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Unformatted text preview: 17-Acetoxyjolkinolide B irreversibly inhibits IKB kinaseand induces apoptosis of tumor cellsShou-Sheng Yan,1Ying Li,3Ying Wang,1Shen-Si Shen,1Yuan Gu,1Hong-Bing Wang,2Guo-Wei Qin,2and Qiang Yu1Departments of1Pharmacology and2Phytochemistry, ShanghaiInstitute of Materia Medica, Shanghai Institutes for BiologicalSciences;3Department of Bioorganic Chemistry, ShanghaiInstitute of Organic Chemistry, Chinese Academy of Sciences,Shanghai, Peoples Republic of ChinaAbstractNuclear factor-KB (NF-KB) is critically important for tumorcell survival, growth, angiogenesis, and metastasis. Oneof the key events in the NF-KB signaling is the activationof inhibitor of NF-KB kinase (IKK) in response to stimuli ofvarious cytokines. We have identified 17-acetoxyjolkino-lide B (17-AJB) from a traditional Chinese medicinal herbEuphorbia fischerianaSteud as a novel small-moleculeinhibitor of IKK. 17-AJB effectively inhibited tumornecrosis factor-Ainduced NF-KB activation and inducedapoptosis of tumor cells. 17-AJB had no effect on bind-ing of tumor necrosis factor-Ato its receptor or on bindingof NF-KB to DNA. It inhibited NF-KB nuclear translocation.Detailed analysis revealed that the direct target of 17-AJBwas IKK. 17-AJB kept IKK in its phosphorylated formirreversibly. This irreversible modification of IKK inacti-vated its kinase activity, leading to its failure to activateNF-KB. The effect of 17-AJB on IKK was specific. It hadno effect on other kinases such as p38, p44/42, andJNK. In addition, 17-AJB induced apoptosis in tumor cells.The effects of 17-AJB on apoptosis correlated with inhibi-tion of expression of the NF-KB-regulated genes. Takentogether, our data suggest that 17-AJB is a novel typeNF-KB pathway inhibitor. Its unique interaction mechanismwith IKK may render it a strong apoptosis inducer of tumorcells and a novel type anticancer drug candidate. [MolCancer Ther 2008;7(6):152332]IntroductionThe root of driedEuphorbia fischerianaSteud (Euphorbia-ceae), named lang-du in traditional Chinese medicine,was first describedf2,000 years ago. This herb has beenused for treatment of cancer, edema, and ascites (1).Chemical investigation of this plant revealed that it mainlycontained diterpenoids, triterpenoids, and steroids (2).Diterpenoids are thought to be the main active compoundsin this plant, and it constitutesf0.1% of the plants totalmass. Twenty carbon skeleton types of diterpenoids havebeen identified and isolated fromEuphorbiagenus (1, 3).Nuclear transcription factor nuclear factor-nB (NF-nB)and its pathway regulators control genes functioning in abroad range of biological processes including innate andadaptive immunity, inflammation, stress responses, B-celldevelopment, lymphoid organogenesis, cell survival/death,and oncogenesis....
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