CN112535689A - 路路通内酯在治疗癌症中的应用 - Google Patents
路路通内酯在治疗癌症中的应用 Download PDFInfo
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- CN112535689A CN112535689A CN202011009622.2A CN202011009622A CN112535689A CN 112535689 A CN112535689 A CN 112535689A CN 202011009622 A CN202011009622 A CN 202011009622A CN 112535689 A CN112535689 A CN 112535689A
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Abstract
本发明发现中药路路通中得到的式I所示化合物对Wnt信号通路表现出靶向抑制作用。因此，式I所示化合物能够开发成为全新的Wnt抑制剂以及治疗癌症，特别是大肠癌的药物，从而为开发中药来源的抗肿瘤药物开辟了新的方向。
Description
技术领域
本发明涉及药物领域。具体地说，本发明涉及路路通内酯治疗癌症，特别是大肠癌中的应用。
背景技术
大肠癌位居全球常见的恶性肿瘤第3位，其死亡率位居第4位。近40年来，大肠癌已成为我国第3位常见的恶性肿瘤，占所有恶性肿瘤发病数的10.30％。大肠癌的高发造成了沉重的医疗、经济负担。大肠癌的主要治疗手段为外科手术、借助仪器进行放射治疗以及利用化学药物辅助治疗，然而即使结合这三种方式，也无法保证患者痊愈，并且术后容易复发。且相关研究显示，在一些发达国家结肠癌患者进行根治术后五年存活率小于60％。
因此，本领域急需开发可用于大肠癌的新型靶向治疗药物。
发明内容
本发明的目的在于提供可用于大肠癌的新型靶向治疗药物，从而为大肠癌的治疗提供一种不良反应轻微的方法。
在第一方面，本发明提供路路通活性提取物，或式I所示化合物或其药学上可接受的盐在制备Wnt/β-catenin信号通路抑制剂中的用途：
在一优选例中，所述路路通提取物是含有有效量，特别是治疗有效量的式I所示化合物的提取物。
在一优选例中，所述路路通活性提取物是路路通浸膏、路路通细粉、路路通提取液、路路通浓缩汁、路路通挥发油。
在具体的实施方式中，所述Wnt/β-catenin信号通路抑制剂是Wnt/β-catenin信号通路相关疾病的治疗药物或食品或保健品。
在优选的实施方式中，所述Wnt/β-catenin信号通路相关疾病是其中Wnt/β-catenin信号通路过表达的疾病。
在具体的实施方式中，所述Wnt/β-catenin信号通路相关疾病是癌症、神经系统疾病、骨病、皮肤病、心血管疾病、纤维化疾病及代谢综合征等疾病。
在具体的实施方式中，所述癌症是大肠癌、肝癌、胃癌、肺癌、前列腺癌、胰腺癌、乳腺癌、卵巢癌及骨肉瘤。
在具体的实施方式中，所述癌症是大肠癌。
在优选的实施方式中，所述癌症是原位癌或转移瘤。
在第二方面，本发明提供一种药物组合物，所述药物组合物包含式I所示化合物或其药学上可接受的盐或者含有有效量，特别是治疗有效量的式I所示化合物的路路通活性提取物，以及任选的药学上可接受的赋形剂，
在一优选例中，所述药物组合物是Wnt/β-catenin信号通路抑制剂。
在一优选例中，所述Wnt/β-catenin信号通路抑制剂是Wnt/β-catenin信号通路相关疾病的治疗药物。
在一优选例中，所述Wnt/β-catenin信号通路相关疾病是其中Wnt/β-catenin信号通路过表达的疾病；包括但不限于癌症、神经系统疾病、骨病、皮肤病、心血管疾病、纤维化疾病及代谢综合征等疾病。
在一优选例中，所述癌症是大肠癌、肝癌、胃癌、肺癌、前列腺癌、胰腺癌、乳腺癌、卵巢癌及骨肉瘤；优选大肠癌。
在第三方面，本发明提供一种保健品或食品组合物，所述保健品或食品组合物包含式I所示化合物或其药学上可接受的盐或者含有有效量，特别是治疗有效量的式I所示化合物的路路通活性提取物，以及任选的食品学可接受的赋形剂，
在一优选例中，所述路路通活性提取物是路路通浸膏、路路通细粉、路路通提取液、路路通浓缩汁、路路通挥发油。
在第四方面，本发明提供包含路路通活性提取物或式I所示化合物或其药学上可接受的盐的用于治疗或辅助治疗Wnt/β-catenin信号通路相关疾病的药物组合物或保健品或食品组合物，
