acetyl-11-ketoboswellic-acid and boswellic-acid

Nature is the chief source of various remedies which are used to cure various diseases. Boswellic acid (BA) is a secondary metabolite from the pentacyclic terpenoid compound groups that are derived from the plant genus Boswellia. The oleo gum resins of these plants are primarily composed of polysaccharides, with the remaining amounts of resin (30-60%) and essential oils (5-10%) soluble in organic solvents. BA and its analogs are also reported to exhibit various in vivo and biological responses for example anti-inflammatory, anti-tumor, free radical scavenging activity, etc. Among all analogs, 11-keto-β-boswellic acid (KBA) and 3-O-acetyl-11-keto-β-boswellic acid (AKBA) has been demonstrated to be the most effective at reducing cytokine production and inhibiting the inflammatory responsecausing enzymes. In this review, we summarized the computational ADME prediction via the SwissADME computational tool and the structure-activity relationship of the Boswellic acid scaffold for the aspect of anticancer and antiinflammatory potency. In addition to these research findings which are associated with the therapy of acute inflammation and some cancers, the potential of boswellic acids against other disorders was also discussed.

Topics: Anti-Inflammatory Agents; Boswellia; Humans; Plant Extracts; Structure-Activity Relationship; Triterpenes

A double-blind, placebo-controlled human trial was conducted to evaluate the safety and efficacy of a standardized oral supplementation of Boswellin®, a novel extract of Boswellia serrata extract (BSE) containing 3-acetyl-11-keto-β-boswellic acid (AKBBA) with β-boswellic acid (BBA). A total of 48 patients with osteoarthritis (OA) of the knee were randomized and allocated to the BSE and placebo groups for intervention. Patients were administered BSE or placebo for a period of 120 days. The trial results revealed that BSE treatment significantly improved the physical function of the patients by reducing pain and stiffness compared with placebo. Radiographic assessments showed improved knee joint gap and reduced osteophytes (spur) confirming the efficacy of BSE treatment. BSE also significantly reduced the serum levels of high-sensitive C-reactive protein, a potential inflammatory marker associated with OA of the knee. No serious adverse events were reported. This is the first study with BSE conducted for a period of 120 days, longer than any other previous clinical trial on patients with OA of the knee. The findings provide evidence that biologically active constituents of BSE, namely, AKBBA and BBA, act synergistically to exert anti-inflammatory/anti-arthritic activity showing improvement in physical and functional ability and reducing the pain and stiffness.

Topics: Aged; Boswellia; Double-Blind Method; Female; Humans; Male; Middle Aged; Osteoarthritis, Knee; Pain; Pain Measurement; Pilot Projects; Plant Extracts; Triterpenes

Specialized pro-resolving mediators (SPM), primarily produced in innate immune cells, exert crucial bioactions for resolving inflammation. Among various lipoxygenases (LOX), 15-LOX-1 is key for SPM biosynthesis, but cellular activation principles of 15-LOX-1 are unexplored. It was shown that 3-O-acetyl-11-keto-β-boswellic acid (AKBA) shifts 5-LOX regiospecificity from 5- to 12-lipoxygenation products. Here, it is demonstrated that AKBA additionally activates cellular 15-LOX-1 via an allosteric site accomplishing robust SPM formation in innate immune cells, particularly in M2 macrophages. Compared to ionophore, AKBA-induced LOX activation is Ca

Topics: Allosteric Regulation; Animals; Arachidonate 15-Lipoxygenase; HEK293 Cells; Humans; Inflammation; Lipids; Lipoxygenase; Mice; Scavenger Receptors, Class E

