CN111973743A - Rna结合蛋白zcchc4的靶向药物的应用 - Google Patents
Rna结合蛋白zcchc4的靶向药物的应用 Download PDFInfo
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- CN111973743A CN111973743A CN201910432889.3A CN201910432889A CN111973743A CN 111973743 A CN111973743 A CN 111973743A CN 201910432889 A CN201910432889 A CN 201910432889A CN 111973743 A CN111973743 A CN 111973743A
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- zcchc4
- interfering rna
- coding sequence
- antisense oligonucleotide
- tumor
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Abstract
本发明涉及生物技术和医学领域,具体是RNA结合蛋白ZCCHC4靶向药物的应用,具体涉及ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸在制备用于抗肿瘤的药物中的用途,且进一步涉及上述物质在制备化疗药物增敏剂中的用途以及相应的药物组合物。本发明可用于抑制肿瘤发生发展,提高化疗药物对肿瘤的疗效,具有广泛的应用前景。
Description
技术领域
本发明涉及生物技术和医学领域,具体地说,是一种RNA结合蛋白ZCCHC4的靶向药物在抗肿瘤,促进肿瘤化疗疗效中的效应、作用机制、实施方法和用途。
背景技术
肝癌是男性第五大常见肿瘤类型,女性第七大常见肿瘤类型(Bray,F.等,International journal of cancer.2013;132:1133-1145.),70%-90%的原发性肝癌是肝细胞性肝癌(hepatocellular carcinoma,HCC)。中国是肝癌大国,2015年的新发病例和死亡病例分别是466100例和422100例,在全球病例中占了超过半数。在中国,肝癌患者的生存率较差,年龄标准化后的五年生存率仅为10.1%,造成生存率低下的主要原因是缺乏有效的早期诊断方法,大多数肝癌患者被确诊时已是癌症晚期阶段(Fu,J.等,Cancerletters.2018;412:283-288.)。由于肝癌风险因素的多样性、个体对环境或遗传因素的敏感性差异、肿瘤形态的多样性、以及信号通路紊乱和肿瘤微环境的差异性,肝癌是一种异质性极高的疾病。肝癌异质性限制了肝癌的早期发现以及特异性治疗靶标的选择(Schork,N.J.,Nature.2015;520:609-611;Cyranoski,D.,Nature.2016;529:9-10.)。此外,由于晚期肝癌恶性程度高、肿瘤进展快,同时现有化疗药物的毒性较高、选择性较低,导致晚期肝癌的治疗效果不佳(Fu,J.等,Cancer letters.2018;412:283-288.)。因此,深入理解肝癌发生发展机制,发现抑制肝癌发生发展的新靶点迫在眉睫。
转录后修饰是重要的表观调控机制,参与多种生命活动,如多能干细胞分化(Ye,J.等,Cell stem cell.2014;15:271-280)、精子形成(Lin,Z.等,Biochimica etbiophysica acta.Gene regulatory mechanisms.2018.)、肿瘤发生发展(Qi,L.等,Cancerresearch.2014;74:1301-1306.)以及心脏纤维化、先天性巨结肠症、类风湿性关节炎、系统性硬化症、系统性红斑狼疮、颞叶癫痫、自闭症、肺动脉高压等疾病形成过程(Piletic,K.等,Archives of toxicology.2016;90:2405-2419.)。转录后修饰包括RNA剪接、编辑、3’多聚腺苷酸化、5’加帽、RNA稳定性、RNA定位、RNA修饰、RNA翻译、RNA降解等RNA代谢过程(Dreyfuss,G.等,Molecular cell biology.2002;3:195-205;Mitchell,S.F.等,Molecular cell.2014;54:547-558.)。非编码RNA和RNA结合蛋白(RNA binding protein,RBP)是转录后修饰的重要参与者,许多RNA都与RNA结合蛋白结合在一起形成核糖核蛋白复合物(ribonucleoprotein complex,RNP)发挥作用,RNP结构或功能缺陷会导致疾病发生,包括肿瘤形成(Mihailovic,M.K.等,Biochemistry.2017;56:1367-1382;Cooper,T.A.等,Cell.2009;136:777-793;Pereira,B.等,Trends in cancer.2017;3:506-528.)。
肿瘤中RBP表达异常和功能异常已被广泛报道。许多文献提供免疫组化的证据指出RBP在癌组织中的表达与癌旁组织存在差异,且与病人的预后相关(Patry,C.等,Cancerresearch.2003;63:7679-7688;Busa,R.等,Oncogene.2007;26:4372-4382;Yang,G.等,Gastroenterology.2010;138:231-240;King,C.E.等,Cancer research.2011;71:4260-4268;Ortiz-Zapater,E.等,Nature medicine 2011;18:83-90;Janiszewska,M.等,Genes&development.2012;26:1926-1944.),对TCGA(the Cancer Genome Atlas)数据库进行生物信息分析,发现在不同肿瘤中癌与癌旁的RBP表达差异是一致的(Wang,J.