17-Acetoxyjolkinolide B irreversibly inhibits I kappa B kinase and induces apoptosis of tumor cells

Nuclear factor-kappa B (NF-kappa B) is critically important for tumor cell survival, growth, angiogenesis, and metastasis. One of the key events in the NF-kappa B signaling is the activation of inhibitor of NF-kappa B 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-kappa B 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-kappa B to DNA. It inhibited NF-kappa B 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-kappa B. 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-kappa B-regulated genes. Taken together, our data suggest that 17-AJB is a novel type NF-kappa B 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.