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      17-Acetoxyjolkinolide B irreversibly inhibits IkappaB kinase and induces apoptosis of tumor cells.

      Molecular cancer therapeutics
      Antineoplastic Agents, chemistry, pharmacology, Apoptosis, drug effects, Cell Line, Tumor, Cell Nucleus, metabolism, Cytokines, DNA, Neoplasm, Diterpenes, therapeutic use, Doxorubicin, Drug Synergism, Gene Expression Regulation, Neoplastic, Humans, I-kappa B Kinase, antagonists & inhibitors, I-kappa B Proteins, NF-kappa B, Neoplasms, drug therapy, enzymology, pathology, Phosphorylation, Phytotherapy, Protein Binding, Protein Processing, Post-Translational, Protein Transport, Receptors, Tumor Necrosis Factor, Signal Transduction, Tumor Necrosis Factor-alpha

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          Abstract

          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.

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