等,BMCgenomics.2015;16Suppl:S5;Kechavarzi,B.等,Genome biology.2014;15:R14;Sebestyen,E.等,Genome research.2016;26:732-744.)。肿瘤中造成RBP功能异常的因素包括基因组改变(Sebestyen,E.等,Genome research.2016;26:732-744.)、转录和转录后修饰调控(David,C.J.等,Nature.2010;463:364-368;Jiang,Y.等,The Journal ofbiological chemistry.2014;289:3164-3175.)以及翻译后修饰(Babic,I.等,Oncogene.2004;23:3781-3789;Nakka,K.K.等,Proceedings of the National Academyof Sciences of the United States of America.2015;112:E3374-3383.)。RBP能够通过调节RNA的成熟、翻译、定位和稳定性影响肿瘤的发生发展,还能通过结合DNA影响肿瘤发生发展。由于RBP在转录后修饰中的重要作用,即使是微小的改变也能造成重大的影响。RBP功能的异常常常能够影响多个肿瘤标志性特征,如肿瘤增殖、肿瘤转移、肿瘤死亡抵抗、肿瘤代谢紊乱、肿瘤免疫逃逸、肿瘤基因组不稳定性等。RBP功能复杂,既有促癌的,也有抑癌的。如KHSRP在肝癌和肺癌中是促癌基因(Malz,M.等,Hepatology.2009;50:1130-1139.),但在乳腺癌中是抑癌基因(Puppo,M.等,Cell reports.2016;16:967-978.),而同一家族成员中LARP6在乳腺癌中是促癌基因(Stavraka,C.等,Biomolecules.2015;5:2701-2722.),而LARP7在乳腺癌中是抑癌基因(Ji,X.等,eLife.2014;3:e02907.)。
目前,已有部分RBP进入肿瘤治疗相关临床试验。RBP可以用来指导临床肿瘤患者用药和预后,如Tatarian T团队发现细胞质HuR(cHuR)可以作为胰腺癌患者化疗反应的预测标志物(Tatarian,T.等,Annals of surgery.2018;267:364-369.)。RBP也可以直接作为临床肿瘤患者的用药靶点,如靶向eIF4E的药物与伊立替康联合使用,能提高结直肠癌的治疗效果(Duffy,A.G.等,International journal of cancer.2016;139:1648-1657.)。这些临床试验为RBP的临床应用打开了一扇窗。
发明内容
基于上述背景,本发明探索肝癌中是否存在可以用作治疗靶标的RBP。本发明研究发现,ZCCHC4参与调控宿主抗乙型肝炎病毒免疫反应,提示其在肝癌中发挥作用。ZCCHC4是包含CCHC锌指结构域的RNA结合蛋白(RBP),关于这个蛋白的功能研究目前知之甚少。本发明拟研究ZCCHC4在肝癌发生发展中的作用及机制,以期为肝癌的治疗寻找新的靶标,为临床治疗提供参考。
本发明的目的在于提供ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸在抗肿瘤中的用途,并进一步提供它们增强肿瘤对化疗药物的敏感性的辅助用途。本发明的药物、药物组合物可用于有效抗肿瘤并增强化疗治疗。
本发明的第一方面,提供ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸在制备用于抗肿瘤的药物中的用途。
进一步的,所述ZCCHC4选自:
(a)SEQ ID NO:2所示的氨基酸序列;或
(b)与SEQ ID NO:2所示的氨基酸序列同源,且具有促进肿瘤发生发展作用的蛋白质或多肽;或
(c)(a)或(b)的氨基酸序列中经过取代、缺失或添加一个或几个氨基酸、且具有促进肿瘤发生发展作用的由(a)或(b)衍生的蛋白质或多肽;
所述ZCCHC4编码序列选自:
(i)SEQ ID NO:1的核苷酸序列;或
(ii)在严格条件下与(i)限定的核苷酸序列杂交的分子;或
(iii)(i)或(ii)的核苷酸序列中经过取代、缺失或添加一个或几个核苷酸、且编码具有促进肿瘤发生发展作用的蛋白质或多肽的分子。
进一步的,所述ZCCHC4的抑制剂选自:阻断ZCCHC4促瘤功能的小分子化合物、以脂质体或者纳米颗粒包裹的靶向ZCCHC4的化合物。
进一步的,所述ZCCHC4编码序列的干扰RNA或反义寡核苷酸选自:能与ZCCHC4编码序列杂交的特异性抑制ZCCHC4转录的干扰RNA或反义寡核苷酸、经过修饰增加稳定性的ZCCHC4编码序列干扰RNA或反义寡核苷酸、脂质体或其他适配子承载的干扰RNA或反义寡核苷酸。
在本发明的一个优选实施方式中,所述ZCCHC4编码序列的干扰RNA的核苷酸序列如SEQ ID NO:3所示。所述干扰RNA(si-ZCCHC4)包括顺义链和反义链,序列分别如SEQ IDNO:3和SEQ ID NO:5所示,合成时在3'增加2个dT使序列更加稳定。具体序列如下:
si-ZCCHC4序列:
5'-GGUGACAAGAAGUCUAACATT-3'(顺义);
5'-UGUUAGACUUCUUGUCACCTT-3'(反义)。
在本发明的一个实施例中,所述ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸发挥抗肿瘤功能。所述ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸抑制肝癌细胞的增殖和活力,抑制肿瘤发生发展;并通过抗肿瘤作用增加肿瘤细胞对化疗药物敏感性,进一步作为辅助化疗的药物增加化疗对肿瘤的治疗效果。
进一步的,所述药物的给药方法选自:(1)给予ZCCHC4编码序列的干扰RNA或反义核苷酸:包括反义核苷酸直接注射法、脂质体包裹干扰RNA直接注射法;瘤内给药;(2)给予ZCCHC4蛋白抑制剂:包括直接注射ZCCHC4蛋白的小分子抑制剂、瘤内给药。
本发明的第二方面,提供ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸在制备化疗药物增敏剂中的用途。
