中草药  2014, Vol. 45 Issue (19): 2855-2863
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引用本文doi: 10.7501/j.issn.0253-2670.2014.19.024
程齐来, 李映辰, 李洪亮, 黄志勤, 刘塔斯. 植物源核转录因子-κB抑制剂研究进展[J]. 中草药, 2014, 45(19): 2855-2863.
CHENG Qi-lai, LI Ying-chen, LI Hong-liang, HUANG Zhi-qin, LIU Ta-si. Advances in studies on inhibitors of NF-κB derived from plant[J]. Chinese Traditional and Herbal Drugs, 2014, 45(19): 2855-2863.
植物源核转录因子-κB抑制剂研究进展
程齐来1,2, 李映辰1,李洪亮2, 黄志勤2, 刘塔斯1     
1. 湖南中医药大学, 湖南 长沙 410208;
2. 赣南医学院药学院, 江西 赣州 341000
收稿日期: 2014-5-5;
基金项目： 国家自然科学基金资助项目（81360627）;江西省自然科学基金资助项目（20132BAB205088）
作者简介：程齐来（1978—），男，在读博士，副教授，从事中药资源开发与利用研究。Tel: 18970786158 E-mail: cql_57@126.com
通讯作者：刘塔斯（1952—），女，博士生导师，教授，从事中药资源开发与利用研究。Tel: 13036794420 E-mail: liutasi@126.com
摘要：核转录因子-κB（NF-κB）控制500个以上基因的表达，是炎症、细胞增殖与凋亡的下游调节中心，其在人类健康的诸多方面（包括先天与后天性免疫的发生与发展）起着重要的作用。NF-κB的降解与许多疾病如癌症、慢性炎症有关。尽管有大量文献报道了源自天然或人工合成的NF-κB抑制剂，然而这些调节子并不能充分地针对治疗目的，因此寻找有医疗用途、副作用小、高效、特异的NF-κB抑制剂仍然是当前研究的重点。来源于植物的天然产物及其衍生物主要有酚类、萜类、生物碱类、木脂素类等物质，近年来有越来越多的新化合物被分离与鉴定，并具有良好的药用价值。开发治疗癌症和免疫失调等与NF-κB相关疾病的有效、安全的药物，植物源天然产物是具有前景的先导化合物来源。针对近年来出现的植物源NF-κB抑制剂进行简要的概述。
关键词： 核转录因子-κB     核转录因子-κB抑制剂     癌症     炎症     天然产物    
Advances in studies on inhibitors of NF-κB derived from plant
CHENG Qi-lai1,2, LI Ying-chen1, LI Hong-liang2, HUANG Zhi-qin2, LIU Ta-si1    
1. Hunan University of Chinese Medicine, Changsha 410208, China;
2. School of Pharmacy, Gannan Medical University, Ganzhou 341000, China
Abstract: Plant secondary metabolites (natural products) have been a source for many medicines. Their functions in plants often remain unknown, but in recent years there are more and more new compounds isolated and identified and their medicinal potentials are investigated. The major classes of plant natural products and various derivatives thereof are: phenolics, terpenoids, alkaloids, and lignans. The major transcription factor, nuclear factor-κB (NF-κB) is a central downstream regulator of inflammation, cell proliferation, and apoptosis which controls the expression of more than 500 genes. It plays an essential role in several aspects of human health including the development of innate and adaptive immunity. The degradation of NF-κB is associated with many ailments including cancer and chronic inflammatory diseases. In spite of a vast literature describing NF-κB inhibitors from many natural or synthetic sources, such modulators have not been fully tapped for therapeutic purposes and the search for effective and specific inhibitors for therapeutic use with fewer side effects is still relevant and ongoing. Plant-derived phytochemicals are promising the lead compounds to develop potent and safe inhibitors for cancer and inflammatory disorders driven by NF-κB. The recent knowledge on the plant-derived phytochemicals and their major NF-κB molecular targets are briefly reviewed in this paper.
Key words: nuclear factor-κB     inhibitors of NF-κB     cancer     inflammation     natural product    

核转录因子-κB（NF-κB）家族调控数百个与多种细胞过程有关的基因的表达，如细胞增殖、分化和死亡以及先天与后天的免疫反应等。在过去10年间涉及NF-κB的研究领域飞速发展，尽管从发现NF-κB至今仅28年时间，它也就是人类已发现的近2 000个转录因子之一，但是在PubMed数据库中所列的主题与转录因子相关的研究性论文中，约有十分之一与NF-κB相关。在许多癌细胞中NF-κB具有持续活性，牵涉到很多信号通路，极有可能要联网激活[1]。不同的刺激物和高度网络化的通路能调节NF-κB，因此建议在抗癌及抗炎治疗中采用多靶点途径。植物来源化合物以NF-κB通路多个环节为靶点，正成为防治癌症有前景的药物。NF-κB在炎症、免疫失调和癌症以及分子机制尚未明确的相关疾病（如疲劳、抑郁、失眠等）的发生发展过程中占主要作用[2]。因此，NF-κB被认为是合成和天然新药治疗性调整的一个重要靶点。 1NF-kB信号通路

