|Glioblastoma Treatments: Supplements: Boswellic Acids||
Boswellia (Boswellic Acids)
Boswellia is an herbal extract available widely and inexpensively which may provide important therapeutic benefits for brain tumor patients in a variety of areas, including the control of edema, tumor growth and proliferation.
Extracts of the Boswellia serrata and Boswellia carterii plants, both in the frankincense family, have been used for hundreds of years in traditional medicine for the treatment of inflammatory diseases such as bowel disease and joint pain.
For brain tumor patients, especially those using corticosteroids like dexamethasone (Decadron) to control peritumoral edema, boswellia is an important substance to discuss. Unfortunately, boswellia is virtually unknown amongst mainstream North American doctors, however it has been designated an orphan drug by the European Commission for the treatment of peritumoral edema resulting from brain tumors.11
The effects of Boswellic Acids are very complex and the ideal dosage is a topic of great debate, with the range of possibilities rather dramatic. There is evidence that Boswellic Acids can cross the blood-brain barrier based on in vivo animal studies7, and it has been shown to have significant effects on the invasiveness of GBM cells in vitro.8
From a wide variety of studies, boswellic acids have been shown to:
Further research into the constituent components of boswellia indicate that it is also directly cytotoxic to brain tumor cancer cells. Boswellia extracts have been shown to be both cytotoxic to glioma cells and anti-proliferative in a dose-dependent manner during studies with rats10.
Clinical trials have demonstrated promising benefits from boswellic acids in rheumatoid arthritis, chronic colitis, ulcerative colitis, Crohn's disease, and bronchial asthma, in addition to benefits for brain tumor patients3. Burning boswellia resin has also been shown to have anti-depressive and anti-anxiety effects8.
Boswellia extracts are usually made from the tree's resin or gum and extracts from the Boswellia carteri tree contain at least 15 triterpene acids6. The most potent anti-inflammatory boswellic acids are acetyl-11-keto-beta-boswellic acid (AKBA) and 11-keto-beta-boswellic acid (KBA).
Boswellic acids have a variety of molecular targets in addition to 5-lipoxygenase (5-Lox), the primary enzyme in leukotriene biosynthesis. Other potentially therapeutic targets of boswellic acids include topoisomerases, angiogenesis, and cytochrome p450 enzymes15. In addition, boswellic acids may stimulate or inhibit mitogen-activated protein kinase (MAPK), especially p38, depending on the type of cell affected16.
Perhaps one of the most important studies of boswellia aside from all the anti-inflammatory, anti-edema research, is a German study of boswellia's effects against topoisomerases I and IIalpha4. Amazingly, the authors showed that the aceytl-boswellic acids are "more potent inhibitors of human topoisomerases I and IIalpha than camptothecin, and amsacrine or etoposide, respectively." Camptothecin is the organic alktylator from which CPT-11 (irinotecan) is derived. Both CPT-11 and VP-16 (etoposide) are common chemo agents in brain tumor therapies. Human topoisomerases I and IIalpha bind directly to an immobilized derivative of acetyl-boswellic acids. One of the authors of this study, Prof. Thomas Simmet, has reportedly suggested that patients using pharmaceutical topoisomerase inhibitors such as CPT-11 should not concomitantly use boswellia extracts, but there is no independent confirmation of this statement to date.
Another study demonstrated that boswellia extract contains at least 2 other constituent substances with therapeutic potential, incensole and incensole acetate, which inhibit nuclear factor-kappaB (NF-kappaB)9. NF-kappaB can transcriptionally activate genes leading to the synthesis of anti-apoptotic, chemoresistant, growth promoting, and angiogenic proteins in gliomas, in which NF-kappaB has been shown to be activated17.
Boswellic acids are known to inhibit several important cytochrome P450 metabolizing enzymes, including CYP2D6 and CYP3A4. To what extent the P450 inhibition may affect the metabolizing of other substances and drugs is unknown. Such inhibition can be either positive or detrimental to other therapies. In one study, boswellic acids were identified as "moderate to potent inhibitors" of several P450 enzymes, however they were found to not be the principle inhibitory constituents of whole boswellia extract18. Historically, boswellia is known for its lack of contraindications with other substances and appears to be a safe adjuvant substance, however clearly more research needs to be done in this area.
The boswellic acids with a keto group have been shown in vitro to inhibit Pgp, or P-glycoprotein, however this inhibition probably does not inhibit availability through the blood brain barrier of other Pgp substrates, however it remains to be tested whether these boswellic acids create drug interactions at the gastrointestinal level2.
Another potential benefit to cancer patients taking boswellia may be diarrhea control. Boswellia extract has been shown to reduce diarrhea in vivo in rats without slowing intestinal motility in healthy animals, both in the small and in the large intestine. The mechanism behind this effect may be due primarily to 3-acetyl-11-keto-beta-boswellic acid (AKBA)13. Interestingly, the calcium-channel blockers verapamil and nifedipine may inhibit this effect.
The mechanisms of boswellic acids are not completely understood, however their chemical similarity to steroids is the subject of much research. Boswellic acids (all?) are pentacyclic triterpenic acids, like the chemical squalene. In humans, squalene is processed biosynthetically into lanosterol, the structural precursor of all human steroids. Many pentacyclic triterpenes have antiproliferative and cytotoxic effects against different tumor types.12
The elimination half-life of 11-Keto beta-boswellic acid (KBA), one of the two primary anti-inflammatory boswellic acids identified, is about 6 hours. This suggests that boswellic acids should ideally be given orally every 6 hours to maintain maximum plasma levels1. Administration with a high-fat meal has been shown to increase plasma levels by several fold5. KBA has been found to be extensively metabolized in the liver via oxidation to hydroxylated metabolites, however no metabolites of AKBA have been discovered7. This reinforces the need to improve the bioavailability of AKBA, especially since it is the most potent anti-inflammatory boswellic acid.