给予ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义核苷酸,联合化疗药物,能够增强化疗药物治疗肿瘤的效果。
进一步的,所述化疗药物增敏剂为增强肿瘤对化疗药物敏感性的辅助药物,或提高化疗药物对肿瘤的疗效的辅助药物。
进一步的,所述肿瘤包含:原发性肝细胞肝癌、肺癌、胰腺癌、结肠癌。
进一步的,所述化疗药物包括:奥沙利铂、阿霉素等DNA损伤类化疗药物。
进一步的,所述ZCCHC4的抑制剂选自:阻断ZCCHC4促瘤功能的小分子化合物、以脂质体或者纳米颗粒包裹的靶向ZCCHC4的化合物。
进一步的,所述ZCCHC4编码序列的干扰RNA或反义寡核苷酸选自:能与ZCCHC4编码序列杂交的特异性抑制ZCCHC4转录的干扰RNA或反义寡核苷酸、经过修饰增加稳定性的ZCCHC4编码序列干扰RNA或反义寡核苷酸、脂质体或其他适配子承载的干扰RNA或反义寡核苷酸。
在本发明的一个优选实施方式中,所述ZCCHC4编码序列的干扰RNA的核苷酸序列如SEQ ID NO:3所示。所述干扰RNA(si-ZCCHC4)包括顺义链和反义链,序列分别如SEQ IDNO:3和SEQ ID NO:5所示,合成时在3'增加2个dT使序列更加稳定。具体序列如下:
si-ZCCHC4序列:
5'-GGUGACAAGAAGUCUAACATT-3'(顺义);
5'-UGUUAGACUUCUUGUCACCTT-3'(反义)。
进一步的,所述药物的给药方法选自:(1)给予ZCCHC4编码序列的干扰RNA或反义核苷酸:包括反义核苷酸直接注射法、脂质体包裹干扰RNA直接注射法;瘤内给药;(2)给予ZCCHC4蛋白抑制剂:包括直接注射ZCCHC4蛋白的小分子抑制剂、瘤内给药。
在本发明的一个实施例中,所述ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸增强肝癌对化疗药物的敏感性。所述ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸增强奥沙利铂和阿霉素对肝癌细胞的杀伤能力。
在本发明的一个实施例中,所述ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸增加肝癌化疗疗效。所述ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸增强了奥沙利铂抑制肿瘤进展的效果。
在本发明的一个实施例中,所述ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸增强肺癌、胰腺癌、结肠癌对化疗药物的敏感性。所述ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸增强奥沙利铂对肺癌细胞、胰腺癌细胞、结肠癌细胞的杀伤能力。
本发明的第三方面,提供一种抗肿瘤的药物组合物,其包含:
(A)治疗有效量的ZCCHC4抑制剂和ZCCHC4编码序列的干扰RNA或反义寡核苷酸;以及
(B)药学上或免疫学上可接受的载体或赋形剂。
进一步的,所述药物组合物中ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸占药物组合物总重量的0.001~99.9wt%。
进一步的,所述药物组合物中ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸占药物组合物总重量的1~95wt%,优选为5~90wt%,更优选10~80wt%。余量为药学上可接受的载体以及其它添加剂等物质。
进一步的,在给予本发明的药物组合物之前、同时或之后,给予抗肿瘤的其它活性物质。所述其它活性物质具有抗肿瘤的效果,可以为化疗药物、靶向药物或者其他具有抗肿瘤效果的药物。
本发明的第四方面,提供一种增强肿瘤对化疗药物敏感性的辅助药物,其包含:
(A)治疗有效量的ZCCHC4抑制剂和ZCCHC4编码序列的干扰RNA或反义寡核苷酸;以及
(B)药学上或免疫学上可接受的载体或赋形剂。
本发明的第五方面,提供联合化疗药物和,ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸,在制备用于抗肿瘤的药物中的用途。
本发明的第六方面,提供一种抗肿瘤的药物组合物,其包含:
(A)治疗有效量的ZCCHC4抑制剂和ZCCHC4编码序列的干扰RNA或反义寡核苷酸;和
(B)化疗药物;和
(C)药学上或免疫学上可接受的载体或赋形剂。
进一步的,所述肿瘤包含:原发性肝细胞肝癌、肺癌、胰腺癌、结肠癌。
进一步的,所述化疗药物包括:奥沙利铂、阿霉素等DNA损伤类化疗药物。
本领域的技术人员可对前述的技术方案和技术特征进行任意组合而不脱离本发明的发明构思和保护范围。本发明的其它方面由于本文的公开内容,对本领域的技术人员而言是显而易见的。
本发明通过大量的研究和动物模型试验,发现ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸能够发挥抗肿瘤并增强肿瘤对化疗敏感性的作用,提高肿瘤治疗效果。在此基础上完成了本发明。
具体而言,针对肿瘤相关基因进行应用研究是肿瘤分子生物学和细胞生物学研究的热点,将抗肿瘤的核苷酸和蛋白质应用于肿瘤治疗是人工干预肿瘤的有效技术,因此无论是在功能基因组研究,还是肿瘤相关的基因治疗方面均具有广阔地应用前景。
本发明针对肿瘤相关RNA结合蛋白ZCCHC4,对其抑制剂或编码序列的干扰RNA或反义寡核苷酸在抗肿瘤方面的功能和作用进行了研究,并且验证了应用该分子对增强化疗药物抗肿瘤效果的作用。实验证明:1)干扰ZCCHC4能够抑制肝癌细胞增殖;2)干扰ZCCHC4可以促进奥沙利铂对肝癌细胞的杀伤能力;3)干扰ZCCHC4可以促进阿霉素对肝癌细胞的杀伤能力;4)干扰ZCCHC4可以促进奥沙利铂对肺癌细胞、胰腺癌细胞、结肠癌细胞的杀伤能力;5)干扰ZCCHC4可以增强奥沙利铂抑制肝癌体内进展的作用。这些实验结果提示ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸具备抗肿瘤和增强肿瘤化疗效果的应用前景。由此,本发明提供了将ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸应用于抗肿瘤和辅助化疗药物治疗肿瘤中的方法和策略,特别是用于控制肝细胞性肝癌。
