Research Highlights from 2004 to 2006

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

Büchele B, Zugmaier W, Estrada A, Genze F, Syrovets T, Paetz C, Schneider B, Simmet T Planta Med. 2006 Nov;72(14):1285-9

The 3α-acetyl-11-keto-α-boswellic acid (3α-acetoxy-11-oxo-olean-12-en-24-oic acid, compound 1) used in this study was synthesized by a radical-type reaction using bromine and the 3α-acetyl-α-boswellic acid was isolated from the oleo-gum-resin of Boswellia carterii. 1D and 2D NMR (COSY, HMBC, ROESY) at 500 MHz were used for shift assignments and structure verification. The compound investigated is present in a herbal preparation extracted from Boswellia serrata oleo-gum-resin, it inhibits the growth of chemotherapy-resistant human PC-3 prostate cancer cells in vitro and induces apoptosis as shown by activation of caspase 3and the induction of DNA fragmentation. In addition, compound 1 is active in vitro as shown by inhibition of proliferation and induction of apoptosis in PC-3 prostate cancer cells xenotransplanted onto the chick chorioallantoic membrane.

Boswellic acids in chronic inflammatory diseases

Ammon HP Planta Med. 2006 Oct;72(12):1100-16

This is a review article on oleo gum resin of Boswellia used in the traditional medicines of India and African countries. The anti-inflammatory actions are due to some boswellic acids. The most evident action is the inhibition of 5-lipoxygenase. Leukocyte elastase and oxygen radicals are also 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, TABBAta K, Nakamura Y, Nishimura R, Kimura Y, Suzuki T
J Ethnopharmacol. 2006 Sep 19;107(2):249-53

This study evaluated the role of Boswellic acid isolated from the Boswellia carterii in the treatment of anti-inflammatory actions. Fifteen triterpene acids of the β-boswellic acids, two of the α-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, TABBAta K, Banno N, Tokuda H, Nishimura R, Nakamura Y, Kimura Y, Yasukawa K, Suzuki T Biol Pharm Bull. 2006 Sep;29(9):1976-9

In this study fifteen triterpene acids viz. seven of the β-boswellic acids (1-7), two of the α-boswellic acids (oleanane-type) (8, 9), two of the lupeolic acids (lupane-type) (10, 11), and four of the tirucallane-type (12-14, 16), two membrane-type diterpenes (17, 18), and triterpene acid (15) were examined for inhibitory effects. On evaluation against the Epstein-Barr virus early antigen (EBV-EA) activation, seven compounds, 2, 10, 11, 13-16, and five compounds against a nitrogen oxide (NO) donor(NOR 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 against neuroblastoma cell lines.

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):1071-8

In the present study, the authors analyzed the new activity profile of Boswellic acids. It can inhibit the 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 the 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-β-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):1099-107

Investigators explored the increasing evidence that boswellic acid may be used as a potential anticancer agent. They showed that acetyl-keto-β-boswellic acid (AKBBA) inhibited cellular growth in colon cancer cell lines via p21 dependent mechanism and concluded that AKBBA inhibited cell 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):G1131-7

This study was to determine whether the acetyl-11-keto-β-boswellic acid [AKBBA] confers protection in experimental murine colitis induced by dextran sodium sulfate (DSS). The treatment with sAKBBA showed decreased disease activity and prevented the DSS colitis-associated P-selectin upregulation. These findings demonstrated a major site of action of the novel anti-inflammatory agent, AKBBA.

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):553-60

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

Modulation of Pgp function by boswellic acids

Weber CC, Reising K, Müller WE, Schubert-Zsilavecz M, Abdel-Tawab M Planta Med. 2006 May;72(6):507-13

This research report analyzed the modulatory effects of Boswellic acids on the transport activity of P-glycoprotein (Pgp). in vitro studies revealed that boswellic acids, as well as keto-boswellic acids, inhibit the Pgp in micormolecular range. The study concluded that 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 and this data could not exclude the possibility of drug interactions caused by modulation of Pgp by Boswellia serrata on the gastrointestinal level.

Regulation of vascular responses to inflammation: inducible matrix metalloproteinase-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):653-60

This study analyzed the role of Boswellia extract on TNF-α-inducible matrix metalloproteinase (MMP) expression in human microvascular endothelial cells (HMECs) as critical elements in the pathophysiology of inflammation. Pretreatment of HMECs for 2 days with Boswellia extract potentially prevented TNFapha-induced expression and activity of MMPs (3, 10 and 12) and showed protection against experimental arthritis in vitro. Boswellia extract containing 30% AKBBA showed more effectiveness than Boswellia extract containing 3% AKBBA in both in vitro and in vitro experiments. In sum, the study suggests that BE has potent anti-inflammatory properties both in vitro and in vitro.

Acetyl-11-keto-β-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):3127-40

This report summarises the role of Acetyl-11-keto-β-boswellic acid (AKBBA), a component of Boswellia serrata. They found that AKBBA potentiated apoptosis induced by TNF and chemotherapeutic agents suppressed TNF-induced invasion and inhibited receptor activator of NFKB ligand-induced osteoclastogenesis. Overall, results indicated that AKBBA 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-β boswellic acid

Bishnoi M, Patil CS, Kumar A, Kulkarni SK Indian J Exp Biol. 2006 Feb;44(2):128-32

The present study assessed the combined effects of cyclooxygenase and 5-lipoxygenase inhibitors in different animal models of nociception. AKBBA is a 5-lipoxygenase inhibitor. AKBBA (100 mg/kg) produced a dose-dependent, significant antinociceptive effect in different animal models of nociception. However, the effect of the combination of nimesulide (1 mg/kg) with AKBBA was more pronounced as compared to naproxen (5 mg/kg) and rofecoxib (1 mg/kg). The present finding provided evidence for the potentiation of the antinociceptive effect of NSAIDs with AKBBA.

