Quercetin

What Is It?

Quercetin is one of the most abundant dietary flavonoids$^{1}$ found mainly in raw capers and various other fruits and vegetables$^{2}$. It is known for its bitter flavor and strong antioxidant activity. Quercetin has been investigated for its antiallergic, anti-inflammatory, and anti-viral properties. In addition, numerous cell line and animal model studies have demonstrated its strong anticancer activities against breast, lung, liver, ovarian, and prostate cancers$^{3}$. Additionally, quercetin is especially of interest due to its low toxicity profile against healthy cells$^{4}$. While very little clinical data exists on quercetin as a dietary intervention to prevent cancer, in vitro (cell lines) and in vivo (animal models) data provides an extensive mechanistic explanation for its cancer-preventative and cancer-treating properties that could inform future studies in humans. It has been shown to combat oxidative stress, reduce inflammation, and inhibit cancer cell growth, all of which are functions that make it a potentially important anticancer nutrient.  

What Are Its Other Names?

Quercetin is chemically known as 3,3′,4′,5,7‐pentahydroxyflavone (C15H10O7), but may be referred to as sophoretin, meletin, quercetine, xanthaurine, quercitol, quertine, or quercitin$^{5}$. 

What Foods Have It?

Quercetin is predominantly found in capers, lovage, dill, cilantro, red onions, and various berries. The data below has been extracted from the United States Department of Agriculture (USDA) database for the flavonoid content of selected foods, arranged in order of quercetin concentration$^{2}$. 

It is important to note that the dietary content of quercetin will vary based on the particular crop and food storage conditions$^{6}$ as well the form in which quercetin is found in food. For instance, quercetin in onions has the highest bioavailability (fraction of the ingested substance that exerts activity in the body) in humans due to its particular chemical nature$^{7}$, as it exists bonded to a chemical group called a glucoside. Quercetin in its free form, however, has been noted to have low bioavailability in humans, due to its hydrophobicity$^{8}$ (low solubility in water).

What Are Its Main Benefits?