本文中提供的所有数值范围旨在清楚地包括落在范围端点之间的所有数值及它们之间的数值范围。可对本发明提到的特征或实施例提到的特征进行组合。本说明书所揭示的所有特征可与任何组合物形式并用,说明书中所揭示的各个特征,可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明,所揭示的特征仅为均等或相似特征的一般性例子。
如本文所用,“含有”、“具有”或“包括”包括了“包含”、“主要由……构成”、“基本上由……构成”、和“由……构成”;“主要由……构成”、“基本上由……构成”和“由……构成”属于“含有”、“具有”或“包括”的下位概念。
ZCCHC4编码序列
如本文所用,术语“ZCCHC4基因”、“ZCCHC4编码基因”、“ZCCHC4蛋白编码基因”或“ZCCHC4蛋白编码序列”可互换使用,均是指一种编码本发明所述的ZCCHC4蛋白或多肽的序列,其可为SEQ ID NO:1(人全长)序列所示的核苷酸序列、在严格条件下与这些序列杂交的分子、或与上述分子高度同源的家族基因分子,所述基因的干扰RNA或反义寡核苷酸对肿瘤的发生发展具有一定的抑制作用。本发明的ZCCHC4基因可选自:(i)SEQ ID NO:1所示的核苷酸序列;或(ii)在严格条件下与(i)限定的序列杂交且干扰后具抗肿瘤活性的分子。
如本文所用,术语“严格条件”是指:(1)在较低离子强度和较高温度下的杂交和洗脱,如0.2×SSC,0.1%SDS,60℃;或(2)杂交时加有变性剂,如50%(v/v)甲酰胺,0.1%小牛血清/0.1%Ficoll,42℃等;或(3)仅在两条序列之间的相同性至少在50%,优选55%以上、60%以上、65%以上、70%以上、75%以上、80%以上、85%以上或90%以上,更优选是95%以上时才发生杂交。
本发明的ZCCHC4基因核苷酸全长序列或其片段通常可以用PCR扩增法、重组法或人工合成的方法获得。对于PCR扩增法,可根据本发明所公开的有关核苷酸序列,尤其是开放阅读框序列来设计引物,并用市售的cDNA库或按本领域技术人员已知的常规方法所制备的cDNA库作为模板,扩增而得有关序列。当序列较长时,常常需要进行两次或多次PCR扩增,然后再将各次扩增出的片段按正确次序拼接在一起。
应理解,本发明的ZCCHC4基因优选获自人,获自其它动物的与人SETD2基因高度同源(如具有50%以上,优选55%以上、60%以上、65%以上、70%以上、75%以上、80%以上,更优选85%以上如85%、90%、95%、98%甚至99%或以上的序列相同性)的其它基因也在本发明优选考虑的等同范围之内。比对序列相同性的方法和工具也是本领域周知的,如BLAST。
ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸
本发明中还涉及ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸。术语“抑制剂”或“ZCCHC4的抑制剂”可互换使用,是指可抑制ZCCHC4表达水平或活性的物质。可用于本发明中的抑制剂包括但不限于:阻断ZCCHC4蛋白促瘤功能的小分子化合物、以脂质体或者纳米颗粒包裹的靶向ZCCHC4的化合物。术语“ZCCHC4编码序列的干扰RNA或反义寡核苷酸”与“干扰RNA或反义寡核苷酸”可互换使用,是指可以抑制ZCCHC4编码序列表达水平和活性的物质。可用于本发明中的干扰RNA或反义寡核苷酸包括但不限于:能与ZCCHC4编码序列杂交的特异性抑制ZCCHC4转录的干扰RNA(如SEQ ID NO:3的核苷酸序列)或反义寡核苷酸、经过修饰增加稳定性的ZCCHC4编码序列干扰RNA或反义寡核苷酸、脂质体或其他适配子承载的干扰RNA或反义寡核苷酸。
本发明的ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸可发挥抗肿瘤并增强化疗药物治疗肿瘤的效果。
药物、药物组合物
本发明还提供了一种药物、药物组合物,其中含有有效量的本发明的ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸,以及药学上或免疫学上可接受的载体。术语“活性物质”或“本发明的活性物质”可互换使用,是指ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸。
在较佳的实施方案中,所述药物组合物可用于抗肿瘤治疗或作为增强化疗治疗肿瘤效果的辅助药物。例如奥沙利铂治疗肝癌等。
如本文所用,术语“含有”或“包括”包括了“包含”、“基本上由……构成”、和“由……构成”。如本文所用,术语“药学上可接受的”成分是适用于人和/或动物而无过度不良反应(如毒性、刺激和变态反应)的,即有合理的效益/风险比的物质。如本文所用,术语“有效量”是指可对人和/或动物产生功能或活性的且可被人和/或动物所接受的量。
如本文所用,术语“药学上可接受的载体”指用于治疗剂给药的载体,包括各种赋形剂和稀释剂。该术语指这样一些药剂载体:它们本身并不是必要的活性成分,且施用后没有过分的毒性。合适的载体是本领域普通技术人员所熟知的,在《雷明顿药物科学》(Remington’s Pharmaceutical Sciences,Mack Pub.Co.,N.J.1991)中可找到关于药学上可接受的赋形剂的充分讨论。
在组合物中药学上可接受的载体可含有液体,如水、盐水、甘油和乙醇。另外,这些载体中还可能存在辅助性的物质,如填充剂、崩解剂、润滑剂、助流剂、泡腾剂、润湿剂或乳化剂、矫味剂、pH缓冲物质等。通常,可将这些物质配制于无毒的、惰性的和药学上可接受的水性载体介质中,其中pH通常约为5-8,较佳地,pH约为6-8。
