCs by interfering with several major signaling pathways. One pathway that quercetin blocks is mediated by the mammalian target of rapamycin (mTOR) which controls essential cell growth pathways and gets overactivated in CFCs. Quercetin is also known to inhibit CFC growth by interfering directly with the progression of the normal cell replication cycle. Quercetin has been shown to stop the cell cycle at a certain phase preventing the cell from dividing.

Quercetin also activates AMP-activated protein kinase (AMPK) which functions as a sensor of cellular energy (ATP) and suppresses cell proliferation when energy levels are low. The loss of AMPK signaling in CFCs enables them to maintain high metabolic and growth rates, a process that is reversed by quercetin.

Quercetin can also lower the expression of several receptors for growth factors that CFCs require to progress. One is human epidermal growth factor receptor 2 (Her-2/neu) which is overexpressed in some breast CFCs. Studies suggest that quercetin can also resist breast CFC growth by competing with estrogen for binding in estrogen receptors (ER). Most types of breast CFCs express ERs on their cell membrane but these receptors occur also in other types such as lung CFCs. ERs are usually targeted with the antiestrogen agent tamoxifen. In the studies where the efficacy of tamoxifen and quercetin to bind ER and another receptor called type II estrogen-binding site (type II EBS) were compared, the ability of quercetin to bind the receptors and inhibit the growth of CFCs was equal to or better than that of tamoxifen.

Quercetin has been found to resist tumor growth by interfering with glycolysis, the primary method of energy production in CFCs. It achieves this by reducing the expression of glucose transporters (GLUT1) thereby decreasing cellular glucose uptake. Additionally, quercetin inhibits the activity of lactate dehydrogenase A (LDHA), an enzyme used by CFCs to produce energy through fermentation.

Another way by which quercetin has been shown to limit the energy production and growth of CFCs is to interfere with their supply of iron. Iron is an essential element in numerous cellular processes including DNA synthesis and energy production. Due to rapid replication and DNA synthesis, CFCs require iron more than healthy cells and therefore are more sensitive to iron deficiency. Quercetin is known to act as a strong iron chelator and in studies, quercetin has prevented the proliferation of CFCs by depleting them from iron through chelation. Quercetin can also inactivate hypoxia-inducible factor-1 α (HIF-1α) which is switched on in CFCs as a response to low levels of oxygen (hypoxia). The increased uptake and accumulation of iron is partly dependent on HIF-1α activity.

Activated HIF-1α makes CFCs also produce vascular endothelial growth factor (VEGF) which attracts new blood vessels to grow towards the tumor. This provides CFCs with more glucose and also new routes to metastasize. Quercetin has been shown to lower the production of VEGF and to inhibit CFCs from spreading and forming metastases.

Quercetin also prevents CFCs from producing enzymes called matrix metalloproteinases (MMPs) which are also needed for metastases. These enzymes are responsible for degrading proteins that hold the cells and tissues together. Healthy cells use MMPs for renewing and remodeling structures but in CFCs, MMPs are overproduced and used to break down tissues for invading and spreading to distant organs.

Induces Apoptosis

Quercetin has been shown to restore the ability of CFCs to undergo programmed cell death (apoptosis). It achieves this by acting on multiple pathways that have been altered in CFCs. One is the Akt/PKB signaling pathway that quercetin suppresses. The Akt/PKB pathway is normally regulated by a suppressor gene PTEN which enables the cell to control its division cycle and apoptosis. Inactivated PTEN is one of the most common changes in genetic expression in CFCs and the result is that Akt/PKB pathway is continuously active. The highly active Akt/PKB pathway causes the cell to divide rapidly and to lose its ability to die when appropriate. It is associated with poor survival and resistance to hormones and chemotherapy in individuals with CFCs.

Quercetin also allows apoptosis to happen in CFCs through inhibition of nuclear factor-kappa B (NF-κB). NF-κB is activated in CFCs as a result of oxidative stress and inflammation and it regulates several genes involved in apoptosis which are called inhibitors of apoptosis (IAPs) and B-cell lymphoma-2 (Bcl-2). Quercetin has also been shown to activate the tumor suppressor p53 which is responsible for inducing cell death in response to various stressors but is also often inactivated in CFCs.

CFCs are more sensitive to oxidative stress than normal cells and therefore can be selectively targeted. Quercetin has been found to cause the death of CFCs by increasing oxidative stress inside them. Accumulated oxidative stress depletes the antioxidant enzyme glutathione and cells die from oxidative damage. Studies have found that apoptosis due to oxidative stress was synergistically enhanced when quercetin was combined with curcumin. Like curcumin, quercetin is also able to eliminate CFC stem cells.

Modifies the Immune System

Experimental studies have demonstrated that quercetin can alter the function of the immune system and strengthen the immune response against tumors. This effect was detected at concentrations of quercetin that can be achieved by oral ingestion, not requiring IV administration. Therefore, daily oral intake of quercetin can be viewed as an immune enhancer.

Quercetin can regulate the differentiation of helper T lymphocytes (Th). Th cells can specialize into Th-1 or Th-2 cells, which differ from each other by the cytokines they produce and their effects on the immune response.

Th-1 cells produce interleukin 2, IFNγ, and IL-12 and enhance antitumor immune response. However, the conditions surrounding CFCs (the tumor microenvironment) cause Th cells to differentiate into Th2 cells that produce IL-4, IL-5, IL-6, and IL-10 cytokines and cannot eliminate CFCs. A tumor microenvironment dominated by the Th2 cell type is associated with tumor-supporting immunity and metastases. Quercetin has been shown to counteract this process by enhancing the gene expression and the production of Th-1 cytokine IFNγ and downregulating the production of Th-2 derived cytokine IL-4. Therefore, quercetin can shape the immune response into Th1 dominating antitumor response by regulating the production of cytokines.

Summary

Flavonoids, like quercetin and soy, must be considered indispensable therapies along the path of eliminating CFCs as well as preventing them from metastasizing. If a pharmaceutical drug could produce the far-reaching beneficial effects as these flavonoids, they would be “top sellers”.  However, sadly the synthetic drugs produced by these companies, usually have only one beneficial consequence and multiple undesired effects, called side effects.

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