Cell lines and animal models have shown that quercetin has potent anticancer effects against prostate, breast, liver, colon, cervical, and lung cancer$^{3}$. It has further demonstrated antiallergic, antioxidant, and anti-inflammatory activities. Note that since the vast majority of the data derives from cell lines and animal models, the applicability of these findings to humans is limited. The human body is very complex and the effect of ingested compounds on target tissues is subject to variability. Thus, until further studies are conducted in humans, quercetin should not be wholly relied on for human benefits.  Cancer Prevention and Treatment Quercetin has been shown to prevent the development of numerous cancers, including prostate, breast, liver, colon, cervical, and lung cancer. In human studies, consuming fruits and vegetables rich in quercetin has been associated with lower risks of ovarian cancer$^{9}$. Another clinical trial also investigated the impact of a flavonoid-rich diet on serum IL-6 concentrations and colorectal adenoma recurrence within a large group of 2,079 individuals given the diet for 4 years. The researchers found that quercetin intake may reduce serum IL-6 levels, thereby reducing inflammation (explained further below) and consequently reducing the recurrence risk of colorectal adenomas$^{10}$. In in vitro (cell line) and in vivo (animal model) studies, quercetin was shown to inhibit enzymes involved in the activation of cancer-causing chemicals, or carcinogens, thus preventing them from acting to convert healthy cells into cancerous cells$^{11,12}$. Importantly, quercetin has been shown to leave healthy cells alone, indicating its specificity for cancer cells$^{3}$. Further, in mice humanized with prostate cancer tissue, quercetin inhibited the ability of cancer cells to develop their own system of blood vessels for nourishment, a process known as angiogenesis, which is a key hallmark of cancer cells$^{13,14}$. On another note, numerous cell studies have shown that quercetin enhances the anticancer activity of chemotherapy drugs, such as cisplatin$^{15}$, doxorubicin$^{16}$, and daunorubicin. It also serves to combat drug resistance by sensitizing cancer cells to the action of these drugs$^{15-19}$, via mechanisms discussed below in the “What are Its Mechanisms of Action?” section.  Antiallergic Activities Cell studies have shown quercetin’s ability to inhibit the release of histamine from specific immune cells involved in allergic responses known as mast cells$^{1}$, highlighting its potential for use in humans as an anti-allergy compound. It inhibits calcium influx and a host of molecules including leukotrienes and prostaglandins which normally function to activate mast cells$^{1,20}$. Human studies are still required to substantiate this, however. Anti-inflammatory Activities Quercetin was shown in several studies to combat inflammation at a cellular and systemic level. In a study involving healthy amateur sportsmen, 500 mg of quercetin was administered daily for two months and shown to lead to a considerable reduction in C-Reactive Peptide, or CRP, and IL-6, two key markers of systemic inflammation$^{21}$. Note that the quercetin treatment worked in supplementation with vitamin C as a co-factor, which served to improve the bioavailability of quercetin. On the other hand, this improvement did not occur when the same treatment was given to women with rheumatoid arthritis$^{22}$. Furthermore, cell and animal studies have demonstrated quercetin’s ability to inhibit enzymes and compounds involved in inflammatory responses. It was shown to inhibit the expression of cyclooxygenase, an important enzyme responsible for inflammation, thereby reducing circulating levels of prostaglandins (compounds involved in inflammation)$^{14,23}$.  Antioxidant Effects Due to its chemical structure, quercetin is a potent antioxidant capable of eliminating free radicals$^{24}$, which are compounds capable of cancer-causing DNA damage$^{1}$. Two clinical trials demonstrated quercetin’s ability to reduce oxidation in the body and related DNA damage$^{25,26}$, when it was consumed in onions or fruit juice. In vitro, it was shown that quercetin metabolites from enterocytes and liver cells impede the oxidation of LDL (low-density lipoprotein) cholesterol$^{3}$, which prevents inflammation and atherosclerosis development.  Cardiovascular Benefits Quercetin has been used to protect against coronary heart disease. In one study, the intake of flavonols (a subclass of flavonoids of which quercetin belongs) by a group of Japanese women was inversely correlated with plasma total cholesterol and LDL cholesterol concentration, and quercetin as a single compound was significantly inversely correlated with both. This reduction in plasma cholesterol is linked to a low incidence of coronary heart disease (CHD) among Japanese women, who consume a diet high in flavonols and isoflavones compared to women in other countries$^{27}$.

What Are Its Main Drawbacks?

Due to quercetin’s hydrophobicity, lack of stability in physiologic conditions, and low bioavailability after oral ingestion, clinical trials have been constrained and evidence in human populations for its cancer-preventative properties is lacking$^{24}$. Due to its low absorption in the gastrointestinal tract and poor solubility, the oral delivery of quercetin must be improved. Furthermore, at a dose greater than 1 gram a day, it may lead to kidney damage$^{28}$ (demonstrated in animal studies only, however) and is therefore not recommended by Mount Sinai Health for pregnant or breast-feeding people as well as those with kidney disease. According to The Mount Sinai Health System, it may also reduce the effectiveness of certain antibiotics, enhance the retention of corticosteroids, and enhance the effect of anticoagulants$^{29}$.

What Are Its Mechanisms of Action?