Boswellic acids have been recognized as anti-inflammatory and immunomodulatory agents with potentials to control autoimmune and inflammatory diseases. However, their effects on T cell proliferation and activation are not fully elucidated. In this study, we investigated effects of individual compounds including β-Boswellic acids (β-BA), 11-keto-β-Boswellic acid (β-KBA), 3-O-acetyl β-Boswellic acids (β-ABA), and 3-O-acetyl-11-keto-β-Boswellic acid (β-AKBA) on human peripheral blood mononuclear cells (PBMCs) and their potential role in modulating immune responses. We showed that β-BA, KBA, and AKBA at a 0.025 µM concentration significantly reduced T cell proliferation without inducing cytotoxicity, however, ABA showed cytotoxic effects at this concentration. β-BA and KBA showed significantly reduced T cell proliferation at 0.05 µM concentration without cytotoxic effects. Interestingly, we found that AKBA at 0.025 µM concentration significantly reduced CD25 expression on both CD4

Topics: CD8-Positive T-Lymphocytes; Cell Proliferation; Humans; Leukocytes, Mononuclear; Lymphocyte Activation

This study aimed to compare the effect of Boswellic acid derivatives on the viability, apoptosis, and epigenomic profiling of breast cancer. According to the viability assays, 3-O-acetyl-11-keto-β-Boswellic acid (AKBA) showed more toxicity against MDA-MB-231 cells when compared with the 3-O-acetyl-β-Boswellic acid (ABA). In contrast, ABA revealed less toxicity against MCF-10A. Cell cycle and apoptosis assays determined the maximum apoptotic effect of AKBA on MCF-7, and MDA-MB-231 cells. Interestingly, β-Boswellic acid (BA) and ABA did not promote the apoptosis in MCF-10A cells. Transwell migration assay indicated the greatest normalized inhibition (around 160%) in the migration of MDA-MB-231 cells induced by AKBA. The expression of P53, BAX, and BCL2 genes in cancerous cell lines has affirmed that both AKBA and ABA could induce the maximal apoptosis. Western-blot investigation demonstrated that the maximum over-expression of P53 protein (1.96 times) was caused by AKBA in MDA-MB-231 cells, followed by ABA in MCF-7 cells. The BCL2 protein expression was in agreement with the previously reported results. The global DNA methylation in both cancerous cells was reduced by ABA. These results suggest that ABA represented more epigenetic modulatory effect while AKBA shows more cytotoxic and apoptotic effect against breast cancer cell lines.

Topics: Epigenesis, Genetic; Epigenomics; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Tumor Suppressor Protein p53

In continuation of our search for leads from medicinal plants against protozoal pathogens, we detected antileishmanial activity in polar fractions of a dichloromethane extract from

Topics: Animals; Cell Line; Humans; Inhibitory Concentration 50; Leishmania donovani; Macrophages; Mice; Plant Extracts; Rats; Resins, Plant; Triterpenes

In the current investigation, a series of heterocyclic derivatives of boswellic acids were prepared along with new monomers of 3-

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Dimerization; Female; Humans; Ovarian Neoplasms; Triterpenes

Boswellic acids constitute a group of unique pentacyclic triterpene acids from

Topics: Anti-Inflammatory Agents; Blood Platelets; Boswellia; Calcium; Humans; Plant Extracts; Structure-Activity Relationship; Triterpenes

A library of boswellic acid analogues were synthesized and tested for their anti-inflammatory potential on key inflammatory mediators, TNF-α and IL-6. The study led to the identification of lead compounds showing significant inhibition of the cytokines, TNF-α and IL-6 both in vitro and in vivo.

Topics: Animals; Anti-Inflammatory Agents; Humans; Interleukin-6; Mice; Triterpenes; Tumor Necrosis Factor-alpha

