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.
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.
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DOI：
10.1016/j.intimp.2011.12.009
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发表时间：
2012-02
影响因子：
5.6
通讯作者：
Pace TW
中科院分区：
文献类型：
--
作者：
Olivera A;Moore TW;Hu F;Brown AP;Sun A;Liotta DC;Snyder JP;Yoon Y;Shim H;Marcus AI;Miller AH;Pace TW
核因子-κ B（NF-κB）是炎症反应的关键信号分子。数据表明，姜黄素，咖喱香料姜黄的天然成分，作为NF-κB抑制剂，并表现出抗炎和抗癌特性。已经开发了对NF-κB和其他炎症信号传导途径具有增强活性的姜黄素类似物，包括称为3，5-双（2-氟亚苄基）-4-哌啶酮（EF 24）的合成单酮化合物。3，5-双（2-吡啶亚甲基）-4-哌啶酮（EF 31）是一种结构相关的姜黄素类似物，其抑制NF-κB的效力尚未确定。为了检查EF 31与EF 24和姜黄素相比的活性，将小鼠RAW 264.7巨噬细胞用EF 31、EF 24、姜黄素（1-100μM）或媒介物（DMSO 1%）处理1小时。用脂多糖（LPS）（1µg/mL）处理后，评估NF-κB通路活性。与EF 24（IC 50 ~35µ M）和姜黄素（IC 50>50µM）相比，EF 31（IC 50 ~5µ M）对LPS诱导的NF-κB DNA结合的抑制作用显著更强。此外，EF 31对NF-κB核转位的抑制作用以及对下游炎症介质（包括促炎细胞因子mRNA和蛋白质（肿瘤坏死因子-α、白细胞介素-1 β和白细胞介素-6））的诱导作用显著增强。关于这些对NF-κB活性影响的机制，与EF 24（IC 50 ~131µM）相比，EF 31（IC 50 ~1.92µM）对IκB激酶β的抑制作用显著更强。最后，EF 31在NF-κ B依赖性癌细胞系中表现出强毒性，而在RAW 264.7巨噬细胞中具有最小且可逆的毒性。这些数据表明，EF 31是比EF 24或姜黄素更有效的NF-κB活性抑制剂，同时表现出抗炎和抗癌活性。因此，EF 31代表了用于进一步治疗开发的有前景的姜黄素类似物。
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.
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影响因子：
2.3
作者：
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