title: Inhibition of IkappaB kinase-nuclear factor-kappaB signaling pathway by 3,5-bis(2-flurobenzylidene)piperidin-4-one (EF24), a novel monoketone analog of curcumin.
abstract: The nuclear factor-kappaB (NF-kappaB) 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-kappaB 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-kappaB signaling pathway through direct action on IkappaB 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-kappaB, with an IC(50) value of 1.3 microM compared with curcumin, with an IC(50) value of 13 microM; 3) EF24 effectively inhibits tumor necrosis factor (TNF)-alpha-induced IkappaB 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-alpha-induced NF-kappaB signaling by EF24 extends the therapeutic application of EF24 to other NF-kappaB-dependent diseases, including inflammatory diseases such as rheumatoid arthritis.
authors.affiliation: Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Kasinski
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Du
authors.forename: Shala L
authors.initials: SL
authors.lastname: Thomas
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Shi-Yong
authors.initials: SY
authors.lastname: Sun
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: Cun-Yu
authors.initials: CY
authors.lastname: Wang
authors.forename: Mamoru
authors.initials: M
authors.lastname: Shoji
authors.forename: Aiming
authors.initials: A
authors.lastname: Sun
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.forename: Dennis
authors.initials: D
authors.lastname: Liotta
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
mesh_terms: D001597:Benzylidene Compounds / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003474:Curcumin / Q000031:analogs & derivatives* / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010766:Phosphorylation / Q000187:drug effects; D010881:Piperidones / Q000737:chemistry / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C524042:3,5-bis(2-fluorobenzylidene)piperidin-4-one; D001597:Benzylidene Compounds; D016328:NF-kappa B; D010881:Piperidones; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase; D003474:Curcumin