CN107427592A - 使用luterion抑制癌细胞中端粒酶的方法 - Google Patents
使用luterion抑制癌细胞中端粒酶的方法 Download PDFInfo
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Abstract
本发明涉及一种通过luterion抑制癌细胞中端粒酶的方法,更具体地涉及一种抑制癌组织、癌细胞或癌症患者中端粒酶活性的方法,所述方法中施用的是:包含luterion的抗癌组合物;用于抑制癌细胞中端粒酶活性的组合物;以及luterion。本发明的luterion通过抑制癌细胞中端粒酶活性具有仅有效抑制癌细胞的增殖而不影响正常细胞的优点。
Description
技术领域
本发明涉及一种使用luterion抑制癌细胞中端粒酶的方法,更具体地涉及一种抑制癌组织、癌细胞或癌症患者中端粒酶活性的方法,所述方法中施用的是:包含luterion的抗癌组合物;用于抑制癌细胞中端粒酶活性的组合物;以及luterion。
背景技术
端粒酶是催化端粒重复序列添加至染色体末端的核糖核蛋白(Blackburn,Ann.Rev.Biochem.,61:113-129,1992)。除了诸如造血干细胞之外的特定细胞,在正常细胞中未发现端粒酶活性,而在大多数癌细胞中则观察到高端粒酶活性。由于端粒酶被认为参与维持癌细胞的无限增殖,端粒酶活性的检测与定量对于癌症的诊断至关重要。此外,预期端粒酶活性的抑制剂作为抗癌剂对于正常细胞几乎无副作用(Counter C.M.等,EMBO J.,11:1921-1929,1989;Counter C.M.等,Proc.Natl.Acad.Sci.USA,91:2900-2904,1994;Chadeneau C.等,Cancer Res.,55:2533-2536,1995;Hiyama等,Nature Med.,1:249-255,1995;Shay J.W.等,Mol.Cell.Biol.,15:425-432,1995)。
已经将人端粒酶与编码蛋白质的基因和RNA一起克隆,并且正进行许多研究以发现端粒酶抑制剂(US 6,261,836;US 5,583,016)。迄今为止鉴定的端粒酶抑制剂包括小分子化合物和寡核苷酸。多个文献揭示抑制端粒酶的寡核苷酸等靶向编码端粒酶蛋白质组分的mRNA(其人形式是人端粒酶逆转录酶或hTERT)或端粒酶全酶的RNA组分(其人形式是人端粒酶RNA或hTR)。靶向hTERT mRNA的寡核苷酸通常结合mRNA以引起mRNA的破坏,由此用作预防hTERT蛋白产生的传统反义药物(US 6,444,650)。某些靶向hTR的寡核苷酸结合存在于端粒酶全酶中的hTR分子以破坏酶功能(US 6,548,298)。hTERT(人端粒酶逆转录酶)是调控癌细胞永生性和增殖能力的最重要的酶之一。尽管在无限克隆的生殖细胞、造血细胞和癌细胞中这样的端粒酶具有80%至90%的端粒酶活性,但是正常细胞并不具有这样的活性(Bryan,T.M.等,Curr.Opin.Cell Biol.,11:318-324,1999)。最近,已经尝试使用这样的端粒酶特性通过开发参与细胞生长的端粒酶的抑制剂来抑制癌细胞的增殖(Bryan,T.M.等,Embo J.14:4240-4248,1995;Artandi,S.E.等,Nat.Med.6:852-855,2000)。
已有报道,由端粒酶RNA组分定义的反义策略,诸如肽核酸(Norton等,NatureBiotech.14:615-619,1996)和硫代磷酸寡核苷酸抑制端粒酶活性。由于端粒酶是逆转录酶,还有报道使用逆转录酶诸如AZT或者其他核苷的抑制剂。
目前公开了:由于通过顺铂交联端粒重复序列,进行端粒酶抑制(如果可能的话)(Burger等,Eur.J.Cancer,33:638-644,1997),一种使用反义寡核苷酸抑制hTERT(其是端粒酶基因的模板RNA)的作用以抑制端粒酶活性的方法(Pitts,A.E.等,Proc.Natl.Acad.Sci.,USA,95:11549-11554,1998;Kondo,Y.等,Oncogene,19:2205-2211,2000),一种使用锤头核酶抑制端粒酶模板RNA的方法(Yokoyama,Y.等,Cancer Res.,58:5406-5410,1998),逆转录酶活性的抑制剂(Strahl,C.