本发明的组合物中的活性物质占组合物总重量的0.001~99.9wt%;优选为组合物总重量的1~95wt%,较优选为5~90wt%,更优选10~80wt%。余量为药学上可接受的载体以及其它添加剂等物质。
如本文所用,术语“单位剂型”是指为了服用方便,将本发明的组合物制备成单次服用所需的剂型,包括但不限于各种固体剂(如片剂)、液体剂、胶囊剂、缓释剂。
在本发明的一优选实施方式中,所述组合物为单位剂型或多剂型,且其中活性物质的含量为0.01~2000mg/剂,优选0.1~1500mg/剂,更优选1~1000mg/剂。在本发明的另一个优选例中,每天施用1~6剂本发明的组合物,优选施用1~3剂;最优选的,每天服用的剂量为1剂。
应理解,所用ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸等活性物质的有效剂量可随待施用或治疗的对象的严重程度而变化。具体情况根据对象的个体情况(例如对象体重、年龄、身体状况、所需达到的效果)来决定,这在熟练医师可以判断的范围内。
本发明的组合物,可以为固态(如颗粒剂、片剂、冻干粉、栓剂、胶囊、舌下含片)或液态(如口服液)或其它合适的形状。给药途径可采用:(1)反义核苷酸直接注射法、脂质体包裹干扰RNA直接注射法;直接注射ZCCHC4蛋白的小分子抑制剂;瘤内给药。
此外,本发明的组合物中还可含有用于增强其他活性物质治疗肿瘤的效果,其他活性物质选自下组:常用的化疗药物;靶向治疗药物;其他肿瘤治疗策略。
本发明优点在于:
1、本发明揭示了ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸的抗肿瘤功能;
2、基于上述功能,本发明的ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸可进一步用于增强化疗药物抗肿瘤效果,且该效果在不同类型肿瘤中皆成立。
附图说明
图1:ZCCHC4敲除抑制细胞增殖。图为CCK8增殖分析(*,P<0.05;**,P<0.01)。
图2:ZCCHC4的干扰RNA转染HepG2细胞和SMMC-7721细胞导致奥沙利铂诱导凋亡增加。图为流式细胞分析(*,P<0.05)。
图3:ZCCHC4的干扰RNA转染HepG2细胞和SMMC-7721细胞导致阿霉素诱导细胞凋亡增加。图为流式细胞分析(*,P<0.05;**,P<0.01)。
图4:ZCCHC4的干扰RNA转染A549细胞,BXPC-3细胞和HCT116细胞细胞导致奥沙利铂诱导细胞凋亡增加。图为流式细胞分析(*,P<0.05;**,P<0.01)。
图5:瘤内注射ZCCHC4干扰RNA增强奥沙利铂疗效。图为小鼠肿瘤大小(*,P<0.05)。
具体实施方式
下面结合实施例对本发明提供的具体实施方式作详细说明。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。本领域技术人员可对本发明做出适当的修改、变动,这些修改和变动都在本发明的范围之内。
下列实施例中未注明具体条件的实验方法,可采用本领域中的常规方法,例如参考《分子克隆实验指南》(第三版,纽约,冷泉港实验室出版社,New York:Cold SpringHarbor Laboratory Press,1989)或按照供应商所建议的条件。
除非另外说明,否则百分比和份数按重量计算。除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1:干扰ZCCHC4抑制肝癌细胞增殖
HepG2细胞和SMMC-7721细胞(购自ATCC)用DMEM培养基培养,接着用针对ZCCHC4的小干扰RNA(si-ZCCHC4)及模拟物对照(si-模拟物)转染细胞(转染试剂INTERFERin购自Polyplus公司)。
针对ZCCHC4的干扰RNA(si-ZCCHC4)及模拟物对照(Si-模拟物)购自Genephama公司,si-ZCCHC4的顺义链和反义链序列分别如SEQ ID NO:3和SEQ ID NO:5所示;Si-模拟物的顺义链和反义链序列分别如SEQ ID NO:4和SEQ ID NO:6所示,合成时在3'增加2个dT使序列更加稳定。具体序列如下:
si-ZCCHC4序列:
5'-GGUGACAAGAAGUCUAACATT-3'(顺义);
5'-UGUUAGACUUCUUGUCACCTT-3'(反义)。
Si-模拟物序列:
5'-UUCUCCGAACGUGUCACGUTT-3'(顺义);
5'-ACGUGACACGUUCGGAGAATT-3′(反义)。
HepG2或SMMC-7721细胞系以1×103/孔均匀铺在96孔板里,设置至少5个复孔,待细胞贴壁后转染干扰RNA siZCCHC4或si模拟物,干扰24h后,换新鲜培养基,每孔加入10μlCCK8溶液,37℃避光孵育2h,酶标仪测定450nm光吸收值。细胞增殖情况如图1所示。
结果显示:干扰ZCCHC4后HepG2和SMMC-7721细胞系的增殖能力减弱。
该结果表明:干扰ZCCHC4表达抑制肝癌细胞增殖。
实施例2:干扰ZCCHC4促进奥沙利铂(OXA)诱导肝癌细胞凋亡
HepG2和SMMC-7721细胞系以4×104/ml密度铺于24孔板中,利用Interferin试剂转染干扰RNA siZCCHC4或si模拟物24h后,换新的培养基,62.5μM OXA(Sigma-Aldrich)36h后,收集上清,并收集消化下来的细胞,将上清和细胞混合、离心,进行凋亡实验。结果如图2所示。
结果显示:干扰ZCCHC4后OXA诱导的HepG2细胞和SMMC-7721细胞凋亡增加。
该结果表明:干扰ZCCHC4增强OXA对肝癌细胞的杀伤能力。
实施例3:干扰ZCCHC4促进阿霉素(DOX)诱导肝癌细胞凋亡
HepG2和SMMC-7721细胞系以4×104/ml密度铺于24孔板中,利用Interferin试剂转染干扰RNA siZCCHC4或si模拟物24h后,换新的培养基,2μM DOX(Sangon)36h后,收集上清,并收集消化下来的细胞,将上清和细胞混合、离心,进行凋亡实验。结果如图3所示。
结果显示:干扰ZCCHC4后DOX诱导的HepG2细胞和SMMC-7721细胞凋亡增加。