1986年，Sen等[3]首次从鼠B淋巴细胞核提取物中，发现一种能与免疫球蛋白κ轻链基因增强子κB序列（GGGACTTTCC）特异结合，调节其基因表达的核蛋白因子，称之为核转录因子-κB（NF-κB）。随后大量的研究又陆续发现了NF-κB家族的其他成员，其构成亚基分别是NF-κB1（P50）、NF-κB2（P52）、P65（RelA）、c-Rel（Rel）、RelB等，因这些亚基的N-末端均连有约300个氨基酸残基的Rel& lt; span style='font-family:宋体'>同源区（rel homology domain，RHD），故统称为NF-κB/Rel蛋白家族。其RHD内含DNA结合区、二聚体化区和核定位序列，分别具有与DNA κB序列结合，与同源或异源亚基二聚体化以及与NF-κB抑制蛋白（IκB）家族成员相互作用并携带核定位信号（NLS），参与活化的NF-κB由细胞质向细胞核的迅速移动等功能。

最基本的NF-κB信号通路，包括受体和受体近端信号衔接蛋白、IκB激酶复合物、IκB蛋白和NF-κB二聚体。当细胞受到各种胞内外刺激后，IκB激酶被激活，从而导致IκB蛋白磷酸化、泛素化，进而IκB蛋白被降解，NF-κB二聚体得到释放。然后NF-κB二聚体通过各种翻译后的修饰作用而被进一步激活，并转移到细胞核中。在细胞核中，其与目的基因结合，以促进目的基因的转录。NF-κB的经典信号通路和非经典信号通路的主要区别在于：在NF-κB经典信号通路中，IκB蛋白的降解使NF-κB二聚体得到释放；而在NF-κB非经典信号通路中，则是通过p100到p52的加工处理，使信号通路激活。众多刺激能诱导经典NF-κB活性，NF-κB典型的诱导剂包括细胞因子肿瘤坏死因子（TNF）、白细胞介素-1（IL-1）、病毒和细菌产物脂多糖（LPS，可以诱发toll样受体及细胞应激，如DNA损伤、活性氧、缺氧）。大多数诱导物聚集在IκB激酶α，β（IKKα，β）二聚体。非经典途径通过受体信号和IKKα激活，α聚体的活化能使蛋白前体处理形成有活性的p50/p52聚体[4]。这个通路对次级淋巴器官的发展是非常有必要的。大多数NF-κB抑制剂影响经典通路，而有一些抑制剂同时影响2条通路。

正常生理状态下，一种NF-κB的反应就是自动自我约束，通过负反馈环的诱导，包括伴随下调信号通路导致IKK活化的蛋白表达的IκBs转录，如A20。然而在癌症与慢性炎症疾病发生时，NF-κB活性调节失调，这种情况发生要么是通过导致IKK-NF-κB信号高水平的突变，要么是通过对激活NF-κB的外部刺激物的持续暴露，如系统或组织微环境细胞激素的释放。与其他信号通路如磷脂酰肌醇3-激酶（PI3K）相互影响会导致汇集于IKK的蛋白激酶B（AKT）及丝裂原活化蛋白激酶（MAPK）的信号活化，而且肿瘤抑制蛋白如p53为NF-κB活性调节提供了一个重要的机制。这些通路联合确定了NF-κB正常的生理作用，同时也决定了在疾病、肿瘤、抗细胞凋亡、对化疗的反应及慢性炎症中NF-κB的相关生理功能[5]。 2 植物源NF-κB抑制剂

一些在临床上的常用药物最初是从植物提取物中发现的，如阿司匹林源自柳树皮，紫杉醇来自于太平洋紫杉以及二甲双胍源自法国紫丁香等。植物作为药源还有很大的潜力，其中有成千上万还未被鉴定的化合物可能被开发成新药，或作为新药有机合成与修饰的先导结构。

目前有关抑制或调控NF-κB的天然产物已有一些报道，本文主要针对源自植物的天然产物进行概述。对近年来发现的植物源NF-κB抑制剂的归纳总结见表 1。表 1中共列举了59个化合物，其中酚类22个（1～22）、醌类5个（23～27）、萜类及其衍生物21个（28～48）、生物碱7个（49～55），其他类化合物4个（56～59）。许多植物的次生代谢产物如酚类、萜类和生物碱具有重要的药理作用，包括抗炎与抗癌作用。它们在植物界有限的分类群中呈差异性分布。表 1中所列的59个化合物中，只有菊科的不同种有5个化合物，21个科有1个化合物，3个科有2个化合物，6个科有3个化合物，2个科有4个化合物。大部分的天然产物对NF-κB的表达有抑制效果。

