How I learned about Quercetin’s potential:
Sometime ago I had access to a number of chemosensitivity test results and performed some analysis on them. These chemosensitivity tests are performed by specialized laboratories and essentially consists in collecting blood from patients, capturing the circulating tumor cells and then exposing these tumor cells to various chemicals in order to identify those substances that have the most chance of eradicating the tumor of each patient. After that, the patient can go back to his hospital or a private clinic that can administrate the substance with an improved chance of success. Such test are currently debated but at least may represent a guide for most of us. Similar statistics is available from various labs.
Note that in this graph
- only includes the natural substances and a few synthetic (like DCA), i.e. not included chemo substances. Also, note that it only includes the effective natural substances and many with non or only limited effectiveness were left out
- average effectiveness represents the average effectiveness of a specific substance across the included number of patients and normalized to the most effective substance in this set
- chance for effectiveness represents the percentage of cases for which a specific substance is indicated as effective in killing the cancer. So if the number is 100% it means that according to the chemo sensitivity analysis, cancer cells from all patients responded to that specific substance
As we can see from this analysis, the most effective substance and with the highest chance of effectiveness is Quercetin. It looks even better then Curcumin which I already like a lot! According to the above statistics one may argue that patients don’t even need to perform a chemo sensitivity analysis to know that Quercetin may be effective.
Quercetin, as most of the substances in its category, has a poor bio-availability when administrated via oral route. That doesn’t mean that it would not be absorbed, but a lot has to be taken in order to reach the therapeutic dose.
As a results I started to search on understanding more about Quercetin and its anti cancer mechanism and at the same time search for research where Quercetin was administer via IV as this would be the most effective way to reach most tumor locations. After spending a lot of time on this subject, I fortunately found that in some countries Quercetin is administrated in hospitals in IV form to address other health issues than cancer.
Indeed the anti cancer potential of Quercetin is intensively studied in the academic environment so that today there are more than 2000 publications on this subject http://www.ncbi.nlm.nih.gov/pubmed/?term=quercetin+cancer
What is Quercetin
Quercetin is a flavonol found in many fruits, vegetables, leaves and grains. It can be used as an ingredient in supplements, beverages, or foods. Quercetin is one of the most abundant dietary flavonoids with an average daily consumption of 25–50 mgs. It can be found in many vegetables and fruits, and even in honey but when I speak of quercetin I think of onion, so here is an onion picture 🙂
Clinical Trials in Humans
Quercetin was administered intravenous in an ethanol vehicle to six normal human volunteers in 1975 at a fixed dose of 100 mg without side effects. This study also indicated very low oral bioavailability when administrated orally (Ref.)
About 20 years latter, in 1996, another clinical trial has been performed, an escalation Phase I trial using 60 mg/m2 as the starting dose administrated intravenous. (Ref.) The starting dose of 60 mg/m2 was chosen based on the previous volunteer study from 1976. Thereafter, doses were increased so that 1400 mg/m2 as the bolus dose was found as the max safe dose which was suggested for Phase II trials, given either in 3-week or weekly intervals.
Treated patients: the median age was 56 (range, 23-78) years. The tumor histologies of the treated patients were: large bowel, 14; ovary, 10; pancreas, 7; melanoma, 6; stomach, 5; renal, 2; hepatoma, 3; and non-small cell lung, 2. Two patients had other diagnoses: one with testicular teratoma and one with gastrinoma.
Conventionally Phase I trials should lead to a recommendation of the dose to be explored in Phase II trials. However, next to identifying the recommended dose this study has also demonstrated anticancer effects of Quercetin. Specifically, one patient with cisplatin refractory ovarian cancer had a large and sustained fall in serum CA 125 levels. Another patient with hepatocellular carcinoma had a fall of a-fetoprotein from 460 to 40. (Ref.)
Although this trial clearly demonstrated safety anti cancer effect of quercetin, with a clear conclusion of the authors: “In conclusion, quercetin can be safely administered by i.v. bolus at a dose injection. The plasma levels achieved inhibited lymphocyte tyrosine kinase activity, and evidence of antitumor activity was seen.”, after this trial there was never any next phase performed.
Quercetin has a wide range of biological activities:
- Quercetin is known to be a MCT inhibitor (Ref1, Ref2.). MCT1 and MCT4 inhibition is associated with anti cancer effects due to mechanisms such as those discussed in a previous post (Ref.), i.e. pH modulation. MCT1 inhibitors are presently developed by pharmaceutical industry as anti cancer drugs. (Ref.) The MCT1 inhibition is also an activity that is know to help against auto immune diseases. As a side note, due to this mechanism, Quercetin can also address eye related diseases such as Keratoconus (Ref.). I personally know someone (a medical doctor) who was treated with IV Quercetin intensively and succeed to cure her eye surprising hospitals who were expecting needs for surgery, etc.
