Research highlights from 2004 to 2006

Characterization of 3alpha-acetyl-11-keto-alpha-boswellic acid, a pentacyclic triterpenoid inducing apoptosis in vitro and in vivo

Büchele B, Zugmaier W, Estrada A, Genze F, Syrovets T, Paetz C, Schneider B, Simmet T
Planta Med 2006 Nov; 72(14); 1285-1289

In this study authors characterized role of 3Alpha-acetyl-11-keto-alpha-boswellic acid (3alpha-acetoxy-11-oxo-olean-12-en-24-oic acid, 1). This was synthesized by a radical-type reaction using bromine and 3alpha-acetyl-alpha-boswellic acid isolated from the oleo-gum-resin of Boswellia carterii. The compound present in herbal preparation extracted from Boswellia serrata oleo-gum-resin, inhibits the growth of chemotherapy resistant human PC-3 prostate cancer cells in vitro and induces apoptosis.

Boswellic acids in chronic inflammatory diseases

Ammon HP
Planta Med. 2006 Oct; 72(12); 1100-1116

This is a review article about Oleogum resins from Boswellia species used in traditional medicine in India and African countries. The mechanism of action is due to boswellic acids. The most evident action is the inhibition of 5-lipoxygenase. Leukocyte elastase and oxygen radicals are targets. Clinical studies, so far with pilot character, suggest efficacy in autoimmune diseases such as rheumatoid arthritis, Crohn’s disease, ulcerative colitis and bronchial asthma.

Anti-inflammatory activities of the triterpene acids from the resin of Boswellia carteri

Banno N, Akihisa T, Yasukawa K, Tokuda H, Tabata K, Nakamura Y, Nishimura R, Kimura Y, Suzuki T
J Ethnopharmacol 2006 Sep; 107(2); 249-253

Authors in this study evaluated the role of Boswellic acid in the treatment of rheumatoid arthritis. Fifteen triterpene acids, viz., seven of the beta-boswellic acids, two of the alpha-boswellic acids, two of the lupeolic acids, and four of tirucallane-type, along with two membrane-type diterpenes were isolated and identified. Of the 17 compounds, 14 showed inhibitory activity against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation in mice.

Cancer chemopreventive effects and cytotoxic activities of the triterpene acids from the resin of Boswellia carteri

Akihisa T, Tabata K, Banno N, Tokuda H, Nishimura R, Nakamura Y, Kimura Y, Yasukawa K, Suzuki T
Biol Pharm Bull. 2006 Sep; 29(9); 1976-1979

In this study Fifteen triterpene acids, viz., seven of the beta-boswellic acids (1-7), two of the alpha-boswellic acids (oleanane-type) (8, 9), two of the lupeolic acids (lupane-type) (10, 11), and four of the tirucallane-type (12-14, 16), and two membrane-type diterpenes (17, 18), triterpene acid 15, were examined for inhibitory effects. On evaluation against EBV-EA activation seven compound, 2, 10, 11, 13-16, 1, 7, 13, and 14-16, showed potent inhibitory effects. Fifteen compounds, 1-7, 9-11, 13-15, 17 and 18 exhibited potent cytotoxic activities.

Boswellic acids stimulate arachidonic acid release and 12-lipoxygenase activity in human platelets independent of Ca2+ and differentially interact with platelet-type 12-lipoxygenase

Poeckel D, Tausch L, Kather N, Jauch J, Werz O
Mol Pharmacol 2006 Sep; 70(3); 1071-1078

In the present study, authors analyzed the new activity profile of Boswellic acids. It can inhibit transformation of arachidonic acid to leukotrienes via 5 lipoxygenase but can enhance the liberation of arachidonic acid. They explored the molecular mechanisms underlying the boswellic acid-induced release of arachidonic acid. They show that boswellic acids induce release of arachidonic acid and the synthesis of 12-H(P)ETE in human platelets by unique Ca2+-independent routes, and identified p12-LO as a selective molecular target of boswellic acids.

Acetyl-keto-beta-boswellic acid inhibits cellular proliferation through a p21-dependent pathway in colon cancer cells

Liu JJ, Huang B, Hooi SC
Br J Pharmacol 2006 Aug; 148(8); 1099-1107

Investigators explored the increasing evidence that boswellic acid may be used as a potential anticancer agent. They showed that acetyl-keto-beta-boswellic acid (AKBA) inhibited cellular growth in several colon cancer cell lines and concluded that AKBA inhibited cellular growth in colon cancer cells

Mechanisms underlying the anti-inflammatory actions of boswellic acid derivatives in experimental colitis

Anthoni C, Laukoetter MG, Rijcken E, Vowinkel T, Mennigen R, Müller S, Senninger N, Russell J, Jauch J, Bergmann J, Granger DN, Krieglstein CF
Am J Physiol Gastrointest Liver Physiol 2006 Jun; 290(6); G1131-1137

Recent clinical trials by the group on the gum resin of Boswellia serrata have shown promising results in patients with ulcerative colitis. The objective was to determine whether a semisynthetic form of acetyl-11-keto-beta-boswellic acid [sAKBA], confers protection in experimental murine colitis. The treatment of established colitis with sAKBA largely prevented the P-selectin upregulation normally associated with DSS colitis. Findings demonstrated an anti-inflammatory effects of AKBA.