在第五方面，本发明提供路路通活性提取物或式I所示化合物或其药学上可接受的盐，用作Wnt/β-catenin信号通路抑制剂。
在一优选例中，所述路路通提取物是含有有效量，特别是治疗有效量的式I所示化合物的提取物。
在一优选例中，所述路路通活性提取物是路路通浸膏、路路通细粉、路路通提取液、路路通浓缩汁、路路通挥发油。
在一优选例中，所述Wnt/β-catenin信号通路抑制剂是Wnt/β-catenin信号通路相关疾病的治疗药物或食品或保健品。
在一优选例中，所述Wnt/β-catenin信号通路相关疾病是其中Wnt/β-catenin信号通路过表达的疾病；包括但不限于癌症、神经系统疾病、骨病、皮肤病、心血管疾病、纤维化疾病及代谢综合征等疾病。
在一优选例中，所述癌症是大肠癌、肝癌、胃癌、肺癌、前列腺癌、胰腺癌、乳腺癌、卵巢癌及骨肉瘤；优选大肠癌。
在一优选例中，所述癌症是原位癌或转移瘤。
在第六方面，本发明提供路路通活性提取物或式I所示化合物或其药学上可接受的盐，用于治疗Wnt/β-catenin信号通路相关疾病。
在一优选例中，所述路路通提取物是含有有效量，特别是治疗有效量的式I所示化合物的提取物。
在一优选例中，所述路路通活性提取物是路路通浸膏、路路通细粉、路路通提取液、路路通浓缩汁、路路通挥发油。
在一优选例中，所述Wnt/β-catenin信号通路抑制剂是Wnt/β-catenin信号通路相关疾病的治疗药物或食品或保健品。
在一优选例中，所述Wnt/β-catenin信号通路相关疾病是其中Wnt/β-catenin信号通路过表达的疾病；包括但不限于癌症、神经系统疾病、骨病、皮肤病、心血管疾病、纤维化疾病及代谢综合征等疾病。
在一优选例中，所述癌症是大肠癌、肝癌、胃癌、肺癌、前列腺癌、胰腺癌、乳腺癌、卵巢癌及骨肉瘤；优选大肠癌。
在一优选例中，所述癌症是原位癌或转移瘤。
在第七方面，本发明提供一种Wnt/β-catenin信号通路相关疾病的治疗方法，其特征在于，将治疗有效量的式I所示化合物或其药学上可接受的盐或路路通活性提取物给予需要治疗所述疾病的患者。
在一优选例中，所述路路通提取物是含有有效量，特别是治疗有效量的式I所示化合物的提取物。
在一优选例中，所述路路通活性提取物是路路通浸膏、路路通细粉、路路通提取液、路路通浓缩汁、路路通挥发油。
在一优选例中，所述Wnt/β-catenin信号通路相关疾病是其中Wnt/β-catenin信号通路过表达的疾病；包括但不限于癌症、神经系统疾病、骨病、皮肤病、心血管疾病、纤维化疾病及代谢综合征等疾病。
在一优选例中，所述癌症是大肠癌、肝癌、胃癌、肺癌、前列腺癌、胰腺癌、乳腺癌、卵巢癌及骨肉瘤；优选大肠癌。
在一优选例中，所述癌症是原位癌或转移瘤。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了式I所示化合物对2种大肠癌细胞、3种非小细胞肺癌细胞、4种胰腺癌细胞、前列腺癌细胞、胃癌细胞、卵巢癌细胞、乳腺癌细胞、肝癌细胞、骨肉瘤细胞克隆形成的影响。
图2显示了式I所示化合物对大肠癌细胞(HCT116)皮下移植瘤的影响；其中图2A显示了式I所示化合物对肿瘤增殖的抑制作用；图2B显示了给药14天后。式I所示化合物对肿瘤体积的影响；图2C显示了移植瘤取材后的图片；图2D显示了式I所示化合物对裸鼠皮下异体移植瘤瘤重的抑制情况。
图3显示了式I所示化合物具有Wnt/β-catenin通路抑制作用；其中图3A显示了式I所示化合物(10、20μM)可以抑制细胞内β-catenin介导的转录活性；图3B显示了斑马鱼胚胎“眼缺失”实验的给药分组和结果；图3C显示了在斑马鱼胚胎6hpf时给予Wnt/β-catenin通路激活剂(6BIO)同时给予式I所示化合物(10μM)和相同体积的DMSO处理24小时的结果；图3D显示了在斑马鱼胚胎6hpf时给予Wnt/β-catenin通路激活剂(6BIO)同时给予式I所示化合物(10μM)和相同体积的DMSO处理66小时的结果(放大倍数：40)。
具体实施方式
发明人经过广泛而深入的研究，出乎意料地发现式I所示化合物对大肠癌和Wnt信号通路表现出靶向抑制作用，从而能够开发成为全新的大肠癌治疗药物和Wnt抑制剂。在此基础上完成了本发明。
术语定义
