Received for publication February 11, 2008.
Revised June 23, 2008.
Accepted for publication June 23, 2008.

Inhibition of IKK-NF-B signaling pathway by EF24, a novel monoketone analogue of curcumin

Abstract

The nuclear factor kappa-B (NF-B) 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-B 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-B signaling pathway through direct action on the I-B kinase (IKK). We demonstrate that (i) EF24 induces death of lung, 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-B with an IC₅₀ of 1.3 µM compared with curcumin with an IC₅₀ of 13 µM, (iii) EF24 effectively inhibits TNF-induced I-B 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. Our 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 TNF-induced NF-B signaling by EF24 extends the therapeutic application of EF24 to other NF-B-dependent diseases, including inflammatory diseases such as rheumatoid arthritis.

Key words: Tumor necrosis factor, NFkappaB, Mechanisms of cell killing/apoptosis