Effect of Boswellia serrata on intestinal motility in rodents: inhibition of diarrhoea without constipation

Borrelli F, Capasso F, Capasso R, Ascione V, Aviello G, Longo R, Izzo AA
Br J Pharmacol 2006 Jun; 148(4); 553-560

Present clinical study evaluated the effect of a Boswellia serrata gum resin extract (BSE) on intestinal motility and diarrhoea in rodents. BSE depressed electrically, acetylcholine and barium chloride induced contractions in the isolated guinea-pig ileum. BSE prevents diarrhoea and normalizes intestinal motility in pathophysiological states without slowing the rate of transit in control animals. These results explain the clinical efficacy of BSE in reducing diarrhoea in inflammatory bowel disease patients.

Modulation of P-glycoprotein [Pgp] function by boswellic acids

Weber CC, Reising K, Müller WE, Schubert-Zsilavecz M, Abdel-Tawab M
Planta Med. 2006 May; 72(6); 507-513

This research report analyzed the role of Boswellic acids, in the treatment of peritumoral oedema and chronic inflammatory diseases, especially role of P-glycoprotein (Pgp), for drug disposition and resulting clinical response. Pharmacokinetic studies revealed that the concentrations of 11-keto-beta-boswellic acid (KBA) and the acetyl-11-keto-beta boswellic acid (AKBA) are much lower in plasma than in the orally administered extract. The inhibition of Pgp at the blood-brain barrier by Boswellia extract is probably not relevant for the brain availability of other Pgp substrates, because of the low plasma.

Regulation of vascular responses to inflammation: inducible matrix metallo proteinase-3 expression in human microvascular endothelial cells is sensitive to antiinflammatory Boswellia

Roy S, Khanna S, Krishnaraju AV, Subbaraju GV, Yasmin T, Bagchi D, Sen CK
Antioxid Redox Signal 2006 Mar-Apr; 8(3-4); 653-660

In this study authors analyzed the role of Boswellia extract (BE) on endothelial cells as critical elements in the pathophysiology of inflammation. Of the 522 genes induced by TNFalpha in HMECs, 113 genes were sensitive to BE. In the current work, they tested the effects of BE on TNFalpha-inducible MMP expression in HMECs. Acetyl-11-ketobeta- boswellic acid (AKBA) is known to be an active principle in BE. In vivo, BE protected against experimental arthritis. In vitro and in vivo, BE30% was more effective than BE3%. In sum, BE has potent anti-inflammatory properties both In vitro and In vivo.

Acetyl-11-keto-beta-boswellic acid potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis by suppressing NF-kappa B and NF-kappa B-regulated gene expression

Takada Y, Ichikawa H, Badmaev V, Aggarwal BB
J Immunol 2006 Mar 1; 176(5); 3127-3140

This report summarises the role of Acetyl-11-keto-beta-boswellic acid (AKBA), a component of Boswellia serrata. They found that AKBA potentiated apoptosis induced by TNF and chemotherapeutic agents suppressed TNF-induced invasion and inhibited receptor activator of NF-kappaB ligand-induced osteo clastogenesis. Overall, results indicated that AKBA enhances apoptosis induced by cytokines and chemotherapeutic agents, inhibits invasion, and suppresses osteoclastogenesis.

Potentiation of antinociceptive effect of NSAIDs by a specific lipooxygenase inhibitor, acetyl 11-keto-beta boswellic acid

Bishnoi M, Patil CS, Kumar A, Kulkarni SK
Indian J Exp Biol. 2006 Feb; 44(2); 128-132

The present study authors aimed to assess the combined effects of cyclo oxygenase and 5-lipoxygenase inhibitors in different animal models. AKBA is a 5-LOX inhibitor. AKBA produced dose dependent significant antinociceptive effect in different animal models of nociception. However, the effect of combination of nimesulide with AKBA was pronounced as compared to naproxen and rofecoxib. The present finding provided an evidence for the potentiation of antinociceptive effect of NSAIDs with AKBA.