- It seems to also have Na/K ATPase inhibition capabilities. This action is also well know to lead to anti cancer effects and other substances that are Na/K ATPase inhibitors such as Oleandrin, Ouabain, Bufalin, etc. (i.e. cardiac glycosides) are know to have strong anti cancer effect
- Inhibits cell cycle at G1 and S phase in vitro, inhibits phosphorylation of protein kinase C (PKC) and tyrosine kinase (Ref.), which ultimately blocks cellular signal transduction leading to decreased tumor growth. Inhibits the ras cascade, which is important for cellular proliferation and induces apoptosis. This is a general class of intra-cellular signals that strongly stimulate cell division. Note: Niclosamide, Mebendazole, Baicalein and Genistein are also Tyrosine kinase inhibitors.
- Inhibitor of phosphatidyl-3 kinase (Ref.) and l-phosphatidylinosotol-4 kinase also relevant for cardiovascular diseases (Ref.)
- Antioxidant, anti-platelet (reducing cyclicAMP), and anti-atherogenic activities (Ref.) – the vascular protective effect associated with eNOS up-regulation (Ref.)
- Vasodilatory action: “During the injection of quercetin, all of the patients experienced transient flushing for up to S mm. This was not associated with a fall in blood pressure, and must therefore be related to dilation of blood vessels smaller than resistance vessels. Quercetin is known to have vasodilator effects, inhibiting the spontaneous myogenic contractions of rat portal vein with an IC50 of 9 uM and reversing phorbol l2-myristate 13-acetateinduced aortic contractions with an IC50 of 1 1 uM (33), suggesting involvement of protein kinase C. Other biological activities of quercetim may have contributed to the vasodilator effect, including inhibition of phosphodiesterases (34).” (Ref.)
- Anti inflammatory (Inhibits production of leukotrienes and prostaglandins, inhibits lymphocytes, and suppresses macrophage phagocytosis)
- Antiviral activity: Binds to viral coat and may inhibit nucleic acid synthesis, competitive inhibitor of reverse transcriptase (Ref, Ref1, Ref2, Ref3, Ref4, Ref5)
- Antihistamine: Inhibits the release of histamine and basophils from mast cells in lung and intestinal tissues (Ref1., Ref2.)
- At low dose anti-oxidant; At high dose pro-oxidant (see https://www.cancertreatmentsresearch.com/?p=1321#comment-1152) To act as an anti oxidant it has to be administrated at low dose and/or together with glutathione (Ref.). To act as a pro oxidant it has to be administrated at high dose or for long time and/or together with a glutathione depliting drug (such as paracetamol).
More about Quercetin potential is discussed in details in the following reference http://www.altmedrev.com/publications/16/2/172.pdf
Formulation & Administration:
Oral administration: As discussed above Quercetin administrated orally is only little absorbed so that it is difficult to reach the therapeutic plasma level. However, if IV administration is not an option I would consider 6g/day as an intensive anti cancer dose against active disease and 1-3g/day as a maintenance dose.
IV administration: The best way do administrate quercetin is intravenous. However, compared to e.g. 3BP, DCA, 2DG or Vitamin C, it is challenging to formulate Quercetin in IV form as it is not water soluble. Quercetin is little soluble in ethanol and this is how it has been used in the firs clinical trial performed in 1976. Yet, they only used 100mg/patient while in the clinical trial from 1996 it has been indicated that the effective safe dose may be around 1400mg/m2. At this dose we would need to use too much ethanol and that is not feasible. As a result, the clinical trial in 1996 have decided to use DMSO to solve Quercetin. This is again a tricky technique since Quercetin solved in DMSO and mixed with water will immediately precipitate. So here is what they did:
“Quercetin was made up in DMSO on the day of use and supplied in glass syringes. It was administered via the side arm of a polypropylene giving set through which RIMSO 50 (50% volume DMSO and 50% water) was being slowly injected. A total volume of 50 ml of RIMSO 50 was injected with each quercetin injection. This was essential to prevent precipitation of quercetin in the giving set. The rate of i.v. injection of quercetin at the starting dose of 60 mg/m2 was initially rapid over 30 s, but at doses above 945 mglm2, it was increased to 5 mm because of pain on injection. When the quercetin injection was completed, the drip was left in situ, and 200 ml saline were infused over the succeeding 30 mm.” (Ref.)
Based on the experience from clinical trial the dose can go to higher levels, but above 900mg/m2 we need to make sure the patient is hydrated with 1000ml slaine before and 500ml saline after the Quercetin administration.
Note that as with Curcumin IV, the addition of DMSO may increase the effectiveness of Quercetin so the dose may need to be reduced.