该结果表明:干扰ZCCHC4增强DOX对肝癌细胞的杀伤能力。
实施例4:干扰ZCCHC4促进奥沙利铂(OXA)诱导肺癌细胞、胰腺癌细胞、结肠癌细胞凋亡
A549、BXPC-3、HCT116细胞系分别以4×104/ml、4×104/ml、、8×104/ml密度铺于24孔板中,利用Interferin试剂转染干扰RNA siZCCHC4或si模拟物24h后,换新的培养基,62.5μM OXA(Sigma-Aldrich)分别刺激48、36、24h后,收集上清,并收集消化下来的细胞,将上清和细胞混合、离心,进行凋亡实验。结果如图4所示。
结果显示:干扰ZCCHC4后OXA诱导的A549、BXPC-3、HCT116细胞凋亡增加。
该结果表明:干扰ZCCHC4增强OXA对肺癌、胰腺癌、结肠癌细胞的杀伤能力。
实施例5:瘤内注射ZCCHC4干扰RNA增强奥沙利铂(OXA)疗效。
选取6-8周雄性裸鼠,以1×107HepG2细胞/只老鼠的剂量进行皮下注射,从小鼠成瘤后的第10天开始瘤内注射10nmol干扰RNA(si-ZCCHC4或si-模拟物),每周2次,第11天开始腹腔注射5mg/kg的OXA溶液或者对照5%葡萄糖溶液,每5天注射1次,共注射3次,同时实验过程中监测肿瘤大小。测量时选取肿瘤的最长直径(a mm)和最短直径(b mm),肿瘤大小计算公式为a×b×b/2(mm3)。结果如图5所示。
结果显示:干扰ZCCHC4联合OXA化疗能够显著抑制体内肝癌的生长。
该结果表明:瘤内注射ZCCHC4干扰RNA增强了OXA疗效。
以上已对本发明创造的较佳实施例进行了具体说明,但本发明创造并不限于所述实施例,熟悉本领域的技术人员在不违背本发明创造精神的前提下还可做出种种的等同的变型或替换,这些等同的变型或替换均包含在本申请权利要求所限定的范围内。
序列表
<110> 中国人民解放军第二军医大学
<120> RNA结合蛋白ZCCHC4的靶向药物的应用
<130> /
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atggcggcct ccaggaatgg gtttgaagcc gtggaggcag agggcagcgc agggtgccgg 60
ggaagctcgg gaatggaggt ggtgcttcct ttggatcctg ccgtccccgc cccgctgtgc 120
cctcacggac ccactcttct gtttgtaaag gtgacccaag ggaaagaaga aactcggagg 180
ttttatgcct gttcagcctg tagagataga aaagactgta atttttttca gtgggaagat 240
gaaaagttgt caggagctag acttgctgcc cgagaagctc ataaccgaag atgtcagcct 300
cccctgtccc gaacgcagtg tgtggaaagg tacttgaagt ttattgagtt gcccttgact 360
cagagaaagt tttgtcaaac atgtcagcag ttgttgttac cagatgactg ggggcaacat 420
agtgagcatc aggttctggg taatgtgtcc attacccagt taagaaggcc cagtcaactc 480
ctttatccac tggaaaacaa gaagacaaat gcccagtatc tgtttgctga tcggagctgt 540
cagttcttgg tagacttact ttctgccctc ggattcagaa gagtactgtg tgttggaaca 600
ccaaggttgc atgagctgat caagttgaca gcatcaggtg acaagaagtc taacattaaa 660
agccttttat tggatattga ttttcggtat tcacagtttt atatggaaga tagcttttgc 720
cattataata tgtttaacca tcatttcttt gatggaaaga ctgcccttga agtatgcaga 780
gcatttttac aggaagataa aggcgaagga atcattatgg tgacggatcc tccgtttggt 840
ggcttggttg aacctctggc tattacattc aagaagttaa ttgctatgtg gaaagaaggt 900
caaagccaag atgacagtca caaagaacta cccattttct ggattttccc ctattttttt 960
gaatcccgaa tttgtcagtt ttttccaagc ttccagatgc tggattacca ggtagattat 1020
gataatcatg cactttataa acacggaaag acaggtcgaa aacagtctcc cgtgcgtatt 1080
ttcaccaaca ttccgcccaa caaaataatc cttcctactg aagaagggta cagattttgc 1140
tctccgtgtc aacggtatgt ttctctagag aatcaacact gtgagctctg taattcttgc 1200
acatccaagg atggcaggaa atggaaccat tgctttctct gtaaaaagtg tgtaaagcct 1260
tcctggatcc actgtagcat ctgcaatcac tgtgctgttc cagatcattc ttgtgagggc 1320
cccaaacatg gctgctttat ttgtggtgaa ctggatcata aacgcagtac ttgtcctaac 1380
attgctacat ctaagagagc taacaaagct gtcagaaagc agaagcaaag aaaaagtaat 1440
aagatgaaaa tggagaccac gaaaggacaa tccatgaatc atacatctgc tacaaggaga 1500