除非另有定义，本文中使用的所有技术和科学术语具有与所公开的发明所属领域的技术人员的普遍理解相同的含义。为便于理解本发明，对本发明涉及的相关术语作如下定义和解释，但本发明的范围并不限于这些具体的定义。
Wnt/β-catenin信号通路
Wnt信号通路是一个进化上非常保守的蛋白质作用网络。经典Wnt信号通路可简单概括为：1)Wnt分泌因子在细胞膜与受体(Frizzled家族及LRP家族)结合；2)信号通过Dishevelled蛋白将导致细胞质内的β-catenin被APC、Axin、CK1α和GSK3β组成的降解复合物磷酸化，使其能够被β-TRCP E3连接酶介导泛素化降解；3)β-catenin在细胞质内聚集并进入细胞核和TCF/LEF(T细胞因子)形成复合物启动靶基因(比如c-myc)的转录。
该通路最先在胚胎发育中发现，通路的异常抑制或激活将导致胚胎发育缺陷。Wnt信号通路不仅与肿瘤侵袭转移的相关事件如癌细胞的迁移黏附、细胞外基质的降解及肿瘤的血管生成密切相关，而且在调节肿瘤干细胞的自我更新、增殖与分化中发挥重要作用。此外，有研究证实Wnt/β-catenin信号通路与化疗耐药性有关。现在已有大量证据证实Wnt信号通路的异常激活和癌症尤其是大肠癌的发生和发展高度相关。
由于Wnt/β-catenin信号通路在大肠癌发生中的关键作用，过去20多年来世界上有众多研究机构和制药公司致力于Wnt抑制剂的开发研究。不过，迄今为止尚无靶向Wnt/β-catenin信号通路的药物应用于临床，大多数抑制剂处于临床前研究，很少数进入临床1期或2期。Wnt抑制剂开发进展缓慢的原因是大多数抑制剂是靶向Wnt信号通路的上游或中游，但是临床基因组测序表明81.9％的大肠癌组织有APC基因的失活性突变和4.7％β-catenin基因的激活性突变，理论上这些突变将导致β-catenin的降解受阻和异常积聚，Porcupine抑制剂的靶标Wnt蛋白或Tankyrase抑制剂的靶标Axin在通路上处于APC之前，因此对这些异常集聚的β-catenin不能有调控作用。
涉及Wnt/β-catenin信号通路的疾病包括癌症、神经系统疾病、骨病、皮肤病、心血管疾病、纤维化疾病及代谢综合征等疾病；涉及Wnt/β-catenin信号通路的癌症包括但不限于大肠癌、肺癌、前列腺癌、胰腺癌、胃癌、肝癌、乳腺癌、卵巢癌及骨肉瘤；特别是大肠癌。
本发明的化合物及其药学上可接受的盐
在本文中，“本发明的化合物”、“本发明化合物”、“式I所示化合物”、“式I化合物”和“路路通内酯”具有相同的含义，均是指结构如式I所示的化合物
本发明的化合物可以通过各种来源获得，例如可以从中药路路通中分离获得。中药路路通系金缕科植物枫香树的干燥成熟果实，具有有祛风、除湿、通经利尿等功能。式I化合物亦称路路通内酯，其是从路路通中分离得到的一个五环三萜内酯类化合物，分子式为C30H44O4，CAS号：185051-75-6。
在本发明的化合物的基础上，本领域技术人员可以将其制成药学上可接受的盐。例如，可以将本发明的化合物与无机酸或有机酸反应形成常规的可药用盐。所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等，以及所述有机酸包括柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等；或者将本发明的化合物与无机碱形成钠盐、钾盐、钙盐、铝盐或铵盐；或者与有机碱形成甲胺盐、乙胺盐或乙醇胺盐。
路路通活性提取物
本文所述的“路路通活性提取物”具有本领域技术人员常规理解的含义，其是指以路路通为原料，经过物理化学等提取分离过程(例如煎煮法、回流法、浸渍法、渗漉法等)，定向获取和浓集路路通中的路路通内酯而获得的产品。在具体的实施方式中，本文所述的“路路通活性提取物”是指含有有效量，特别是治疗有效量的式I所示化合物的提取物。因此，本文所述的“路路通活性提取物”的获得过程包括富集或浓缩路路通内酯的步骤。
本文所述的“路路通活性提取物”可以采用本领域技术人员已知的任何常规形式，包括但不限于路路通浸膏、路路通细粉、路路通提取液、路路通浓缩汁、路路通挥发油。
本文所述的“治疗有效量”与本领域技术人员常规理解的含义相同；具体地说，是指式I所示化合物的含量能够起到有效治疗某疾病，例如大肠癌的作用。本领域技术人员应理解本文所述的治疗也包括对疾病症状的降低、缓解、减轻等改善作用。
药物组合物或食品或保健品组合物以及相应的剂型
