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

Anlys Olivera, Terry W. Moore, Fang Hu, Andrew P. Brown, Aiming Sun, Dennis C. Liotta, James P. Snyder, Younghyoun Yoon, Hyunsuk Shim, Adam I. Marcus, Andrew H. Miller, Thaddeus W.W. Pace

Research output: Contribution to journalArticle

99 Scopus citations

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 1 h. 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.

Original languageEnglish (US)
Pages (from-to)368-377
Number of pages10
JournalInternational immunopharmacology
Volume12
Issue number2
DOIs
StatePublished - Feb 1 2012
Externally publishedYes

Keywords

  • Anti-cancer
  • Curcumin
  • Inflammation
  • Macrophages
  • NF-κB

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology

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