aagaaaagga gggaaagagc ccatcaatat cttggctctt aa 1542
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Met Ala Ala Ser Arg Asn Gly Phe Glu Ala Val Glu Ala Glu Gly Ser
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Ala Gly Cys Arg Gly Ser Ser Gly Met Glu Val Val Leu Pro Leu Asp
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Pro Ala Val Pro Ala Pro Leu Cys Pro His Gly Pro Thr Leu Leu Phe
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Val Lys Val Thr Gln Gly Lys Glu Glu Thr Arg Arg Phe Tyr Ala Cys
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Ser Ala Cys Arg Asp Arg Lys Asp Cys Asn Phe Phe Gln Trp Glu Asp
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Glu Lys Leu Ser Gly Ala Arg Leu Ala Ala Arg Glu Ala His Asn Arg
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Arg Cys Gln Pro Pro Leu Ser Arg Thr Gln Cys Val Glu Arg Tyr Leu
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Lys Phe Ile Glu Leu Pro Leu Thr Gln Arg Lys Phe Cys Gln Thr Cys
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Gln Gln Leu Leu Leu Pro Asp Asp Trp Gly Gln His Ser Glu His Gln
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Val Leu Gly Asn Val Ser Ile Thr Gln Leu Arg Arg Pro Ser Gln Leu
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Leu Tyr Pro Leu Glu Asn Lys Lys Thr Asn Ala Gln Tyr Leu Phe Ala
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Arg Arg Val Leu Cys Val Gly Thr Pro Arg Leu His Glu Leu Ile Lys
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Leu Thr Ala Ser Gly Asp Lys Lys Ser Asn Ile Lys Ser Leu Leu Leu
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His Tyr Asn Met Phe Asn His His Phe Phe Asp Gly Lys Thr Ala Leu
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Glu Val Cys Arg Ala Phe Leu Gln Glu Asp Lys Gly Glu Gly Ile Ile
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Met Val Thr Asp Pro Pro Phe Gly Gly Leu Val Glu Pro Leu Ala Ile
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Thr Phe Lys Lys Leu Ile Ala Met Trp Lys Glu Gly Gln Ser Gln Asp
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Asp Ser His Lys Glu Leu Pro Ile Phe Trp Ile Phe Pro Tyr Phe Phe
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Glu Ser Arg Ile Cys Gln Phe Phe Pro Ser Phe Gln Met Leu Asp Tyr
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Gln Val Asp Tyr Asp Asn His Ala Leu Tyr Lys His Gly Lys Thr Gly
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Arg Lys Gln Ser Pro Val Arg Ile Phe Thr Asn Ile Pro Pro Asn Lys
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Ile Ile Leu Pro Thr Glu Glu Gly Tyr Arg Phe Cys Ser Pro Cys Gln
