Acetyl-11-Keto-β-Boswellic Acid Potentiates Apoptosis, Inhibits Invasion, and Abolishes Osteoclastogenesis by Suppressing NF-κB and NF-κB-Regulated Gene Expression

Abstract

Acetyl-11-keto-β-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-κB ligand-induced osteoclastogenesis, all of which are known to require NF-κB activation. These observations corresponded with the down-regulation of the expression of NF-κB-regulated antiapoptotic, proliferative, and angiogenic gene products. As examined by DNA binding, AKBA suppressed both inducible and constitutive NF-κB activation in tumor cells. It also abrogated NF-κB activation induced by TNF, IL-1β, okadaic acid, doxorubicin, LPS, H2O2, PMA, and cigarette smoke. AKBA did not directly affect the binding of NF-κB to the DNA but inhibited sequentially the TNF-induced activation of IκBα kinase (IKK), IκBα phosphorylation, IκBα ubiquitination, IκBα 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-κB-dependent reporter gene expression activated by TNFR type 1, TNFR-associated death domain protein, TNFR-associated factor 2, NF-κB-inducing kinase, and IKK, but not that activated by the p65 subunit of NF-κB. Overall, our results indicated that AKBA enhances apoptosis induced by cytokines and chemotherapeutic agents, inhibits invasion, and suppresses osteoclastogenesis through inhibition of NF-κB-regulated gene expression.

Boswellia serrata acts on cerebral edema in patients irradiated for brain tumors

“…7 In recent years, mechanisms of action of boswellic acids have been identified. 8 Takada et al 9 showed that AKBA can potentiate apoptosis, inhibit invasion, and abolish osteoclastogenesis in different human cancer cell lines. The mechanism of these actions was found to be a suppression of nuclear factor jB (NF-jB) and NF-jB-regulated gene expression.…”

Redox Control of Apoptosis: An Update

“…Recently this group has made great progress to fully characterize the NF-B-mediated signaling pathway by isolating and testing the inhibitory activity of several plant-derived natural compounds (1). Among these, curcumin (2,3), and many other polyphenol derivatives (31,32,33,46,49,52,53,54) have been found to inhibit NF-B pathway in several tumor cell lines and at different levels, from I B phosphorylation to the expression of NF-B-regulated gene products. These novel findings could be of great importance in cancer prevention and therapy (27), especially in light of the latest evidence that demonstrates a pivotal role for NAD(P)H:quinone oxidoreductase 1 (NQO1) in producing ROS downstream of TNF engagement, in keratinocytes from NQO1 -/-mice (4).…”

Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer

“…The apoptotic induction of AKBA is independent of Fas and FasL interaction [66], and is p21 dependent but not p53-dependent [78]. In addition, AKBA can enhance the apoptosis induced by TNF-a and some chemotherapeutic agents, as well as inhibit invasion through inhibition of NF-jB activity, and subsequent downregulation of Bcl-2 and Bcl-xL in prostate cancer cell line PC-3 [71,79]. Topical application of BA exhibited significant anti-inflammatory and pro-apoptotic activity in animal models of inflammation and is currently being tested in clinical trials [80][81][82].…”

“…Interestingly, AKBA also exhibited similar anti-tumor activity as BA. AKBA induced cell cycle arrest was mediated by down-regulating the expression of cyclinD1, suppresses MMP activity, and also induced apoptosis by suppressing Bcl-2, and Bcl-xL expression, [71]. Most of the pro-inflammatory effects of TNF-a are mediated through activation of NF-jB.…”