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.