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Arg Tyr Val Ser Leu Glu Asn Gln His Cys Glu Leu Cys Asn Ser Cys
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Thr Ser Lys Asp Gly Arg Lys Trp Asn His Cys Phe Leu Cys Lys Lys
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Cys Val Lys Pro Ser Trp Ile His Cys Ser Ile Cys Asn His Cys Ala
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Val Pro Asp His Ser Cys Glu Gly Pro Lys His Gly Cys Phe Ile Cys
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Gly Glu Leu Asp His Lys Arg Ser Thr Cys Pro Asn Ile Ala Thr Ser
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Lys Arg Ala Asn Lys Ala Val Arg Lys Gln Lys Gln Arg Lys Ser Asn
465 470 475 480
Lys Met Lys Met Glu Thr Thr Lys Gly Gln Ser Met Asn His Thr Ser
485 490 495
Ala Thr Arg Arg Lys Lys Arg Arg Glu Arg Ala His Gln Tyr Leu Gly
500 505 510
Ser
<210> 3
<211> 19
<212> RNA
<213> 人工序列(Artificial)
<400> 3
ggugacaaga agucuaaca 19
<210> 4
<211> 19
<212> RNA
<213> 人工序列(Artificial)
<400> 4
uucuccgaac gugucacgu 19
<210> 5
<211> 19
<212> RNA
<213> 人工序列(Artificial)
<400> 5
uguuagacuu cuugucacc 19
<210> 6
<211> 19
<212> RNA
<213> 人工序列(Artificial)
<400> 6
acgugacacg uucggagaa 19
Claims (10)
1.ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸在制备用于抗肿瘤的药物中的用途。
2.根据权利要求1所述的用途,其特征在于,
所述ZCCHC4选自:
(a)SEQID NO:2所示的氨基酸序列;或
(b)与SEQ ID NO:2所示的氨基酸序列同源,且具有促进肿瘤发生发展作用的蛋白质或多肽;或
(c)(a)或(b)的氨基酸序列中经过取代、缺失或添加一个或几个氨基酸、且具有促进肿瘤发生发展作用的由(a)或(b)衍生的蛋白质或多肽;
所述ZCCHC4编码序列选自:
(i)SEQID NO:1的核苷酸序列;或
(ii)在严格条件下与(i)限定的核苷酸序列杂交的分子;或
(iii)(i)或(ii)的核苷酸序列中经过取代、缺失或添加一个或几个核苷酸、且编码具有促进肿瘤发生发展作用的蛋白质或多肽的分子;
所述ZCCHC4的抑制剂选自:阻断ZCCHC4促瘤功能的小分子化合物、以脂质体或者纳米颗粒包裹的靶向ZCCHC4的化合物;
所述ZCCHC4编码序列的干扰RNA或反义寡核苷酸选自:能与ZCCHC4编码序列杂交的特异性抑制ZCCHC4转录的干扰RNA或反义寡核苷酸、经过修饰增加稳定性的ZCCHC4编码序列干扰RNA或反义寡核苷酸、脂质体或其他适配子承载的干扰RNA或反义寡核苷酸。
3.根据权利要求2所述的用途,其特征在于,所述ZCCHC4编码序列的干扰RNA的核苷酸序列如SEQID NO:3所示。
4.根据权利要求1所述的用途,其特征在于,所述ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸抑制肝癌细胞的增殖,增加肿瘤细胞对化疗药物敏感性。
5.ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸在制备化疗药物增敏剂中的用途。
6.根据权利要求5所述的用途,其特征在于,所述肿瘤包含:原发性肝细胞肝癌、肺癌、胰腺癌、结肠癌。
7.根据权利要求5所述的用途,其特征在于,所述化疗药物包括:奥沙利铂、阿霉素。
8.一种抗肿瘤的药物组合物,其包含:
(A)治疗有效量的ZCCHC4抑制剂和ZCCHC4编码序列的干扰RNA或反义寡核苷酸;以及
(B)药学上或免疫学上可接受的载体或赋形剂。
9.联合化疗药物和,ZCCHC4的抑制剂或ZCCHC4编码序列的干扰RNA或反义寡核苷酸,在制备用于抗肿瘤的药物中的用途。
10.一种抗肿瘤的药物组合物,其包含:
(A)治疗有效量的ZCCHC4抑制剂和ZCCHC4编码序列的干扰RNA或反义寡核苷酸;和
(B)化疗药物;和
(C)药学上或免疫学上可接受的载体或赋形剂。
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HONGHUI MA,等: "N6-Methyladenosine methyltransferase ZCCHC4 mediates ribosomal RNA methylation", 《NATURE CHEMICAL BIOLOGY》 * |
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