title: Inhibition of the NF-κB signaling pathway by the curcumin analog, 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31): anti-inflammatory and anti-cancer properties.
abstract: Nuclear factor kappa B (NF-κB) is a key signaling molecule in the elaboration of the inflammatory response. Data indicate that curcumin, a natural ingredient of the curry spice turmeric, acts as a NF-κB inhibitor and exhibits both anti-inflammatory and anti-cancer properties. Curcumin analogs with enhanced activity on NF-κB and other inflammatory signaling pathways have been developed including the synthetic monoketone compound 3,5-Bis(2-fluorobenzylidene)-4-piperidone (EF24). 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31) is a structurally-related curcumin analog whose potency for NF-κB inhibition has yet to be determined. To examine the activity of EF31 compared to EF24 and curcumin, mouse RAW264.7 macrophages were treated with EF31, EF24, curcumin (1-100 μM) or vehicle (DMSO 1%) for 1h. NF-κB pathway activity was assessed following treatment with lipopolysaccharide (LPS) (1 μg/mL). EF31 (IC(50)~5 μM) exhibited significantly more potent inhibition of LPS-induced NF-κB DNA binding compared to both EF24 (IC(50)~35 μM) and curcumin (IC(50) >50 μM). In addition, EF31 exhibited greater inhibition of NF-κB nuclear translocation as well as the induction of downstream inflammatory mediators including pro-inflammatory cytokine mRNA and protein (tumor necrosis factor-α, interleukin-1β, and interleukin-6). Regarding the mechanism of these effects on NF-κB, EF31 (IC(50)~1.92 μM) exhibited significantly greater inhibition of IκB kinase β compared to EF24 (IC(50)~131 μM). Finally, EF31 demonstrated potent toxicity in NF-κB-dependent cancer cell lines while having minimal and reversible toxicity in RAW264.7 macrophages. These data indicate that EF31 is a more potent inhibitor of NF-κB activity than either EF24 or curcumin while exhibiting both anti-inflammatory and anticancer activities. Thus, EF31 represents a promising curcumin analog for further therapeutic development.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, 1365-B Clifton Road, Atlanta, GA 30322, USA.
authors.forename: Anlys
authors.initials: A
authors.lastname: Olivera
authors.forename: Terry W
authors.initials: TW
authors.lastname: Moore
authors.forename: Fang
authors.initials: F
authors.lastname: Hu
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Brown
authors.forename: Aiming
authors.initials: A
authors.lastname: Sun
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.forename: Younghyoun
authors.initials: Y
authors.lastname: Yoon
authors.forename: Hyunsuk
authors.initials: H
authors.lastname: Shim
authors.forename: Adam I
authors.initials: AI
authors.lastname: Marcus
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Miller
authors.forename: Thaddeus W W
authors.initials: TW
authors.lastname: Pace
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001597:Benzylidene Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010881:Piperidones / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D003474:Curcumin; D004268:DNA-Binding Proteins; D051550:I-kappa B Kinase; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D020929:Mitogen-Activated Protein Kinase Kinases; D016328:NF-kappa B; D010881:Piperidones; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C524042:3,5-bis(2-fluorobenzylidene)piperidin-4-one; C574747:3,5-bis(2-pyridinylmethylidene)-4-piperidone