在本发明的化合物，即路路通内酯的基础上，本发明进一步提供了包含该化合物或路路通活性提取物作为活性成分的药物组合物或食品或保健品组合物。所述药物组合物包含该化合物或路路通活性提取物以及药学上可接受的赋形剂，例如药学上可接受的固体或液体赋形剂和/或辅料。所述食品或保健品组合物包含该化合物或路路通活性提取物以及保健品或食品学上可接受的固体或液体赋形剂和/或辅料。
本领域技术人员可以根据实际需要自主确定所述药物组合物或食品或保健品组合物中作为活性成分的本发明化合物的含量。例如，本发明化合物在药物组合物或保健品组合物中的含量通常为0.1-99％。
基于本发明的教导，本领域技术人员可采用常规方法将本发明的药物组合物或食品或保健品组合物可以制成适合给予有此需要的对象或患者，例如人或动物的相应剂型。
本发明化合物或药物组合物可以采用单位剂量形式给药。给药途径可以为胃肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。相应地，所述的药物组合物的剂型可以包括但不限于口服给药制剂、注射给药制剂、皮肤黏膜途径给药制剂。在具体的实施方式中，所述的口服制剂包括片剂、缓释剂、胶囊剂、控释剂、滴丸剂、液体制剂，所述的注射给药剂型包括肌肉注射、静脉注射、静脉滴注。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羧丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、酷酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本发明化合物的每天的合适剂量范围为0.001-400mg/kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
本发明的优点：
1.本发明的式I所示化合物对涉及Wnt/β-catenin信号通路的肿瘤细胞表现出抑制作用，从而为开发中药来源的抗肿瘤药物开辟了新的方向；
2.本发明的式I所示化合物是全新的大肠癌和Wnt抑制剂；
3.本发明的式I所示化合物具有选择性高、来源丰富和分离技术成熟等优点，从而能够成为非常有前景的大肠癌靶向治疗药物。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，例如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring HarborLaboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
本发明所用试剂和原料均市售可得。
实施例
实验例1.式I所示化合物对涉及Wnt/β-catenin信号通路的肿瘤细胞增殖的抑制作用
实验材料：HCT116细胞、HCC827细胞、H460细胞、PC-3细胞、NCL-N87细胞、U-2OS细胞、SK-OV3细胞、HEPG2细胞、MDA-MB-231细胞购自中国科学院细胞库；H1975细胞、ASPC1细胞、PANC1细胞、CFPAC1细胞、BXPC3细胞、SW480细胞购自ATCC；式I所示化合物购自国家标准物质中心；4％多聚甲醛和结晶紫购自碧云天。
实验步骤：细胞接种6孔板(1500个/孔)，温育24h后给予式I所示化合物(0、5、10、20、40μM)。处理14天后，PBS清洗细胞3遍，4％多聚甲醛固定细胞10min，弃去多聚甲醛，PBS清洗细胞3遍，结晶紫染色10min，PBS清洗3遍，观察克隆情况。
结果：式I所示化合物对2种大肠癌细胞、3种非小细胞肺癌细胞、4种胰腺癌细胞、前列腺癌细胞、胃癌细胞、卵巢癌细胞、乳腺癌细胞、肝癌细胞、骨肉瘤细胞、克隆形成均具有抑制作用(如图1所示)。
实验例2.式I所示化合物对大肠癌细胞(HCT116)皮下移植瘤的影响
实验材料：BALB/c裸鼠(四周龄)，雄性，购自上海西普尔-必凯实验动物有限公司。BALB/c裸鼠在SPF级条件下饲养。
溶液配制：水作为溶媒，将式I所示化合物溶解配制成混悬液。
细胞培养：每日观察HCT116细胞状态，当细胞状态良好，即对数生长期时，可消化收集细胞，加入1mL PBS，小心清洗两遍细胞沉淀，将细胞沉淀重悬于PBS中，将细胞密度调整至为5×106个/mL。