In consideration of the increasing popularity of frankincense and the widely published quality problems associated with botanical dietary supplements, a survey was conducted for the first time on the quality of frankincense containing botanical dietary supplements. Six US products representing 78 % of the units sold and 70 % of the market value, and 11 European products representing 30 % of the units sold and 40 % of the market value were tested for their boswellic acid composition profile, label compliance, and claimed health benefits. Special focus was also set on the statements made with regard to the frankincense applied.Only five products out of seventeen disclosed all relevant information for the Boswellia extract, mentioning the species, the part of plant used, and the boswellic acid content. Whereas all products but one claimed to use Boswellia serrata, three products did not mention the resin as the part applied and 10 products did not declare the boswellic acid content. Apart from the different boswellic acid composition determined with a sensitive LC/MS method, 41 % of the products did not comply with the label declaration. Hence, one product from Italy did not contain any of the six characteristic boswellic acids (KBA, AKBA, αBA, βBA, AαBA, AβBA) at all and another US product contained only traces, suggesting the absence of frankincense or the use of Boswellia frereana instead of B. serrata. In another product, the ratios of the individual boswellic acids were different from B. serrata gum resin, indicating the use of another species such as Boswellia sacra or Boswellia carterii. Furthermore, two products revealed different boswellic acid contents from those declared on the label. Further, two products did not declare the use of manipulated Boswellia gum resin extract being enriched in acetyl-11-keto-boswellic acid content reaching up to 66 %. In addition, consumers could be misled by outdated literature or references to in vitro studies performed at dosages that can never be achieved in humans following oral administration.In summary, this survey reveals that in spite of increased regulations on botanical dietary supplements, the problem of mislabeling still exists and needs to be addressed by the manufacturers, so that consumers get greater confidence in the botanical dietary supplements they use.

Topics: Boswellia; Dietary Supplements; Europe; Food Quality; Molecular Structure; Resins, Plant; Surveys and Questionnaires; Triterpenes; United States

Boswellia serrata and Boswellia sacra (syn. B. carteri) are important medicinal plants widely used for their content of bioactive lipophilic triterpenes. The qualitative and quantitative determination of boswellic acids (BAs) is important for their use in dietary supplements aimed to provide a support for osteoarthritic and inflammatory diseases. We used High Performance Liquid Chromatography (HPLC)-Diode Array Detector (DAD) coupled to ElectroSpray Ionization and tandem Mass Spectrometry (ESI-MS/MS) for the qualitative and quantitative determination of BAs extracted from the gum resins of B. sacra and B. serrata. Limit of detection (LOD), limit of quantification (LOQ), and Matrix Effect were assessed in order to validate quantitative data. Here we show that the BAs quantitative determination was 491.20 g·kg-1 d. wt (49%) in B. sacra and 295.25 g·kg-1 d. wt (30%) in B. serrata. Lower percentages of BAs content were obtained when BAs were expressed on the gum resin weight (29% and 16% for B. sacra and B. serrata, respectively). The content of Acetyl-11-Keto-β-Boswellic Acid (AKBA) was higher in B. sacra (70.81 g·kg-1 d. wt; 7%) than in B. serrata (7.35 g·kg-1 d. wt; 0.7%). Our results show that any claim of BAs content in either B. sacra or B. serrata gum resins equal to or higher than 70% or AKBA contents of 30% are simply unrealistic or based on a wrong quantitative determination.

Topics: Boswellia; Chromatography, High Pressure Liquid; Limit of Detection; Molecular Structure; Plant Extracts; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Triterpenes

A series of AKBA derivatives were synthesized, and evaluated as potent VEGFR-2 inhibitors. The initial biological evaluation indicated that the introduction of C-24 amide group or a heterocycle at C-2,3 position effectively improved the potency. Further structure-activity relationship analysis showed that amide (7, 23, 25, and 26) and heterocycle (19, 34, and 36) substituted AKBA derivatives displayed more potential anti-proliferation activities than AKBA (1) on HUVECs that express high levels of VEGFR-2. Among all tested compounds, compounds 7 and 19 exhibited the best potency (IC₅₀: 2.36 and 2.13 μM) and obvious inhibitory activities with VEGFR-2 inhibition rates of 96% and 94% at 50 μM, respectively.

