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

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.
AuthorsShou-Sheng Yan, Ying Li, Ying Wang, Shen-Si Shen, Yuan Gu, Hong-Bing Wang, Guo-Wei Qin, Qiang Yu
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 6 Pg. 1523-32 (Jun 2008) ISSN: 1535-7163 [Print] United States
PMID18566223 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 17-acetoxyjolkinolide B
  • Antineoplastic Agents
  • Cytokines
  • DNA, Neoplasm
  • Diterpenes
  • I-kappa B Proteins
  • NF-kappa B
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • jolkinolide B
  • Doxorubicin
  • I-kappa B Kinase
Topics
  • Antineoplastic Agents (chemistry, pharmacology)
  • Apoptosis (drug effects)
  • Cell Line, Tumor
  • Cell Nucleus (drug effects, metabolism)
  • Cytokines (pharmacology)
  • DNA, Neoplasm (metabolism)
  • Diterpenes (chemistry, pharmacology, therapeutic use)
  • Doxorubicin (pharmacology)
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • I-kappa B Kinase (antagonists & inhibitors)
  • I-kappa B Proteins (metabolism)
  • NF-kappa B (metabolism)
  • Neoplasms (drug therapy, enzymology, pathology)
  • Phosphorylation (drug effects)
  • Phytotherapy
  • Protein Binding (drug effects)
  • Protein Processing, Post-Translational (drug effects)
  • Protein Transport (drug effects)
  • Receptors, Tumor Necrosis Factor (metabolism)
  • Signal Transduction (drug effects)
  • Tumor Necrosis Factor-alpha (metabolism)

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