裸鼠皮下注射：取待接种的裸鼠，用酒精棉擦拭裸鼠注射部位(右肩胛)，再次吹打细胞悬液防止细胞聚集，用1mL医用注射器将HCT116细胞悬液注射入裸鼠皮下，每只注射1×106个/0.2mL，并且需要特别注意每次注射前均需重悬细胞，避免因细胞不匀而造成成瘤情况出现偏差，并缓慢注入右肩胛皮下，经常观察并记录成瘤情况。瘤体积＝1/2×长度×宽度2。
实验分组：在第7天，皮下移植瘤生长至可触及时，按照肿瘤体积随机分为正常对照组和式I所示化合物组(20mg·kg-1)，每组10只。
除对照组外，每日灌胃式I所示化合物(20mg·kg-1)，正常对照组每日灌胃等量水，连续给药14天后处死小鼠，测量肿瘤体积并称取肿瘤重量。在给药期间每周称重3次。
结果：模型动物口服式I所示化合物(20mg/kg)后，肿瘤体积和重量均能出现一定程度的降低，如图2所示，提示口服关于式I所示化合物可以发挥抗大肠癌的作用。
统计学分析：实验数据以均数±标准差的方式进行表示，两组样本间比较采用t检验，P<0.05为具有统计学意义。
实验例3.式I所示化合物的Wnt/β-catenin通路抑制作用
实验材料：293细胞购自中国科学院细胞库。AB系斑马鱼购自国家斑马鱼资源中心。
TOP/Flash实验步骤：293FT细胞接种96孔白板(20000个/孔)，种板24h后给予转染TOP/Flash质粒及Renilla质粒，6h后给予路路通内酯(0、5、10、20μM)。处理24h后，检测荧光素酶的活性。
斑马鱼胚胎“眼缺失”实验步骤：AB系斑马鱼胚胎6hpf时，根据不同给药组进行分组同时给予相应化合物。其中，模型组给予6BIO(1μM)，式I所示化合物组在给予6BIO(1μM)的同时给予式I所示化合物(10μM)；随后在30hpf和72hpf时观察胚胎状态。
结果显示：式I所示化合物能够抑制细胞内β-catenin介导的转录活性(图3A)；在斑马鱼胚胎发育初期Wnt/β-catenin通路被异常激活会出现“眼缺失现象”，当给予式I所示化合物后，“眼缺失现象”被救援，则可认为该化合物具有Wnt/β-catenin信号通路抑制作用。
本实施例的结果提示式I所示化合物对Wnt信号通路具有抑制作用，并且可以作为新型的大肠癌分子靶向药物。
综合以上实施例，本发明采用大肠癌HCT116细胞皮下移植瘤裸鼠模型，对路路通内酯抗大肠癌药物，尤其是降低皮下移植瘤体积及瘤重作用进行了考察，结果显示，通过口服给药路路通内酯可显著降低小鼠皮下移植瘤体积及瘤重，而各给药组小鼠体重未见明显差异，所以为大肠癌的预防与治疗提供了一种安全、有效、经济的解决办法。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.路路通活性提取物，或式I所示化合物或其药学上可接受的盐在制备Wnt/β-catenin信号通路抑制剂中的用途：
2.如权利要求1所述的用途，其特征在于，所述Wnt/β-catenin信号通路抑制剂是Wnt/β-catenin信号通路相关疾病的治疗药物或食品或保健品。
3.如权利要求2所述的用途，其特征在于，所述Wnt/β-catenin信号通路相关疾病是癌症、神经系统疾病、骨病、皮肤病、心血管疾病、纤维化疾病及代谢综合征等疾病。
4.如权利要求3所述的用途，其特征在于，所述癌症是大肠癌、肝癌、胃癌、肺癌、前列腺癌、胰腺癌、乳腺癌、卵巢癌及骨肉瘤。
5.如权利要求4所述的用途，其特征在于，所述癌症是大肠癌。
6.一种药物组合物，所述药物组合物包含式I所示化合物或其药学上可接受的盐或者含有有效量，特别是治疗有效量的式I所示化合物的路路通活性提取物，以及任选的药学上可接受的赋形剂，
7.一种保健品或食品组合物，所述保健品或食品组合物包含式I所示化合物或其药学上可接受的盐或者含有有效量，特别是治疗有效量的式I所示化合物的路路通活性提取物，以及任选的食品学可接受的赋形剂，
8.包含路路通活性提取物或式I所示化合物或其药学上可接受的盐的用于治疗或辅助治疗Wnt/β-catenin信号通路相关疾病的药物组合物或保健品或食品组合物，
9.路路通活性提取物或式I所示化合物或其药学上可接受的盐，用作Wnt/β-catenin信号通路抑制剂。
10.路路通活性提取物或式I所示化合物或其药学上可接受的盐，用于治疗Wnt/β-catenin信号通路相关疾病。
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