Topics: Cell Proliferation; Dose-Response Relationship, Drug; Human Umbilical Vein Endothelial Cells; Humans; Molecular Structure; Protein Kinase Inhibitors; Structure-Activity Relationship; Triterpenes; Vascular Endothelial Growth Factor Receptor-2

Frankincense has gained increasing attention in the pharmaceutical industry because of its pharmacologically active components such as boswellic acids. However, the identity and overall quality evaluation of three different frankincense species in different Pharmacopeias and the literature have less been reported. In this paper, quantitative analysis and chemometric evaluation were established and applied for the quality control of frankincense. Meanwhile, quantitative and chemometric analysis could be conducted under the same analytical conditions. In total 55 samples from four habitats (three species) of frankincense were collected and six boswellic acids were chosen for quantitative analysis. Chemometric analyses such as similarity analysis, hierarchical cluster analysis, and principal component analysis were used to identify frankincense of three species to reveal the correlation between its components and species. In addition, 12 chromatographic peaks have been tentatively identified explored by reference substances and quadrupole time-of-flight mass spectrometry. The results indicated that the total boswellic acid profiles of three species of frankincense are similar and their fingerprints can be used to differentiate between them.

Topics: Boswellia; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Frankincense; Mass Spectrometry; Triterpenes

The microsomal prostaglandin E2 synthase (mPGES)-1 is the terminal enzyme in the biosynthesis of prostaglandin (PG)E2 from cyclooxygenase (COX)-derived PGH2. We previously found that mPGES-1 is inhibited by boswellic acids (IC50 = 3-30 μM), which are bioactive triterpene acids present in the anti-inflammatory remedy frankincense. Here we show that besides boswellic acids, additional known triterpene acids (i.e., tircuallic, lupeolic, and roburic acids) isolated from frankincense suppress mPGES-1 with increased potencies. In particular, 3α-acetoxy-8,24-dienetirucallic acid (6) and 3α-acetoxy-7,24-dienetirucallic acid (10) inhibited mPGES-1 activity in a cell-free assay with IC50 = 0.4 μM, each. Structure-activity relationship studies and docking simulations revealed concrete structure-related interactions with mPGES-1 and its cosubstrate glutathione. COX-1 and -2 were hardly affected by the triterpene acids (IC50 > 10 μM). Given the crucial role of mPGES-1 in inflammation and the abundance of highly active triterpene acids in frankincence extracts, our findings provide further evidence of the anti-inflammatory potential of frankincense preparations and reveal novel, potent bioactivities of tirucallic acids, roburic acids, and lupeolic acids.

Topics: Animals; Anti-Inflammatory Agents; Boswellia; Characidae; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dinoprostone; Humans; Inhibitory Concentration 50; Intramolecular Oxidoreductases; Lipoxygenase Inhibitors; Molecular Structure; Pentacyclic Triterpenes; Prostaglandin Antagonists; Prostaglandin-E Synthases; Resins, Plant; Structure-Activity Relationship; Tetracycline; Triterpenes

Boswellic acid acylates including their epimers were synthesized and screened against a panel of human cancer cell lines. They exhibited a range of cytotoxicity against various human cancer cell lines thereby leading to the development of a possible SAR. One of the identified lead compounds was found to be an inhibitor of the NF-κB and STAT proteins, warranting further investigations to be developed into a potential anticancer lead.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Flow Cytometry; HL-60 Cells; Humans; Models, Chemical; NF-kappa B; Phosphorylation; STAT Transcription Factors; Triterpenes