Boswellic acids: biological actions and molecular targets

Poeckel D, Werz O Curr Med Chem. 2006;13(28):3359-69

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 human trials 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):224-32

This study addressed the effects of boswellic acids on 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 Mono Mac (MM). AKBBA strongly suppressed the elevation of Ca(2+). AKBBA 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 β-boswellic acid

Poeckel D, Tausch L, Altmann A, Feisst C, Klinkhardt U, Graff J, Harder S, Werz O Br J Pharmacol. 2005 Oct;146(4):514-24

This study addressed the effects of BAs on central signalling pathways in human platelets and on various platelet functions. It found that β-BA (10 microM), the 11-methylene analog of KBBA, caused a pronounced mobilization of Ca2+ from internal stores and induced the phosphorylation of p38 MAPK, extracellular signal-regulated kinase (ERK)2, and Akt. In summary, β-BA potently induces Ca2+ mobilization, activation of protein kinases and elicits functional platelet responses.

Protective effects of nimesulide (COX Inhibitor), AKBBA (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):465-70

This study analyzed the effects of chronic administration (15 days) of 5-LOX inhibitor (acetyl-11-keto-β-boswellic acid; 100 mg/kg) and nimesulide (selective COX-2 inhibitor; 2.42 mg/kg, P.O.), and their combination on the cognitive performance of young and aged mice. To conclude the combination of COX and LOX inhibitors may provide a new therapeutic innovation for Alzheimer’s disease and motor dysfunctions.

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):575-80

This study tested the hypothesis that mixtures of BAs derived from B. carterii have immunomodulatory properties. Seven BAs were confirmed in the ethanolic extract of B. carterii resin prepared in this study. These results indicated 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

This study evaluated the effectiveness of Boswellia extracts in controlled settings of dextran sulfate or trinitrobenzene sulfonic acid-induced colitis. Results suggest that Boswellia is ineffective in ameliorating colitis in these models. Hepato toxicity and increased lipid accumulation were confirmed in HepG2 cells. In summary, Boswellia does not ameliorate the symptoms of colitis and may become hepatotoxic at higher doses.

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):244-55

The present study analyzed the genetic basis of anti-inflammatory effects of standardized Boswellia extract, 5-Loxin, in human microvascular endothelial cells (HMECs). TNF α-induced 522 genes and downregulated 141 genes. Of the 522 genes induced by TNF α in HMEC, 113 genes were sensitive. The results confirming the anti-inflammatory property of BE were also reiterated in carrageenan-induced rat paw inflammation model.

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):381-8

The present study analysed the mechanism of the cytotoxic effect of boswellic acid acetate, a 1:1 mixture of α-boswellic acid acetate and β boswellic acid acetate, isolated from Boswellia carterri on myeloid leukaemia cells in six human myeloid leukaemia cell lines (NB4, SKNO-1, K562, U937, ML-1, and HL-60 cells). More than 50% of cells underwent apoptosis after treatment with 20 μg/mL boswellic acid for 24 hours. It suggests that boswellic acid acetate induces myeloid leukemia cell apoptosis via the caspase-8 mechanism.

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

Syrovets T, Gschwend JE, Büchele B, Laumonnier Y, Zugmaier W, Genze F, Simmet T J Biol Chem. 2005 Feb 18;280(7):6170-80

The present had shown that the natural compounds acetyl-β-boswellic acid and acetyl-11-keto-β-boswellic acid inhibit proliferation and elicit cell death in chemoresistant androgen-independent PC-3 prostate cancer cells. At the molecular level, these compounds inhibited constitutively activated NF-kappaB signaling. Furthermore, AKBBA-gamma-cyclodextrin inhibited the tumor growth and induced apoptosis in nude mice carrying PC-3 tumors and chick chorioallantoic membranes xenografted with PC-3 tumors.

Acetyl-boswellic acids inhibit lipopolysaccharide-mediated TNF-α 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

This study had shown that, in LPS-stimulated human peripheral monocytes, the pentacyclic triterpenes acetyl-α-boswellic acid and acetyl-11-keto-β-boswellic acid (AKBBA) down-regulated the expression of TNF-α through NF-kappaB inhibition. These findings provide a molecular basis for the anti-inflammatory properties ascribed to acetyl-α-boswellic acid- and AKBBA-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):1155-60

This clinical study 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 this randomized, open, single-dose, two-way crossover study, healthy male subjects received three capsules of BSE-018 equivalent to 786 mg dry extract of B.serrata< gum. These data reveal detailed kinetics of BAs after oral dosing of an extract and demonstrate a profound effect of food intake on the pharmacokinetic profile of the BAs.

Pharmacokinetic study of 11-Keto β-Boswellic acid

Sharma S, Thawani V, Hingorani L, Shrivastava M, Bhate VR, Khiyani R Phytomedicine. 2004 Feb;11(2-3):255-60

This study elucidated the effects of Boswellia serrata in humans and determine its optimal dosing. Twelve healthy adult men volunteers were given capsule containing 333 mg of B. serrata extract, orally, after a seven days washout period. The plasma concentration will attain a steady state after approximately 30 hours. B. serrata extract is a safe drug and well-tolerated on oral administration and no adverse effects were seen as a 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):223-32

This study attempted to link the activation of MAPK and mobilization of Ca(2+) to functional responses of polymorphonuclear leucocytes (PMNLs), including the formation of reactive oxygen species, the release of arachidonic acid and leukotriene biosynthesis. It concludes that boswellic acids act by stimulating leucocyte-signaling pathways.