Boswellic acids: biological actions and molecular targets

Poeckel D, Werz O
Curr Med Chem 2006; 13(28); 3359-3369

This review summarises the role of gum resin extracts of Boswellia species for the treatment of not only inflammation but also of cancer. Analysis of the ingredients of these extracts revealed that the pentacyclic triterpenes boswellic acids (BAs) possess biological activities and appear to be responsible for the respective pharmacological actions. This review summarizes the biological actions of BAs on the cellular and molecular level and the beneficial effects manifested in animal studies and trials with human subjects related to inflammation and cancer.

3-O-acetyl-11-keto-boswellic acid decreases basal intracellular Ca2+ levels and inhibits agonist-induced Ca2+ mobilization and mitogen-activated protein kinase activation in human monocytic cells

Poeckel D, Tausch L, George S, Jauch J, Werz O
J Pharmacol Exp Ther 2006 Jan; 316(1); 224-232

In this study authors addressed the effects of boswellic acids on the intracellular Ca(2+) concentration ([Ca(2+)](i)) and on the activation of p38(MAPK) and extracellular signal-regulated kinase (ERK) in the human monocytic cell line. AKBA also strongly suppressed the subsequent elevation of Ca(2+). AKBA interferes with pivotal signaling events in monocytic cells that are usually required for monocyte activation by proinflammatory stimuli.

Induction of central signalling pathways and select functional effects in human platelets by beta-boswellic acid

Poeckel D, Tausch L, Altmann A, Feisst C, Klinkhardt U, Graff J, Harder S, Werz
Br J Pharmacol 2005 Oct; 146(4); 514-524

Authors have addressed the effects of BAs on central signaling pathways in human platelets and on various platelet functions. They found that beta-BA (10 microM), the 11-methylene analogue of KBA, caused a pronounced mobilisation of Ca2+ from internal stores and induced the phosphorylation of p38 MAPK. In summary, beta-BA potently induces Ca2+ mobilisation and elicits functional platelet responses.

Protective effects of nimesulide (COX Inhibitor), AKBA (5-LOX Inhibitor), and their combination in aging-associated abnormalities in mice

Bishnoi M, Patil CS, Kumar A, Kulkarni SK
Methods Find Exp Clin Pharmacol. 2005 Sep; 27(7); 465-470

Authors analysed the critical role of Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX), two enzymes involved in the oxygenation of arachidonic acid, are upregulated in the central nervous system during aging and associated with different aging-related brain pathologies. The present experiment was performed to study the effects of 5-LOX inhibitor, acetyl-11-keto-beta-boswellic acid and nimesulide. To conclude the combination of COX and LOX inhibitors may provide a new therapeutic innovation for Alzheimer’s disease

Boswellia carterii extract inhibits TH1 cytokines and promotes TH2 cytokines In vitro

Chevrier MR, Ryan AE, Lee DY, Zhongze M, Wu-Yan Z, Via CS
Clin Diagn Lab Immunol 2005 May; 12(5); 575-580

In this study authors explored the traditional herbal formulas such as Boswellia carterii used to treat inflammatory arthritis. They contain Boswellic acids (BAs) which have been shown to exhibit anti-inflammatory and antiarthritic properties. This study tests the hypothesis that mixtures of Bas derived from B. carterii have immunomodulatory properties. These results indicate that a purified mixture of BAs from B. carterii plant resin exhibits carrier-dependent immunomodulatory properties In vitro.

Effects of Boswellia serrata in mouse models of chemically induced colitis

Kiela PR, Midura AJ, Kuscuoglu N, Jolad SD, Sólyom AM, Besselsen DG, Timmermann BN, Ghishan FK
Am J Physiol Gastrointest Liver Physiol 2005 Apr; 288(4); G798-808

Authors studied the extracts from Boswellia serrata for their anti-inflammatory activity. In three clinical trials, boswellia showed improved symptoms of ulcerative colitis and Crohn’s disease. The goal was to evaluate effectiveness of boswellia extracts in controlled settings of dextran sulfate or trinitrobenzene sulfonic acid-induced colitis. Results suggest boswellia is ineffective in ameliorating colitis. Hepato toxity and increased lipid accumulation were confirmed in HepG2 cells. In summary, boswellia does not ameliorate symptoms of colitis and in higher doses may become hepatotoxic.

Human genome screen to identify the genetic basis of the anti-inflammatory effects of Boswellia in microvascular endothelial cells

Roy S, Khanna S, Shah H, Rink C, Phillips C, Preuss H, Subbaraju GV, Trimurtulu G, Krishnaraju AV, Bagchi M, Bagchi D, Sen CK
DNA Cell Biol 2005 Apr; 24(4); 244-255

In the present study authors analyzed medicinal plants belonging to the Burseraceae family, including Boswellia, for their anti-inflammatory properties. Although Boswellia extract has proven to be anti-inflammatory in clinical trials, the underlying mechanisms remain. They tested the genetic basis of anti-inflammatory effects in human microvascular endothelial cells. TNF alpha induced 522 genes and downregulated 141 genes. Of the 522 genes induced by TNF alpha in HMEC, 113 genes were sensitive. In carrageenan-induced rat paw inflammation model, authors observed an anti-inflammatory response.

