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Address correspondence to: Dr. Haian Fu, Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Rd., Atlanta, GA 30322. E-mail: hfu@emory.edu

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Research Funding:

National Institute of Dental and Craniofacial Research : NIDCR

This work was supported in part by National Institutes of Health Grants R01-GM53165 (to H.F.)., P01-CA116676 (to F.R.K., H.F., and S.S.), P50-CA128613 (to S.S., F.R.K., J.P.S., and H.F.), and Emory University Research Committee. F.R.K., S.S., and H.F. are Georgia Cancer Coalition Distinguished Scholars. H.F. is a Georgia Research Alliance Distinguished Investigator. Y.D. is Emory Drug Development and Pharmacogenomics Academy Fellow and recipient of Emory Head and Neck Cancer Specialized Programs of Research Excellence P50-CA128613 career development award. S.L.T. is a recipient of American Association for the Advancement of Science/Packard Fellowship and Emory Facilitating Academic Careers in Engineering and Science program fellow.

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

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Journal Title:

Molecular Pharmacology

Volume:

Volume 74, Number 3

Publisher:

, Pages 654-661

Type of Work:

Article | Post-print: After Peer Review

Abstract:

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.

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© 2008 The American Society for Pharmacology and Experimental Therapeutics

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