表 1 植物源NF-κB抑制剂 Table 1 NF-κB inhibitors of plant source

表 1中所列的化合物大部分是酚类和萜类（约占37%），NF-κB不同途径的抑制剂中醌类与生物碱也颇具代表性，还有一些其他类型的化合物如苯酞、环己烷、糖苷、木脂素。这些活性成分存在于植物的不同器官（根、块茎、根茎、叶、茎、树皮、果实和种子）内，同一植物的一些器官（非所有）可能含有相同的活性成分，植物的采收季节也会影响它们的生物活性。

其中一些化合物已经得到较全面的研究，并且它们的许多作用靶点和作用机制也得到了广泛地阐述，如姜黄素、番茄红素、小白菊内酯等。对影响NF-κB活性的化合物的作用方式和特异性的研究将决定一个化合物是否具多靶点或特异性，这2种类型的化合物在临床治疗方面可以单用或与其他药物联合使用。另外，不同的次生代谢物可以调控相同的靶点，如醌类和多种萜类，都表现出通过cystein38抑制p65，通过cystein179抑制IKK。 3 调控靶点

Gupta等[65]已经阐述了大量天然产物对NF-κB信号通路不同水平地调节，表 1中近几年的植物次生代谢产物的调控靶点分类如下。 3.1 上游信号抑制

通过LPS诱导的4型Toll样受体（TLR-4）调节（甘草素、亚丁基苯酞）；活性氧调节（鼠尾草酸、雷公藤红素、大黄素、木犀草素、4,5,7-三羟黄烷酮、迷迭香酸、芝麻素）；通过抑制TNF-α信号（青蒿素、山楂酸、雷公藤甲素、青藤碱、黄睡莲提取物）；通过调节ERK1/2（β-石竹烯）。 3.2 IKK调节

通过直接结合Cys179（白皮杉醇、蟛蜞菊内酯、黄腐醇、蒽贝素、青蒿素、七叶皂素、山楂酸、小白菊内酯、雷公藤甲素、防己碱、头花千金藤碱）。 3.3 IκB调节

通过IκB磷酰化和降解及IκB核易位（鼠尾草酸、白藜芦醇、蒽贝素、青蒿素、巴兰精、雷公藤红素、巴尔喀蒿烯内酯、雷公藤甲素、小檗胺、小檗碱）。 3.4 NF-κB调控

通过调节Cys38（白花丹素、百里香醌、巴兰精、小白菊内酯、胡黄连素、倍半萜内酯）；通过NF-κB磷酰化和乙酰化（鼠尾草酸、姜黄色素、雷公藤红素、薯蓣皂素、雷公藤甲素）。 3.5 NF-κB核易位（转运）

鼠尾草酸、鼠尾草酚、拓木黄酮B、小檗胺。 3.6 影响NF-κB DNA结合活性

豆蔻明、大黄素、巴兰精、番茄红素、印苦楝内酯、雷公藤甲素、防己碱。 3.7 影响NF-κB转录活性

鼠尾草酚、拓木黄酮B、咖啡豆醇、小白菊内酯、北豆根碱、三烯生育酚、那可汀、硫秋水仙苷。 3.8 其他

抑制细胞存活（羽扇豆醇）；诱导细胞凋亡和凋亡蛋白酶活化（迷迭香酸、NUP）；抗癌药物恶性细胞增敏剂（DEDC、NUP）。 4 结语与展望

近些年来有关NF-κB构效关系的研究取得了一些显著的进展，然而把NF-κB作为治疗靶点应用于临床药物开发方面仍方兴未艾。因此，目前研究人员面临的一个主要挑战是开发针对治疗不同疾病的NF-κB抑制剂，这些都是基于它们各自靶向特异通路或细胞的能力，选择性靶向该通路核心组分的有效NF-κB抑制剂的开发需要建立剂量与靶点抑制之间的联系。治疗干预的重点包括IKK靶向上调、IKK活化、IκB降解、NF-κB修饰、NF-κB DNA结合及其转录活性的调控。NF-κB通路治疗潜力的充分实现取决于对其调控复杂性、细胞类型及刺激物（调控成分）的进一步研究。

植物次生代谢物是新药开发必不可少的来源之一。植物中集合了各类复杂的生物分子（次生代谢产物），它们一方面能够精确地选择作用靶点，另一方面能够发挥多向性、多靶点的生物学效应。从植物中寻找有医疗用途、副作用小、高效、特异的NF-κB抑制剂仍然是当前研究的重点，将具有广阔的开发前景。

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