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.
Acetyl-11-keto-beta-boswellic acid (AKBA), a component of an Ayurvedic therapeutic plant Boswellia serrata, is a pentacyclic terpenoid active against a large number of inflammatory diseases, including cancer, arthritis, chronic colitis, ulcerative colitis, Crohn's disease, and bronchial asthma, but the mechanism is poorly understood. We found that AKBA potentiated the apoptosis induced by TNF and chemotherapeutic agents, suppressed TNF-induced invasion, and inhibited receptor activator of NF-kappaB ligand-induced osteoclastogenesis, all of which are known to require NF-kappaB activation. These observations corresponded with the down-regulation of the expression of NF-kappaB-regulated antiapoptotic, proliferative, and angiogenic gene products. As examined by DNA binding, AKBA suppressed both inducible and constitutive NF-kappaB activation in tumor cells. It also abrogated NF-kappaB activation induced by TNF, IL-1beta, okadaic acid, doxorubicin, LPS, H2O2, PMA, and cigarette smoke. AKBA did not directly affect the binding of NF-kappaB to the DNA but inhibited sequentially the TNF-induced activation of IkappaBalpha kinase (IKK), IkappaBalpha phosphorylation, IkappaBalpha ubiquitination, IkappaBalpha degradation, p65 phosphorylation, and p65 nuclear translocation. AKBA also did not directly modulate IKK activity but suppressed the activation of IKK through inhibition of Akt. Furthermore, AKBA inhibited the NF-kappaB-dependent reporter gene expression activated by TNFR type 1, TNFR-associated death domain protein, TNFR-associated factor 2, NF-kappaB-inducing kinase, and IKK, but not that activated by the p65 subunit of NF-kappaB. Overall, our results indicated that AKBA enhances apoptosis induced by cytokines and chemotherapeutic agents, inhibits invasion, and suppresses osteoclastogenesis through inhibition of NF-kappaB-regulated gene expression.
Takada
Yasunari
Y
Cytokine Research Section, Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Ichikawa
Haruyo
H
Badmaev
Vladimir
V
Aggarwal
Bharat B
BB
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002352:Carrier Proteins / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002464:Cell Migration Inhibition; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D010766:Phosphorylation; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D014315:Triterpenes / Q000494:pharmacology*; D048069:Tumor Necrosis Factors / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D006131:Growth Inhibitors; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014315:Triterpenes; D048069:Tumor Necrosis Factors; D025801:Ubiquitin; C094432:acetyl-11-ketoboswellic acid; D051550:I-kappa B Kinase