Inhibition of the NF-¦ÊB signaling pathway by the curcumin analog, 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31): Anti-inflammatory and anti-cancer properties

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• 作者：Anlys Olivera^a ; ^{aolive3@emory.edu} ; Terry W. Moore^b ; ^c ; ^{terry.moore@emory.edu} ; Fang Hu^a ; ^{fhu@emory.edu} ; Andrew P. Brown^c ; ^{andrew.brown@emory.edu} ; Aiming Sun^b ; ^c ; ^e ; ^{asun2@emory.edu} ; Dennis C. Liotta^b ; ^c ; ^e ; ^{dliotta@emory.edu} ; James P. Snyder^b ; ^c ; ^{jsnyder@emory.edu} ; Younghyoun Yoon^d ; ^e ; ^{yyoon2@emory.edu} ; Hyunsuk Shim^d ; ^e ; ^{hshim@emory.edu} ; Adam I. Marcus^e ; ^f ; ^{aimarcu@emory.edu} ; Andrew H. Miller^a ; ^e ; ^{amill02@emory.edu} ; Thaddeus W.W. Pace^a ; ^e ; ^{twpace@emory.edu}
• 关键词：A2780 ; human ovarian carcinoma cells ; AP-1 ; activator protein 1 ; ATF-2 ; activating transcription factor-2 ; ANOVA ; analysis of variance ; CD ; cluster of differentiation ; DMSO ; Dimethyl sulfoxide ; DMEM ; Dulbecco's modified Eagle's medium ; EF24 ; 3 ; 5-Bis(2-flu
• 刊名：International Immunopharmacology
• 出版年：2012
• 出版时间：February 2012
• 年：2012
• 卷：12
• 期：2
• 页码：368-377
• 全文大小：1296 K

文摘

Nuclear factor kappa B (NF-¦ÊB) 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-¦ÊB inhibitor and exhibits both anti-inflammatory and anti-cancer properties. Curcumin analogs with enhanced activity on NF-¦ÊB 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-¦ÊB 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 ¦ÌM) or vehicle (DMSO 1 % ) for 1 h. NF-¦ÊB pathway activity was assessed following treatment with lipopolysaccharide (LPS) (1 ¦Ìg/mL). EF31 (IC₅₀ ~ 5 ¦ÌM) exhibited significantly more potent inhibition of LPS-induced NF-¦ÊB DNA binding compared to both EF24 (IC₅₀ ~ 35 ¦ÌM) and curcumin (IC₅₀ > 50 ¦ÌM). In addition, EF31 exhibited greater inhibition of NF-¦ÊB nuclear translocation as well as the induction of downstream inflammatory mediators including pro-inflammatory cytokine mRNA and protein (tumor necrosis factor-¦Á, interleukin-1¦Â, and interleukin-6). Regarding the mechanism of these effects on NF-¦ÊB, EF31 (IC₅₀ ~ 1.92 ¦ÌM) exhibited significantly greater inhibition of I¦ÊB kinase ¦Â compared to EF24 (IC₅₀ ~ 131 ¦ÌM). Finally, EF31 demonstrated potent toxicity in NF-¦ÊB-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-¦ÊB 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.