Determining effective boswellia dosages is a largely unexplored area, with very few human dosing schedules described in published literature. One Swiss study used a maximum dose of 126 mg/kg/day (126 mg per kilogram of body weight per day) in children for 9 months without any side-effects.14 This study used a German brand of boswellia called H15, which is thus far very difficult to get outside Europe. Such a dosage would translate to about 10 grams (10,000 mg) per day for a 180-pound adult.
One popular AKBA standardized extract is the branded product called 5-Loxin. This standardized extract is intended to provide a significantly higher concentration of AKBA compared to other standardized, "whole" boswellia extacts. 5-Loxin was developed at the Laila Research Center in Vijayawada, India, as a partnership between the Laila Group and PL Thomas. The manufacturer claims 5-Loxin provides a standardized 30% AKBA, which is approximately 10 times the concentration of AKBA in other boswellia extracts. Since it is a standardized extract, 5-Loxin should be identical in all manufactured products.
Taking the manufacturer's concentration claims into consideration, when you are calculating an overall boswellia dosage, mulitply the standardized amount of 5-Loxin by 10 first, and then add that quantity to the quantity of other standardized boswellia in the dosage. Based on the available benefits of various boswellia constituents, the ideal boswellia protocol might include both standardized whole extracts in combination with 5-Loxin products.
Most whole boswellia extracts contain standardized concentrations of 65% or 70%. The results of independent, private lab research indicates that standardized concentrations higher than this should be considered only with extra scrutiny.
Bioavailability is a critical issue for patients taking boswellia because studies have shown very low plasma blood levels after oral consumption. Sterk, et al, showed in 2004 that "food intake profoundly affects the kinetic profile of BA plasma levels, as high-fat meal strongly increases the plasma concentrations of various boswellic acids as compared to the fasted state." This included both KBA and AKBA.5
Dr. Mona Tawab, Head of Research and Development at the Central Laboratory of German Pharmacists, confirmed this in a 2008 study of the pharmacokinetics of boswellia. In private discussions, Dr. Tawab noted that "the concentrations of KBA and AKBA achieved in plasma after the intake of a fat rich meal is still below the identified in vitro concentrations relevant for therapeutic activity."
Her teams studies found that the low bioavailability of AKBA and KBA were due to separate mechanisms. Low AKBA bioavailability is primarily due to poor absorption in the GI tract, while extensive hepatic metabolism is responsible for KBA's poor bioavailability7. Unfortunately, the specific hepatic enzymes responsible for metabolizing KBA are still unknown, however this research is underway.
The combination of low bioavailability for AKBA and KBA, the very low rate of adverse side-effects, and the dose-dependent cytotoxic activity against cancerous cells, all lead to the possibility that relatively high doses of boswellia are necessary to gain therapeutic benefit.
Boswellia extracts have been used for thousands of years in Ayurvedic medicine with few or no adverse side-effects. Most brain tumor patients experience no side-effects from boswellia, however several areas of potential problems should be noted.
There is some research indicating that boswellia extracts may have the potential to increase blood clotting. In one limited, in vitro study, beta boswellic acids were reported to "strongly stimulate the platelet-induced generation of thrombin", which thus results in platelet aggregation and increased risk of clotting19. Interestingly, the authors did not find the same for boswellic acids with a keto group, such as acetyl-11-keto-beta-boswellic acid (AKBA). The authors wrote that keto boswellic acids such as AKBA "do not cause aggregation or significant generation of thrombin." Thrombin is the enzyme generated by blood platelets to initiate blood clotting. Beta boswellic acids may also help release arachidonic acid, which can also increase platelet aggregation.
In addition, there is evidence from pharmaceuticals which inhibit 5-lipoxygenase (5-Lox), that 5-Lox inhibition can increase thromboxanes and thus increased clotting.
Anti-inflammatory substances such as boswellia suppress the body's natural reaction to many types of disease, and although most research has shown benefits to suppressing inflammation, some theoretical scenarios exist in which this may not be beneficial. Several studies link blocking 5-Lox with increased pathogen burdens in various infections ranging from tuberculosis to HIV20,21. Inhibiting leukotriene biosynthesis through 5-Lox is thought to inhibit the ability of white blood cells to release anti-microbial peptides called cathelicidins (or LL-37)22. How and whether this affects brain tumor patients in practice is completely unknown, but anecdotal and historical evidence from thousands of patients would seem to indicate that the infection potential is not significantly increased by taking anti-inflammatories. However, this is certainly an area deserving significant research, especially in patients with natural or chemo-suppressed immune systems.
Other potential problems with boswellia include attempts to ingest the resin powder directly (not in capsule form), which may burn the esophagus. Some patients have also reported mild upset stomach with boswellia. In general, whenever a new herbal supplement is introduced into a patient's protocol, it is wise to begin with small doses and then work up to the target dose gradually. Conversely, suddenly stopping a long-term, high dose regimen of boswellia could potentially result in a rebound effect, exacerbating the potential for peritumoral edema.
For brain tumor patients, boswellia appears to be an ideal over-the-counter supplement providing therapeutic benefits for several symptoms. The combination of an anti-edema drug with cytotoxic activity against the tumor, combined with boswellia's extremely low toxicity, makes boswellia a key supplement for brain tumor patients.
1. Pharmacokinetic study of 11-Keto β-Boswellic Acid
10. PMID: 10894362
11. PMID: 16223251
12. PMID: 12058313
14. PMID: 10994549
15. PMID: 17168710
16. PMID: 16174802
17. PMID: 17127728
18. PMID: 16364338
20. PMID: 17347013
21. PMID: 15143466
22. PMID: 17446260
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