等,Mol.Cell.Biol.,16:53-65,1996),抑制正常端粒酶活性的显性负相hTERT蛋白的表达(Zhang,X.等,Genes Dev.,13:2388-2399;1999;Hahn,W.C.等,Nat.Med.,5:1164-1170,1999)以及作用于G四链体(通过作用于端粒结构抑制端粒酶的作用)的稳定化的小分子抑制剂(Perry,P.J.等,J.Med.Chem.,42:2679-2684,1999;Gowan,S.M.等,Mol.Pharmacol.,60:981-988,200l;Gowan,S.M.等,Mol.Pharmacol.,61:1154-1162,2002;Izbicka,E.等,Cancer Res.,59:639-644,1999)。
同时,本发明的发明人观察到存在于从患者预先排出的体液中的微物质的特性,并将所述微物质命名为“luterial”,于2013年7月12日提交韩国专利申请(韩国专利申请第10-2013-0082060号),还于2014年1月14日提交了一种用于有效分离和培养上述luterial的方法的韩国专利申请(韩国专利申请第10-2014-004525号)。此外,“luterion”—与这样的luterial结构和功能相似的微物质存在于植物和动物中,不仅具有RNA和/或DNA,而且阻断癌细胞的生长,用于使细胞恢复至健康免疫系统。
因此,本发明的发明人发现,为了将luterion应用于药物或食物组合物,有必要收集通过将溶剂添加至植物并振荡而产生的蒸发气体,然后通过过滤和离心有效去除和培养蒸发气体中所包含的luterion,已于2015年1月6日提交专利申请(韩国专利申请第10-2015-0001195号)。
因此,本发明的发明人已经努力发现了抑制端粒酶的新颖物质,结果是,发现luterion抑制癌细胞中的端粒酶活性以抑制癌细胞的增殖,从而实现了本发明。
发明内容
本发明的一个目的是提供一种通过抑制端粒酶活性抑制癌细胞的增殖的抗癌组合物。
本发明的另一目的是提供一种通过抑制癌组织、癌细胞或癌症患者中端粒酶活性而预防或治疗癌症的方法。
为了实现所述目的,本发明提供了一种用于预防或治疗癌症的药物组合物,所述组合物包含luterion作为活性成分。
本发明还提供一种用于预防或缓解癌症的食物组合物,所述组合物包含luterion作为活性成分。
本发明还提供一种用于抑制癌细胞的端粒酶活性的组合物,所述组合物包含luterion作为活性成分。
本发明还提供一种用于预防或治疗癌症的方法,所述方法包括施用包含luterion作为活性成分的组合物。
本发明还提供一种用于抑制癌组织、癌细胞或癌症患者中端粒酶活性的方法,所述方法包括施用包含luterion作为活性成分的组合物。
本发明还提供一种用于抑制癌细胞的增殖的方法,所述方法包括施用包含luterion作为活性成分的组合物。
本发明还提供包含luterion作为活性成分的组合物用于预防或治疗癌症的用途。
本发明还提供包含luterion作为活性成分的组合物用于抑制癌组织、癌细胞或癌症患者中端粒酶活性的用途。
本发明还提供用于制备包含luterion作为活性成分的抗癌组合物的用途。
附图说明
图1是通过共聚焦激光扫描显微镜(Confocal Laser Scanning Microscope,Zeiss)获取的显示其尺寸的luterion的图像。
图2是显示使用Mito-tracker对luterion染色后存在或不存在显色的图像。
图3是显示使用罗丹明123对luterion染色后存在或不存在显色的图像。
图4显示luterion的荧光/非荧光图像的对比(A:詹纳斯绿B阳性,B:罗丹明123阳性,C:Mito-tracker红阳性,以及D:无染色)。
图5显示在常规使用罗丹明123、Mito tracker红和詹纳斯绿B染色后luterion是否显色(A:詹纳斯绿B阳性,B:罗丹明123阳性,C:Mito-tracker红阳性,以及D:无染色)。
图6显示通过测量luterion荧光染色区尺寸鉴定的luterion的尺寸(50nm至800nm)(A:詹纳斯绿B反应尺寸测量,B:罗丹明123反应尺寸测量,C:Mito-tracker红反应尺寸测量,D:无染色反应尺寸测量)。
图7是通过TEM电子显微镜获得的图像,显示luterion具有双膜结构。
图8是通过原子力显微镜获得的图像,显示luterion中包含核酸。
图9是由分析luterion中是否包含RNA而获得的生物分析仪结果(L:对照;1:50nm或更小,2:50nm至100nm,3:100nm至200nm,4:200nm至400nm)。