Boswellia serrata gum resin extracts are used widely for the treatment of inflammatory diseases. However, very low concentrations in the plasma and brain were observed for the boswellic acids (1-6, the active constituents of B. serrata). The present study investigated the effect of phospholipids alone and in combination with common co-surfactants (e.g., Tween 80, vitamin E-TPGS, pluronic f127) on the solubility of 1-6 in physiologically relevant media and on the permeability in the Caco-2 cell model. Because of the high lipophilicity of 1-6, the permeability experiments were adapted to physiological conditions using modified fasted state simulated intestinal fluid as apical (donor) medium and 4% bovine serum albumin in the basolateral (receiver) compartment. A formulation composed of extract/phospholipid/pluronic f127 (1:1:1 w/w/w) increased the solubility of 1-6 up to 54 times compared with the nonformulated extract and exhibited the highest mass net flux in the permeability tests. The oral administration of this formulation to rats (240 mg/kg) resulted in 26 and 14 times higher plasma levels for 11-keto-β-boswellic acid (1) and acetyl-11-keto-β-boswellic acid (2), respectively. In the brain, five times higher levels for 2 compared to the nonformulated extract were determined 8 h after oral administration.

Topics: Absorption; Administration, Oral; Animals; Boswellia; Brain; Caco-2 Cells; Humans; Male; Models, Biological; Permeability; Phospholipids; Poloxamer; Polysorbates; Rats; Solubility; Time Factors; Triterpenes; Vitamin E

Semi-synthetic analogues of β-boswellic acid (BA) and 11-keto-β-boswellic acid (KBA) were comparatively evaluated for in vitro cytotoxicity against human myeloid leukaemia (HL-60) and human cervical carcinoma (HeLa) cells. 2-Cyano analogues of both the triterpenes were observed to have significant cytotoxicity against both the cells, displaying cytotoxicity in HL-60 cells at low concentrations. Further investigations suggested the proapoptotic potential associated with the two molecules to induce cytotoxicity in HL-60 cells, where one of them showed early proapoptotic effect as evidenced by several biological end-points of the apoptosis such as annexinV binding, DNA fragmentation and increase in sub-G0 DNA fraction and apoptotic bodies formation (Hoechst 33258 staining and SEM studies).

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; HeLa Cells; HL-60 Cells; Humans; Nitriles; Oxygen; Triterpenes

4-Amino analogues prepared from beta-boswellic acid and 11-keto-beta-boswellic acid, wherein the carboxyl group in ursane nucleus was replaced by an amino function via Curtius reaction, displayed improved cytotoxicity than the parent molecules. The same molecules also exhibited apoptotic activity by inducing DNA fragmentation.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Boswellia; Cell Line, Tumor; DNA Fragmentation; Growth Inhibitors; Humans; Triterpenes

Boswellic acids inhibit the transformation of arachidonic acid to leukotrienes via 5-lipoxygenase but can also enhance the liberation of arachidonic acid in human leukocytes and platelets. Using human platelets, we explored the molecular mechanisms underlying the boswellic acid-induced release of arachidonic acid and the subsequent metabolism by platelet-type 12-li-poxygenase (p12-LO). Both beta-boswellic acid and 3-O-acetyl-11-keto-boswellic acid (AKBA) markedly enhanced the release of arachidonic acid via cytosolic phospholipase A2 (cPLA2), whereas for generation of 12-hydro(pero)xyeicosatetraenoic acid [12-H(P)ETE], AKBA was less potent than beta-boswellic acid and was without effect at higher concentrations (> or =30 microM). In contrast to thrombin, beta-boswellic acid-induced release of ara-chidonic acid and formation of 12-H(P)ETE was more rapid and occurred in the absence of Ca2+. The Ca2+-independent release of arachidonic acid and 12-H(P)ETE production elicited by beta-boswellic acid was not affected by pharmacological inhibitors of signaling molecules relevant for agonist-induced arachidonic acid liberation and metabolism. It is noteworthy that in cell-free assays, beta-boswellic acid increased p12-LO catalysis approximately 2-fold in the absence but not in the presence of Ca2+, whereas AKBA inhibited p12-LO activity. No direct modulatory effects of boswellic acids on cPLA2 activity in cell-free assays were evident. Therefore, immobilized KBA (linked to Sepharose beads) selectively precipitated p12-LO from platelet lysates but failed to bind cPLA2. Taken together, we show that boswellic acids induce the release of arachidonic acid and the synthesis of 12-H(P)ETE in human platelets by unique Ca2+-independent routes, and we identified p12-LO as a selective molecular target of boswellic acids.

