Embelin, an inhibitor of X chromosome-linked inhibitor-of-apoptosis protein, blocks nuclear factor-kappaB (NF-kappaB) signaling pathway leading to suppression of NF-kappaB-regulated antiapoptotic and metastatic gene products.

Identifying the active chemical ingredients of ancient medicines and the molecular targets of those ingredients is an attractive therapeutic objective. Embelin, identified primarily from the Embelia ribes plant, is one such compound shown to exhibit chemopreventive, anti-inflammatory, and apoptotic activities through an unknown mechanism. Because nuclear factor-kappaB (NF-kappaB) regulates several genes associated with inflammation, proliferation, carcinogenesis, and apoptosis, we postulated that embelin might mediate its activity through modulation of NF-kappaB activation. We found that embelin inhibited tumor necrosis factor (TNF) alpha-induced NF-kappaB activation. Both inducible and constitutive NF-kappaB activation were abrogated by embelin. In addition, NF-kappaB activated by diverse stimuli such as interleukin-1beta, lipopolysaccharide, phorbol myristate acetate, okadaic acid, hydrogen peroxide, and cigarette smoke condensate also was suppressed. We found that embelin inhibited sequentially the TNFalpha-induced activation of the inhibitory subunit of NF-kappaBalpha (IkappaBalpha) kinase, IkappaBalpha phosphorylation, IkappaBalpha degradation, and p65 phosphorylation and nuclear translocation. Embelin also suppressed NF-kappaB-dependent reporter gene transcription induced by TNFalpha, TNF receptor-1 (TNFR1), TNFR1-associated death domain protein, TNFR-associated factor-2, NF-kappaB-inducing kinase, and IkappaBalpha kinase but not by p65. Furthermore, we found that embelin down-regulated gene products involved in cell survival, proliferation, invasion, and metastasis of the tumor. This down-regulation was associated with enhanced apoptosis by cytokine and chemotherapeutic agents. Together, our results indicate that embelin is a novel NF-kappaB blocker and potential suppressor of tumorigenesis.