Capsules: usually found as 500mg capsules and it is very accessible regarding its cost http://www.iherb.com/Quercetin#p=1
Intravenous: as mentioned above Quercetin is administrated in hospitals in one country as a drug against health issues other then cancer. A vial contains 500mg preparation of active bioflavonoid (500mg powder represents 450mg polyvinylpyrrolidone + 50mg Quercetin) and the cost is somewhere in the range of 10-20 euro depending on the source.
Safety and Toxicity:
No clinically significant toxicities were seen until the 10h dose level (1700 mg/m2) when renal toxicity, manifesting as elevation of serum creatinine, occurred. There was no cumulative fall in creatinine clearance with multiple weekly treatments, indicating that any nephrotoxicity due to quercetin was transient and reversible within 7 days. Overall, 2 of 10 patients who were treated at 1400 mg/m2 had clinically significant nephrotoxicity (1 patient with grade 4, and 1 patient with grade 2).
One patient treated at 630 mg/m2 developed grade 3 renal toxicity, with elevation of the serum creatinine to 420 uM by day 10. By day 21 this patient’s serum creatinine had normalized (Fig. 2C).
This patient was keen for additional therapy and was therefore retreated, but with prehydration of 1 liter normal saline given over 1h, and after quercetin treatment, 0.5 liter 5% dextrose was given; there was no fall in creatinine clearance. The next course in this patient was given at 945 mg/m2 with hydration, and no renal toxicity ensued. In other patients, hydration was given before bolus injection of quercetin at 945 mg/m2, and the pretreatment clearance was 82.3 ± 6.7 mI/mm. Thus, a simple outpatient hydration schedule abrogated falls in creatinine clearance.
After the above experience, it has been concluded the following: “Subsequently, as other patients were studied, it became clear that simple i.v. prehydration could at least partially abrogate the nephrotoxicity of quercetin. With this in mind, the ernesis and the pain on injection, we believe that 1400 mg/rn2 given weekly or every 3 weeks can be recommended for Phase II trials.” (Ref.).
Based on this the adverse reactions can be: flushing, sweating. Nephrotoxicity may occur with IV bolus infusions >945 mg/m2.
The serum levels achieved immediately after injection of quercetin were in the range of 200-400 uM at 945 mg/m2, with serum levels above 1 uM being maintained up to 4 h. The distribution half-life was $ 0.7-7.8 min, with a median of 6 min. The elimination half-life was 3.8-86 min, with a median of 43 min (Ref.).
Antiviral activity of quercetin against japanese encephalitis virus http://www.google.com/patents/WO2014142645A1?cl=en
The present invention provides an antiviral medicament for treating Japanese Encephalitis Virus (JEV) infection comprises a natural flavonoid compound namely quercetin. In the present invention, antiviral activity of quercetin was evaluated against JEV replication in African green monkey kidney cell line (Vero). Anti-JEV activities of quercetin were examined at different stages of JEV replication cycle. The effects of quercetin on virus replication were determined from Foci Forming Unit Reduction Assay (FFURA) and quantitative RT-PCR.
Oxidized quercetin reacts with thiols rather than with ascorbate: implication for quercetin supplementation. http://www.ncbi.nlm.nih.gov/pubmed/12914787
When an antioxidant scavenges a reactive species, i.e., when it exerts its antioxidant activity, the antioxidant is converted into potentially harmful oxidation products. In this way, the antioxidant quercetin might yield an ortho-quinone, denoted as QQ, which has four tautomeric forms, i.e., the ortho-quinone and three quinonmethides. We evaluated the interaction of QQ with ascorbate or glutathione (GSH). Ascorbate recycles QQ to the parent compound quercetin, while GSH forms two adducts with QQ, i.e., 6-GSQ and 8-GSQ. When both GSH and ascorbate are present, QQ is converted exclusively into GSQ. In the absence of GSH, protein thiols will be arylated by QQ. This protein arylation is not prevented by ascorbate. Thiol arylation by quinones and quinonmethides can impair several vital enzymes. This implies that the product formed when quercetin displays its antioxidant scavenging effect is toxic in the absence of GSH. Therefore, an adequate GSH level should be maintained when quercetin is supplemented.
Interfering with ROS Metabolism in Cancer Cells: The Potential Role of Quercetin. http://www.ncbi.nlm.nih.gov/pubmed/24281116
A main feature of cancer cells, when compared to normal ones, is a persistent pro-oxidative state that leads to an intrinsic oxidative stress. Cancer cells have higher levels of reactive oxygen species (ROS) than normal cells, and ROS are, in turn, responsible for the maintenance of the cancer phenotype. Persistent ROS stress may induce adaptive stress responses, enabling cancer cells to survive with high levels of ROS and maintain cellular viability. However, excessive ROS levels render cancer cells highly susceptible to quercetin, one of the main dietary flavonoids. Quercetin depletes intracellular glutathione and increases intracellular ROS to a level that can cause cell death.
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