James P. Snyder

Abstract B106: Inhibition of IKKb and NFκB signaling by a novel curcumin analogue

B106 The nuclear factor kappa-B (NF-κB) signaling pathway has been targeted for therapeutic applications in a variety of human diseases such as cancer. A number of naturally occurring substances including curcumin have been investigated for their actions on the NF-κB pathway because of their significant therapeutic potential and safety profile. A synthetic monoketone compound termed EF24 was developed from curcumin and exhibited a potent anticancer activity. Here we report a mechanism by which EF24 potently suppresses the NF-κB signaling pathway in both head and neck cancer and lung cancer cell lines through direct action on the I-κB kinase (IKK). We demonstrate that (i) EF24 induces death of lung, head and neck, breast, ovarian, and cervical cancer cells with a potency about 10 times higher than curcumin does, (ii) EF24 rapidly blocks the nuclear translocation of NF-κB with an IC50 of 1.3 μM compared with curcumin with an IC50 of 13 μM, (iii) EF24 effectively inhibits TNFα-induced I-κB phosphorylation and degradation, suggesting a role of this compound in targeting IKK, and (iv) EF24 indeed directly inhibits the catalytic activity of IKK in an in vitro reconstituted system. This study identifies IKK as an effective target for EF24 and provides a molecular explanation for a superior activity of EF24 over curcumin. The effective inhibition of TNFα-induced NF-κB signaling by EF24 extends the therapeutic application of EF24 to other NF-κB-dependent diseases, including inflammatory diseases such as rheumatoid arthritis. Citation Information: Cancer Prev Res 2008;1(7 Suppl):B106.