Boswellic acid acetate induces apoptosis through caspase-mediated pathways in myeloid leukemia cells

Xia L, Chen D, Han R, Fang Q, Waxman S, Jing Y
Mol Cancer Ther. 2005 Mar; 4(3); 381-388

In the present study authors analysed the mechanism of cytotoxic effect of boswellic acid acetate, a 1:1 mixture of alpha-boswellic acid acetate and beta boswellic acid acetate, isolated from Boswellia carterri on myeloid leukemia cells was investigated in six human myeloid leukemia cell lines (NB4, SKNO-1, K562, U937, ML-1, and HL-60 cells). More than 50% of cells underwent apoptosis after treatment with 20 mug/mL boswellic acid for 24 hours. These data taken together suggest that boswellic acid acetate induces myeloid leukemia cell apoptosis.

Inhibition of IkappaB kinase activity by acetyl-boswellic acids promotes apoptosis in androgen-independent PC-3 prostate cancer cells in vitro and in vivo

Syrovets T, Gschwend JE, Büchele B, Laumonnier Y, Zugmaier W, Genze F, Simmet T
J Biol Chem 2005 Feb 18; 280(7); 6170-6180

Authors analysed the signaling mechanism through NF-kappaB in chemo resistance of various cancers. Here they show that natural compounds acetyl-beta-boswellic acid and acetyl-11-keto-beta-boswellic acid (AKbetaBA) inhibit proliferation and elicit cell death in chemoresistant androgen-independent PC-3 prostate cancer cells. At molecular level these compounds inhibit constitutively activated NF-kappaB signaling. In nude mice carrying PC-3 tumors, systemic application of AKbetaBA-gamma-cyclodextrin inhibited tumor growth and triggered apoptosis.

Acetyl-boswellic acids inhibit lipopolysaccharide-mediated TNF-alpha induction in monocytes by direct interaction with IkappaB kinases

Syrovets T, Büchele B, Krauss C, Laumonnier Y, Simmet T
J Immunol. 2005 Jan 1; 174(1); 498-506

In this study the authors show that, in LPS-stimulated human peripheral monocytes, the pentacyclic triterpenes acetyl-alpha-boswellic acid (AalphaBA) and acetyl-11-keto-beta-boswellic acid down-regulate the TNF-alpha expression. These findings provide a molecular basis for the anti-inflammatory properties ascribed to AalphaBA- and AKbetaBA-containing drugs and suggest acetyl-boswellic acids as tools for the development of novel therapeutic interventions.

Effect of food intake on the bioavailability of boswellic acids from a herbal preparation in healthy volunteers

Sterk V, Büchele B, Simmet T
Planta Med. 2004 Dec; 70(12); 1155-1160

In this study authors investigated the effects of concomitant food intake on the bioavailability of distinct boswellic acids (BAs) from the test preparation BSE-018, a dry extract from Boswellia serrata gum resin. In randomised, open, single dose, two-way crossover study, healthy male subjects received three capsules of BSE-018 equivalent to 786 mg dry extract of Boswellia serrata gum. These data reveal detailed kinetics of BAs after oral dosing of an extract and demonstrate a profound effect of food intake on pharmacokinetic profile of the BAs.

Pharmacokinetic study of 11-Keto beta-Boswellic acid

Sharma S, Thawani V, Hingorani L, Shrivastava M, Bhate VR, Khiyani R
Phytomedicine 2004 Feb; 11(2-3); 255-260

This report analyses the role of Boswellia serrata in treatment of inflammatory diseases. Hence to better elucidate its effects in humans and determine its optimal dosing, this study was planned. Twelve healthy adult men volunteers were given capsule Wok Vel containing 333 mg of Boswellia Serrata Extract, orally, after a seven days washout period. The plasma concentration will attain the steady state after approximately 30 hours. BSE is a safe drug and well tolerated on oral administration and no adverse effects were seen as single dose in 333 mg.

Coupling of boswellic acid-induced Ca2+ mobilisation and MAPK activation to lipid metabolism and peroxide formation in human leucocytes

Altmann A, Poeckel D, Fischer L, Schubert-Zsilavecz M, Steinhilber D, Werz O
Br J Pharmacol 2004 Jan; 141(2); 223-232

The authors have previously shown that 11-keto boswellic acids, the active principles of Boswellia serrata gum resins, activate p38 MAPK and p42/44. They attempted to connect the activation of MAPK and mobilization of Ca (2+) to functional responses of PMNL, including formation of reactive oxygen species, release of arachidonic acid and leukotriene biosynthesis. In summary, they conclude that BAs act via stimulating leucocyte signalling pathways.