1. Induction of Apoptotic Pathways and Halting Cell Cycle Progression: Quercetin has been demonstrated to enhance cancer cell apoptosis, or programmed cell death, and prevent cell division in cell lines and animal models of various cancers. In breast cancer cells, it was shown to inhibit the expression of genes and the function of proteins that suppress apoptosis, such as Twist$^{30}$, as well as those that promote the cell division cycle such as cyclin D1$^{31}$. Furthermore, in breast, pancreatic, liver, lung, and prostate cancer cell lines, quercetin has been shown to activate the caspase proteins responsible for apoptosis (caspase-3, -7, -8, and -9) as well as trigger the release of certain proteins and compounds such as Bcl-2 and cytochrome c which promote apoptosis$^{3}$. Additionally, quercetin halts cancer cells at the G2/M phase, which means that they are not able to proceed to cell division and proliferate further, an important cancer-halting mechanism$^{32}$.
2. Reduction of Reactive Oxygen Species and Improving Antioxidant Defenses: As discussed in the “What Are Its Main Benefits?” section, quercetin is capable of potent antioxidant activity, capturing reactive oxygen species (ROS) and preventing them from exerting harmful oxidative stress on our body. Oxidative stress is a process that interacts with every stage of cancer progression, producing DNA damage and enabling inflammation which both promote cancer development$^{33}$. In a mouse model for skin cancer, 200 and 400 mg/kg of quercetin for 16 weeks was shown to significantly increase plasma levels of superoxide dismutase, catalase, and glutathione – all important enzymes involved in combatting reactive oxygen species and preventing oxidative stress in the body$^{34}$. It also prevented the production of lipid peroxides (which contribute to genome instability) and DNA damage. In ovarian cancer cells, it also improved the expression of endogenous antioxidant enzymes and suppressed intracellular ROS levels$^{35}$.
3. Limiting the Expression of Pro-Metastatic and Pro-Tumor Genes: Quercetin has been shown to act at the genome level, regulating the expression of various genes involved in aiding cancer progression. For instance, cell line studies have demonstrated that it suppresses the expression of Twist and Slug$^{36}$ which are involved in cancer metastasis (spread), cyclin D1$^{37}$ which is involved in cell cycle progression, and matrix metalloproteases 2 and 9$^{38}$, which promote tumor growth by degrading the matrix barriers surrounding cancer tissue and enhancing angiogenesis. Furthermore, quercetin hinders the expression of RAGE and HMGB-1 on the surface of human breast adenocarcinoma cells, which serves to reverse the avoidance of apoptosis caused by these proteins, thus killing cancer cells as a result$^{39}$. Quercetin also suppresses an important growth pathway in cancer cells, the PI3K/Akt/mTOR pathway$^{40}$. When applied to prostate cancer cells, it greatly decreased cell viability and promoted apoptosis by impeding several cell survival pathways and elevating the expression of tumor-silencing microRNAs, including mir-15a and mir-330$^{3}$. 
4. Synergism with Traditional Cancer Therapies: In addition to potentially contributing to cancer prevention, quercetin has shown promise in combatting drug resistance and improving cancer sensitivity to traditional chemotherapy drugs. By modulating a certain pathway called the miR-217-KRAS axis, quercetin was shown to regulate the sensitivity of bone cancer cells to cisplatin$^{17}$, and it also improved the sensitivity of ovarian cancer cells to cisplatin and another chemotherapy drug called paclitaxel$^{41}$. Furthermore, in mouse models of ovarian cancer, quercetin was shown to be a radiosensitizer, enhancing the cancer-combatting action of radiotherapy via suppressing tumor growth and inducing cancer cell apoptosis more than X-rays alone$^{42}$, acting via the p53-induced endoplasmic reticulum (ER) stress pathway. Also, by activating caspase enzymes and other proteins involved in apoptosis, quercetin demonstrated a synergistic effect with doxorubicin in a dose-dependent manner, when tested on multidrug-resistant leukemia cells$^{16}$. With regards to brain cancer cells in vitro, quercetin exhibited a synergistic effect with temozolomide, whereby it significantly reduced cancer cell viability and inhibited colony formation via several molecular pathways$^{43,44}$. It is worth noting that all above mechanisms were elucidated via cell lines and animal models, and for applicability to humans, clinical trials should be conducted to validate the mechanisms through which quercetin acts in our bodies.

What Are Typical Doses and Durations?

Dosage Daily consumption of quercetin varies between diets and between nations and daily flavonoid intake may range from 50 to 800 mg per day, with quercetin representing 75% of that intake. Reports show that the average daily consumption in the USA, Spain, Japan, and China are 9.75, 18.48, 16.2, and 18 mg, respectively$^{45}$. Onions are generally the most consumed source of quercetin in the diet, in addition to red grapes, cherries, and blueberries$^{45}$. In randomized clinical trials (shown below), a daily intake of up to 1000 mg quercetin was found to be safe and potentially beneficial in cancer prevention. Isolated quercetin is also often marketed as a dietary supplement in doses of up to 1000 mg daily. Adverse effects have been rarely reported, although published data for safety assessment regarding long-term use (over 3 months) of doses exceeding 1000 mg is not available$^{28}$. However, as previously mentioned, according to Mount Sinai Health, at a dose greater than 1 gram a day, quercetin may lead to kidney damage$^{28}$ (demonstrated in animal studies only, however) and is therefore not recommended for pregnant or breast-feeding people as well as those with kidney disease.  Duration The duration of the randomized clinical trials investigating quercetin as a cancer-preventative nutrient, shown below, ranged from 4 weeks to 4 years, with none reporting adverse side effects. Daily consumption of quercetin is safe, within reasonable doses$^{45}$, as described above.

