PT  - JOURNAL ARTICLE
AU  - Andrea L. Kasinski
AU  - Yuhong Du
AU  - Shala L. Thomas
AU  - Jing Zhao
AU  - Shi-Yong Sun
AU  - Fadlo R. Khuri
AU  - Cun-Yu Wang
AU  - Mamoru Shoji
AU  - Aiming Sun
AU  - James P. Snyder
AU  - Dennis Liotta
AU  - Haian Fu
TI  - Inhibition of IκB Kinase-Nuclear Factor-κB Signaling Pathway by 3,5-Bis(2-flurobenzylidene)piperidin-4-one (EF24), a Novel Monoketone Analog of Curcumin
AID  - 10.1124/mol.108.046201
DP  - 2008 Sep 01
TA  - Molecular Pharmacology
PG  - 654--661
VI  - 74
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/74/3/654.short
4100  - http://molpharm.aspetjournals.org/content/74/3/654.full
SO  - Mol Pharmacol2008 Sep 01; 74
AB  - The nuclear factor-κB (NF-κB) signaling pathway has been targeted for therapeutic applications in a variety of human diseases, includuing cancer. Many 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 3,5-bis(2-flurobenzylidene)piperidin-4-one (EF24) was developed from curcumin and exhibited potent anticancer activity. Here, we report a mechanism by which EF24 potently suppresses the NF-κB signaling pathway through direct action on IκB kinase (IKK). We demonstrate that 1) EF24 induces death of lung, breast, ovarian, and cervical cancer cells, with a potency about 10 times higher than that of curcumin; 2) EF24 rapidly blocks the nuclear translocation of NF-κB, with an IC50 value of 1.3 μM compared with curcumin, with an IC50 value of 13 μM; 3) EF24 effectively inhibits tumor necrosis factor (TNF)-α-induced IκB phosphorylation and degradation, suggesting a role of this compound in targeting IKK; and 4) 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-α-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.