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Research Articles: Therapeutics, Targets, and Development

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

Departments of ¹ Pharmacology and ² Phytochemistry, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences; ³ Department of Bioorganic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, People's Republic of China

Requests for reprints: Qiang Yu, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China. Phone: 86-21-5080-1790; Fax: 86-21-5080-0306. E-mail: qyu{at}sibs.ac.cn

Abstract

Nuclear factor-B (NF-B) is critically important for tumor cell survival, growth, angiogenesis, and metastasis. One of the key events in the NF-B signaling is the activation of inhibitor of NF-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-–induced NF-B activation and induced apoptosis of tumor cells. 17-AJB had no effect on binding of tumor necrosis factor- to its receptor or on binding of NF-B to DNA. It inhibited NF-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-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-B-regulated genes. Taken together, our data suggest that 17-AJB is a novel type NF-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. [Mol Cancer Ther 2008;7(6):1523–32]

Grant support: China National Science and Technology 973 grant 2004CB518903 and China National Science Foundation grant 30672481.

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Received 11/27/07; revised 3/19/08; accepted 4/22/08.