Summary of Data

A total of 6 randomized clinical trials that investigated quercetin as a cancer-preventative nutrient were identified on PubMed. The data from the trials is summarized below$^{10,25,26,46,47,48}$.

📄 Detailed Quercetin human clinical trial study notes analyzed by Anticancer.ca

References

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16. Chen, F.-Y. et al. Quercetin enhances adriamycin cytotoxicity through induction of apoptosis and regulation of mitogen-activated protein kinase/extracellular signal-regulated kinase/c-Jun N-terminal kinase signaling in multidrug-resistant leukemia K562 cells. Mol Med Rep 11, 341–348 (2015).
17. Zhang, X., Guo, Q., Chen, J. & Chen, Z. Quercetin Enhances Cisplatin Sensitivity of Human Osteosarcoma Cells by Modulating microRNA-217-KRAS Axis. Mol Cells 38, 638–642 (2015).
18. Scambia, G. et al. Quercetin potentiates the effect of adriamycin in a multidrug-resistant MCF-7 human breast-cancer cell line: P-glycoprotein as a possible target. Cancer Chemother Pharmacol 34, 459–464 (1994).
19. Borska, S., Sopel, M., Chmielewska, M., Zabel, M. & Dziegiel, P. Quercetin as a Potential Modulator of P-Glycoprotein Expression and Function in Cells of Human Pancreatic Carcinoma Line Resistant to Daunorubicin. Molecules 15, 857–870 (2010).
20. Kimata, M. et al. Effects of luteolin, quercetin and baicalein on immunoglobulin E-mediated mediator release from human cultured mast cells. Clin Exp Allergy 30, 501–508 (2000).
21. Askari, G., Ghiasvand, R., Feizi, A., Ghanadian, S. M. & Karimian, J. The effect of quercetin supplementation on selected markers of inflammation and oxidative stress. J Res Med Sci 17, 637–641 (2012).
22. Javadi, F. et al. The effect of quercetin on plasma oxidative status, C-reactive protein and blood pressure in women with rheumatoid arthritis. Int J Prev Med 5, 293–301 (2014).
23. Warren, C. A. et al. Quercetin May Suppress Rat Aberrant Crypt Foci Formation by Suppressing Inflammatory Mediators That Influence Proliferation and Apoptosis. J Nutr 139, 101–105 (2009).
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25. Boyle, S. P., Dobson, V. L., Duthie, S. J., Kyle, J. A. & Collins, A. R. Absorption and DNA protective effects of flavonoid glycosides from an onion meal. Eur J Nutr 39, 213–223 (2000).
26. Wilms, L. C. et al. Impact of multiple genetic polymorphisms on effects of a 4-week blueberry juice intervention on ex vivo induced lymphocytic DNA damage in human volunteers. Carcinogenesis 28, 1800–1806 (2007).
27. Arai, Y. et al. Dietary intakes of flavonols, flavones and isoflavones by Japanese women and the inverse correlation between quercetin intake and plasma LDL cholesterol concentration. J Nutr 130, 2243–2250 (2000).
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35. Li, N. et al. Low concentration of quercetin antagonizes the cytotoxic effects of anti-neoplastic drugs in ovarian cancer. PLoS One 9, e100314 (2014).
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• Quercetin
• What Is It?
• What Are Its Other Names?
• What Foods Have It?
• What Are Its Main Benefits?
• What Are Its Main Drawbacks?
• What Are Its Mechanisms of Action?
• What Are Typical Doses and Durations?
• Summary of Data
• References
• About This Article
• Disclaimer