Boswellic Acids Activate p42MAPK and p38 MAPK and Stimulate Ca2+ Mobilization

Altmann, Anja; Fischer, Lutz; Schubert‐Zsilavecz, Manfred; Steinhilber, Dieter; Werz, Oliver

doi:10.1006/bbrc.2001.6153

Cited by 41 publications

(33 citation statements)

References 31 publications

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“…However, in some leukemic cell lines such as HL-60 and CCRF-CEM cells, which do not express 5-lipoxygenase mRNA constitutively, apoptotic and antiproliferative effect of boswellic acids could still be observed, indicating that the blockade of 5-lipoxygenase may not be the only mechanism underlying its apoptotic effect (37). Boswellic acids were reported to inhibit topoisomerases (37,38), and to increase the intracellular calcium and activity of mitogen activated protein (MAP) kinase in human isolated leukocyte (39). Calcium mobilization has been reported to be linked to death receptor and caspase-8 activation (40,41).…”

Section: Discussionmentioning

confidence: 99%

Boswellic acids trigger apoptosis via a pathway dependent on caspase-8 activation but independent on Fas/Fas ligand interaction in colon cancer HT-29 cells

Liu¹

2002

Carcinogenesis

173

125

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Boswellic acids are the effective components of gum resin of Boswellia serrata, which has anti-inflammatory properties. Recent studies on brain tumors and leukemic cells indicate that boswellic acids may have antiproliferative and apoptotic effects with the mechanisms being not studied in detail. We studied their antiproliferative and apoptotic effects on colon cancer cells and the pathway leading to apoptosis. HT-29 cells were treated with β-boswellic acid (BA), keto-β-boswellic acid (K-BA) and acetyl-keto-β-boswellic acid (AK-BA), respectively. Apoptosis was determined by flow cytometry, by cytoplasmic DNA-histone complex and the activity of caspase-3. The cleavage of poly-(ADP-ribose)-polymerase (PARP) and expression of Fas were examined by western blot. Specific caspase inhibitors, polyclonal Fas antibody, and antagonistic Fas antibody ZB4 were employed to elucidate apoptotic pathways. DNA synthesis and cell viability were examined. Both K-BA and AK-BA increased cytoplasmic DNA-histone complex dose-dependently and increased pre-G 1 peak in flow cytometer analysis, with the effects of AK-BA being stronger than K-BA. BA only increased the formation of DNA-histone complex at a high concentration. K-BA and AK-BA increased caspase-8, caspase-9 and caspase-3 activities accompanied by cleavage of PARP. The effects of AK-BA on formation of cytoplasmic DNA histone and on caspase-3 activation were 3.7-and 3.4-fold, respectively, more effective than those induced by camptothecin. The apoptosis induced by AK-BA was inhibited completely by caspase-3 or caspase-8 inhibitor and partially by caspase-9 inhibitor. ZB4 blocked exogenous Fas ligand-induced apoptosis, but had no effect on AK-BA-induced apoptosis. AK-BA had no significant effect on expression of Fas. Apart from apoptotic effect, these acids also inhibited [ 3 H]thymidine incorporation and cell viability to different extent. In conclusion, boswellic acids, particularly AK-BA and K-BA have antiproliferative and apoptotic effects in human HT-29 cells. The apoptotic effect is mediated via a pathway dependent on caspase-8 activation but independent of Fas/FasL interaction.

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Section: Discussionmentioning

confidence: 99%

Boswellic acids trigger apoptosis via a pathway dependent on caspase-8 activation but independent on Fas/Fas ligand interaction in colon cancer HT-29 cells

Liu¹

2002

Carcinogenesis

173

125

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“…Thus, stimulating properties (Safayhi et al, 2000;Altmann et al, 2002Altmann et al, , 2004Poeckel et al, 2005) and inhibitory effects (Safayhi et al, 1992(Safayhi et al, , 1995Werz et al, 1998;Poeckel et al, 2006) of boswellic acids have been reported for these functions, depending on the cell type and the respective experimental settings. For example, for inhibition of 5-lipoxygenase by AKBA, IC 50 values in the range of 1.5 M (Safayhi et al, 1995) up to 50 M (Werz et al, 1997(Werz et al, , 1998 were determined, but also 5-lipoxygenase stimulatory effects in this concentration range were described previously (Safayhi et al, 2000;Altmann et al, 2004).…”

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confidence: 99%

Boswellic Acids Stimulate Arachidonic Acid Release and 12-Lipoxygenase Activity in Human Platelets Independent of Ca²⁺and Differentially Interact with Platelet-Type 12-Lipoxygenase

