Nuclear factor-kappaB (
NF-kappaB) is critically important for
tumor cell survival, growth, angiogenesis, and
metastasis. One of the key events in the
NF-kappaB signaling is the activation of inhibitor of
NF-kappaB kinase (IKK) in response to stimuli of various
cytokines. We have identified
17-acetoxyjolkinolide B (17-AJB) from a traditional Chinese medicinal herb Euphorbia fischeriana Steud as a novel small-molecule inhibitor of IKK. 17-AJB effectively inhibited
tumor necrosis factor-alpha-induced
NF-kappaB activation and induced apoptosis of
tumor cells. 17-AJB had no effect on binding of
tumor necrosis factor-alpha to its receptor or on binding of
NF-kappaB to
DNA. It inhibited
NF-kappaB nuclear translocation. Detailed analysis revealed that the direct target of 17-AJB was IKK. 17-AJB kept IKK in its phosphorylated form irreversibly. This irreversible modification of IKK inactivated its
kinase activity, leading to its failure to activate
NF-kappaB. The effect of 17-AJB on IKK was specific. It had no effect on other
kinases such as p38, p44/42, and JNK. In addition, 17-AJB induced apoptosis in
tumor cells. The effects of 17-AJB on apoptosis correlated with inhibition of expression of the
NF-kappaB-regulated genes. Taken together, our data suggest that 17-AJB is a novel type
NF-kappaB pathway inhibitor. Its unique interaction mechanism with IKK may render it a strong apoptosis inducer of
tumor cells and a novel type anticancer
drug candidate.