Topics: Arachidonate 12-Lipoxygenase; Arachidonic Acid; Blood Platelets; Calcium; Cell-Free System; Humans; Kinetics; Leukotrienes; Phospholipases A; Phospholipases A2; Signal Transduction; Triterpenes

An high-performance TLC (HPTLC) method for the separation of boswellic acids, the active constituents in Boswellia serrata extract, has been developed and TLC of these compounds on silica by automated multiple development (AMD) using solvent gradients was performed. Enhancement of the separation of boswellic acids on HPTLC plates was carried out by AMD chromatography. Densitometric analysis of the developed plate was carried out to quantify the four boswellic acids. 11-Keto-beta-boswellic acid (KBA) and acetyl-11-keto-beta-boswellic acid (AKBA) were quantified by densitometric scanning of the developed plate at 254 nm. beta-Boswellic acid (BA) and acetyl-beta-boswellic acid (ABA) were quantified after derivatization with anisaldehyde sulfuric acid reagent at 560 nm. The AMD system provided a clean separation according to polarity for each of the four groups studied and good results were obtained. The proposed HPTLC method for the simultaneous quantification of the major boswellic acids BA, ABA, KBA, and AKBA was found to be simple, precise, specific, sensitive, and accurate and can be used for routine quality control and for the quantification of these compounds in plant materials. The study of market products revealed significant variations in the content of these pharmacologically active compounds in commercial samples.

Topics: Boswellia; Chromatography, Thin Layer; Plant Extracts; Reference Standards; Silicon Dioxide; Solvents; Terpenes; Triterpenes

To investigate the chemical components of Boswellia carterii.. Chromatographic technologies were used for separation and purification, while spectral analysis was used for structure elucidation.. Six compounds were isolated and their structures were identified as acetyl-alpha-boswellic acid (1), acetyl-beta-boswellic acid (2), lup-20(29)-ene-3 alpha-acetoxy-24-oic acid (3), alpha-boswellic acid (4), beta-boswellic acid (5) and acetyl-11-keto-beta-boswellic acid (6).. Compound 3 is a new constituent.

Topics: Antineoplastic Agents, Phytogenic; Boswellia; Cell Division; HL-60 Cells; Humans; Molecular Structure; Plants, Medicinal; Triterpenes

The gum resin extract from Boswellia serrata (H15), an herbal product, was recently shown to have positive therapeutic effects in inflammatory bowel disease (IBD). However, the mechanisms and constituents responsible for these effects are poorly understood. This study examined the effect of the Boswellia extract and its single constituent acetyl-11-keto-beta-boswellic acid (AKBA) on leukocyte-endothelial cell interactions in an experimental model of IBD. Ileitis was induced by two subcutaneous injections of indomethacin (7.5 mg/kg) in Sprague-Dawley rats 24 h apart. Rats also received oral treatment with the Boswellia extract (H15) or AKBA at two different doses (low and high) equivalent to recommendations in human disease over 2 days. Controls received only the carriers NaHCO3 (subcutaneously) and tylose (orally). Effects of treatment were assessed by intravital microscopy in ileal submucosal venules for changes in the number of rolling and adherent leukocytes and by macroscopic and histological scoring. Increased leukocyte-endothelial cell adhesive interactions and severe tissue injury accompanied indomethacin-induced ileitis. Treatment with the Boswellia extract or AKBA resulted in a dose-dependent decrease in rolling (up to 90%) and adherent (up to 98%) leukocytes. High-dose Boswellia extract as well as both low- and high-dose AKBA significantly attenuated tissue injury scores. Oral therapy with the Boswellia extract or AKBA significantly reduces macroscopic and microcirculatory inflammatory features normally associated with indomethacin administration, indicating that the anti-inflammatory actions of the Boswellia extract in IBD may be due in part to boswellic acids such as AKBA.

