1. 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
- Author
-
Aiming Sun, Anlys Olivera, Andrew H. Miller, Thaddeus W.W. Pace, Adam I. Marcus, Fang Hu, Dennis C. Liotta, Andrew Brown, Hyunsuk Shim, Terry W. Moore, Younghyoun Yoon, and James P. Snyder
- Subjects
Lipopolysaccharides ,Curcumin ,Cell Survival ,medicine.drug_class ,Interleukin-1beta ,Immunology ,Anti-Inflammatory Agents ,Antineoplastic Agents ,IκB kinase ,Pharmacology ,Benzylidene Compounds ,Article ,Anti-inflammatory ,Mice ,chemistry.chemical_compound ,Cell Line, Tumor ,medicine ,Animals ,Immunology and Allergy ,Phosphorylation ,Piperidones ,Cell Proliferation ,Mitogen-Activated Protein Kinase Kinases ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Chemistry ,Cell growth ,Macrophages ,NF-kappa B ,NF-κB ,I-kappa B Kinase ,XIAP ,DNA-Binding Proteins ,Protein Transport ,Biochemistry ,Tumor necrosis factor alpha ,Signal transduction ,Signal Transduction - 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 analogues with enhanced activity on the NF-κB and other inflammatory signaling pathways have been developed including the synthetic monoketone compound termed 3,5-Bis(2-fluorobenzylidene)-4-piperidone (EF24). 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31) is a structurally-related curcumin analogue 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 (1–100µM) or vehicle (DMSO 1%) for 1 hour. NF-κB pathway activity was assessed following treatment with lipopolysaccharide (LPS) (1µg/mL). EF31 (IC50 ~5µM) exhibited significantly more potent inhibition of LPS-induced NF-κB DNA binding compared to both EF24 (IC50~35µM) and curcumin (IC50 >50µM). In addition, EF31 exhibited significantly 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 activity, EF31 (IC50~1.92µM) exhibited significantly greater inhibition of IκB kinase β compared to EF24 (IC50~131µM). 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 analogue for further therapeutic development.
- Published
- 2012