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

被引:167
作者
Takada, Yasunari
Ichikawa, Haruyo
Badmaev, Vladimir
Aggarwal, Bharat B.
机构
[1] Univ Texas, MD Anderson Canc Ctr, Dept Expt Therapeut, Cytokine Res Lab,Cytokine Res Sect, Houston, TX 77030 USA
[2] Sabinsa Corp, Piscataway, NJ 08854 USA
关键词
D O I
10.4049/jimmunol.176.5.3127
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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-kappa B ligand-induced osteoclastogenesis, all of which are known to require NF-kappa B activation. These observations corresponded with the down-regulation of the expression of NF-kappa B-regulated antiapoptotic, proliferative, and angiogenic gene products. As examined by DNA binding, AKBA suppressed both inducible and constitutive NF-kappa B activation in tumor cells. It also abrogated NF-kappa B activation induced by TNF, IL-1 beta, okadaic acid, doxorubicin, LPS, H2O2, PMA, and cigarette smoke. AKBA did not directly affect the binding of NF-kappa B to the DNA but inhibited sequentially the TNF-induced activation of I kappa B alpha kinase (IKK), I kappa B alpha phosphorylation, I kappa B alpha ubiquitination, I kappa B alpha 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-kappa B-dependent reporter gene expression activated by TNFR type 1, TNFR-associated death domain protein, TNFR-associated factor 2, NF-kappa B-inducing kinase, and IKK, but not that activated by the p65 subunit of NF-kappa B. Overall, our results indicated that AKBA enhances apoptosis induced by cytokines and chemotherapeutic agents, inhibits invasion, and suppresses osteoclastogenesis through inhibition of NF-kappa B-regulated gene expression.
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收藏
页码:3127 / 3140
页数:14
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