Topics: Animals; Disease Models, Animal; Follow-Up Studies; Ileitis; Inflammatory Bowel Diseases; Male; Plant Extracts; Plants, Medicinal; Probability; Rats; Rats, Sprague-Dawley; Reference Values; Resins, Plant; Sensitivity and Specificity; Treatment Outcome; Triterpenes

Pentacyclic triterpenes from the 11-keto-boswellic acid series were identified as the active principal ingredients of Boswellia resin, inhibiting the key enzyme of leukotriene biosynthesis, 5-lipoxygenase (5-LO). Of the genuine boswellic acids hitherto characterized, 3-O-acetyl-11-keto-beta-boswellic acid, AKBA (1), proved to be the most potent inhibitor of 5-LO. In the course of purification of further boswellic acid derivatives from Boswellia resin, we observed the degradation of the natural compound 3-O-acetyl-11-hydroxy-beta-boswellic acid (2) to the thermodynamically more stable product 3-O-acetyl-9, 11-dehydro-beta-boswellic acid (4). The metastable intermediate of this conversion, under moderate conditions of workup in methanolic solutions, was identified as 3-O-acetyl-11-methoxy-beta-boswellic acid (3). The novel artifactual boswellic acid derivatives inhibited 5-LO product formation in intact cells with different characteristics: 4 almost totally abolished 5-LO activity, with an IC(50) of 0.75 microM, whereas 3 and 9,11-dehydro-beta-boswellic acid (5), the deacetylated analogue of 4, were incomplete inhibitors. The data suggest that the conditions chosen for the workup of Boswellia extracts could significantly influence the potency of their biological actions and their potential therapeutic effectiveness.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 5-Lipoxygenase; Chromatography, Gel; Chromatography, High Pressure Liquid; Gas Chromatography-Mass Spectrometry; Leukotrienes; Lipoxygenase Inhibitors; Magnetic Resonance Spectroscopy; Medicine, Traditional; Neutrophils; Plants, Medicinal; Resins, Plant; Spectrophotometry, Ultraviolet; Triterpenes

Steroids are essential for the control of oedema in human malignant glioma patients but may interfere with the efficacy of chemotherapy. Boswellic acids are phytotherapeutic anti-inflammatory agents that may be alternative drugs to corticosteroids in the treatment of cerebral oedema. Here, we report that boswellic acids are cytotoxic to malignant glioma cells at low micromolar concentrations. In-situ DNA end labelling and electron microscopy reveal that boswellic acids induce apoptosis. Boswellic acid-induced apoptosis requires protein, but not RNA synthesis, and is neither associated with free radical formation nor blocked by free radical scavengers. The levels of BAX and BCL-2 proteins remain unaltered during boswellic acid-induced apoptosis. p21 expression is induced by boswellic acids via a p53-independent pathway. Ectopic expression of wild-type p53 also induces p21, and facilitates boswellic acid-induced apoptosis. However, targeted disruption of the p21 genes in colon carcinoma cells enhances rather than decreases boswellic acid toxicity. Ectopic expression of neither BCL-2 nor the caspase inhibitor, CRM-A, is protective. In contrast to steroids, subtoxic concentrations of boswellic acids do not interfere with cancer drug toxicity of glioma cells in acute cytotoxicity or clonogenic cell death assays. Also, in contrast to steroids, boswellic acids synergize with the cytotoxic cytokine, CD95 ligand, in inducing glioma cell apoptosis. This effect is probably mediated by inhibition of RNA synthesis and is not associated with changes of CD95 expression at the cell surface. Further studies in laboratory animals and in human patients are required to determine whether boswellic acids may be a useful adjunct to the medical management of human malignant glioma.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Drug Resistance, Neoplasm; Drug Synergism; Fas Ligand Protein; Glioma; Humans; Membrane Glycoproteins; Mice; Neoplasm Proteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Triterpenes; Tumor Cells, Cultured; Tumor Suppressor Protein p53