Poeckel¹,

Tausch²,

Kather³

et al. 2006

Mol Pharmacol

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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-lipoxygenase (p12-LO). Both ␤-boswellic acid and 3-O-acetyl-11-keto-boswellic acid (AKBA) markedly enhanced the release of arachidonic acid via cytosolic phospholipase A 2 (cPLA 2 ), whereas for generation of 12-hydro(pero)xyeicosatetraenoic acid [12-H(P)ETE], AKBA was less potent than ␤-boswellic acid and was without effect at higher concentrations (Ն30 M). In contrast to thrombin, ␤-boswellic acid-induced release of arachidonic acid and formation of 12-H(P)ETE was more rapid and occurred in the absence of Ca 2ϩ . The Ca 2ϩ -independent release of arachidonic acid and 12-H(P)ETE production elicited by ␤-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, ␤-boswellic acid increased p12-LO catalysis approximately 2-fold in the absence but not in the presence of Ca 2ϩ , whereas AKBA inhibited p12-LO activity. No direct modulatory effects of boswellic acids on cPLA 2 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 cPLA 2 . 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 Ca 2ϩ -independent routes, and we identified p12-LO as a selective molecular target of boswellic acids.

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“…Moreover, the C3-OH moiety chosen to link KBA is no pharmacophore since esterification with glutaric acid did not hamper the interference with catG or docking into the active center. In fact, the esterified analogs of KBA (i.e., AKBA and Glut-KBA) were even somewhat superior in inhibiting catG, and also for other targets, AKBA is frequently more potent than KBA (37)(38)(39). Finally, BAs are highly rigid molecules, thus favoring tight binding to catG.…”

Section: Discussionmentioning

confidence: 99%

Identification of Human Cathepsin G As a Functional Target of Boswellic Acids from the Anti-Inflammatory Remedy Frankincense

Tausch

Henkel

Siemoneit

et al. 2009

The Journal of Immunology

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Frankincense preparations, used in folk medicine to cure inflammatory diseases, showed anti-inflammatory effectiveness in animal models and clinical trials. Boswellic acids (BAs) constitute major pharmacological principles of frankincense, but their targets and the underlying molecular modes of action are still unclear. Using a BA-affinity Sepharose matrix, a 26-kDa protein was selectively precipitated from human neutrophils and identified as the lysosomal protease cathepsin G (catG) by mass spectrometry (MALDI-TOF) and by immunological analysis. In rigid automated molecular docking experiments BAs tightly bound to the active center of catG, occupying the same part of the binding site as the synthetic catG inhibitor JNJ-10311795 (2-[3-{methyl[1-(2-naphthoyl)piperidin-4-yl]amino}carbonyl)-2-naphthyl]-1-(1-naphthyl)-2-oxoethylphosphonic acid). BAs potently suppressed the proteolytic activity of catG (IC50 of ∼600 nM) in a competitive and reversible manner. Related serine proteases were significantly less sensitive against BAs (leukocyte elastase, chymotrypsin, proteinase-3) or not affected (tryptase, chymase). BAs inhibited chemoinvasion but not chemotaxis of challenged neutrophils, and they suppressed Ca2+ mobilization in human platelets induced by isolated catG or by catG released from activated neutrophils. Finally, oral administration of defined frankincense extracts significantly reduced catG activities in human blood ex vivo vs placebo. In conclusion, we show that catG is a functional and pharmacologically relevant target of BAs, and interference with catG could explain some of the anti-inflammatory properties of frankincense.

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Boswellic Acids Activate p42MAPK and p38 MAPK and Stimulate Ca2+ Mobilization

Cited by 41 publications

References 31 publications

Boswellic acids trigger apoptosis via a pathway dependent on caspase-8 activation but independent on Fas/Fas ligand interaction in colon cancer HT-29 cells

Boswellic acids trigger apoptosis via a pathway dependent on caspase-8 activation but independent on Fas/Fas ligand interaction in colon cancer HT-29 cells

Boswellic Acids Stimulate Arachidonic Acid Release and 12-Lipoxygenase Activity in Human Platelets Independent of Ca²⁺and Differentially Interact with Platelet-Type 12-Lipoxygenase

Identification of Human Cathepsin G As a Functional Target of Boswellic Acids from the Anti-Inflammatory Remedy Frankincense

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Boswellic Acids Activate p42MAPK and p38 MAPK and Stimulate Ca2+ Mobilization

Cited by 41 publications

References 31 publications

Boswellic acids trigger apoptosis via a pathway dependent on caspase-8 activation but independent on Fas/Fas ligand interaction in colon cancer HT-29 cells

Boswellic acids trigger apoptosis via a pathway dependent on caspase-8 activation but independent on Fas/Fas ligand interaction in colon cancer HT-29 cells

Boswellic Acids Stimulate Arachidonic Acid Release and 12-Lipoxygenase Activity in Human Platelets Independent of Ca2+and Differentially Interact with Platelet-Type 12-Lipoxygenase

Identification of Human Cathepsin G As a Functional Target of Boswellic Acids from the Anti-Inflammatory Remedy Frankincense

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Boswellic Acids Stimulate Arachidonic Acid Release and 12-Lipoxygenase Activity in Human Platelets Independent of Ca²⁺and Differentially Interact with Platelet-Type 12-Lipoxygenase