图10是说明测量端粒酶活性计划的示意图。
图11是通过luterion处理的正常细胞(成纤维细胞)和癌细胞(肺癌、乳腺癌、结肠癌)中的端粒酶活性。
图12显示与luterion处理浓度相应的正常细胞(成纤维细胞)和不同癌细胞(肺癌、乳腺癌、结肠癌、肝癌、白血病)的细胞活力。
图13显示使用不同来源的luterion处理的胰腺癌细胞系(AsPC-1)中对于细胞增殖的抑制。
图14显示使用不同来源的luterion处理的肺癌细胞系(A549)中对于细胞增殖的抑制。
图15显示使用不同来源的luterion处理的乳腺癌细胞系(BT-20)中对于细胞增殖的抑制。
具体实施方式
除非本发明另外表明,否则本发明所使用的所有技术和科学术语具有与本发明所属领域的技术人员通常理解的相同的含义。一般而言,本发明所使用的命名法和下文所描述的实验方法为本领域公知和常用。
本发明所使用的术语“luterial”和“luterion”由本发明的发明人所命名,其具有50nm至400nm尺寸的纳米尺寸活物质,存在于包括动物和植物在内的所有活生物体,当融合时获得从病毒样尺寸达800nm至1200nm,但是在1200nm波长或更长时被列为表现基因异常和病理现象的突变体的微物质。luterial和luterion与外来体(exosome)或微泡(microvesicle)的区别在于它们具有DNA和RNA(见图8和9)且具有迁移性和粘附性。luterial是指存在于生态系统中宿主体内的纳米尺寸活物质。在包括人的动物中,其可存在于血液、唾液、淋巴液、精液、阴道液、母乳(尤其是初乳)、脐带血、脑细胞、脊髓或骨髓中。另一方面,luterion是指纳米尺寸活物质,这些宿主可为例如食物,并且可主要存在于植物和食物中。
证实线粒体被詹纳斯绿B(Janus green B)和荧光染料罗丹明123、Mitotracker、吖啶橙和DAPI染色,luterial和luterion也被与线粒体的那些染料相同的染色剂染色(参见图1至6)。它们具有与线粒体相似的双膜的膜结构,并且具有其中内嵴(internalcristae)结构不完整的结构(参见图7)。其在与线粒体相同的激光波长范围被观察到。因此,它们还可被称为“假线粒体”、“线粒体类似物”或“原线粒体(proto-mitochondria)”。
luterion丰富存在于植物的茎部,并且本发明的发明人已经分离了源于植物的luterion并测定了其特性,提交了韩国专利申请(韩国专利申请第10-2015-0001195号)。所分离的luterion具有如下特性:
(a)包括小于红细胞的圆形或椭圆形尺寸(50nm至800nm),并且在正常细胞中具有迁移性;
(b)具有核酸;
(c)当免疫化学荧光染色时具有与线粒体相似的反应;
(d)表现融合(fusion)和/或分裂(fission)生态型;
(e)在不存在融合的情况下成熟至尺寸达300nm,成熟成包含DNA的假线粒体,并且在通过扫描电子显微镜(SEM)或透射电子显微镜(TEM)获得的图像上显示线粒体样结构;
(f)当发生融合时其尺寸增加数千nm;
(g)产生尺寸大于正常来源(较长直径是500nm或更多)的突变体luterial;
(h)显示不同于外来体的光反应。
此外,其具有如下特性中的一种或多种:
(i)显示自发荧光(autofluorescence);
(j)产生200nm至400nm尺寸的ATP;
(k)粘附性;
(l)双膜结构;
(m)在某些条件下爆发突变的luterial,在突变的luterial爆发之后具有干性(stemness);
(n)具有调整p53基因和端粒的功能;以及
(o)包含CD39或CD73的表面抗原。
此外,luterion在室温短时间内不溶解或消失,并且即使保存长时间也不通过融合而突变。
预期luterion和luterial不仅参与信号传导、细胞分化、细胞死亡,而且还参与细胞周期和细胞生长的调节。本发明的发明人已经发现luterial与癌症的诊断密切相关(韩国专利申请第10-2013-0082060号,国际专利申请第WO2015/005553号)。
此外,证实在正常细胞中通过luterion处理增加端粒酶的表达且增加端粒的长度(韩国专利申请第10-2015-00007522号),并且luterion显示增加正常细胞中端粒酶活性的抗衰老活性。
本发明的术语“正常细胞”是指具有正常衰老过程的细胞,其并非由于端粒酶活性增加而具有进行无限增殖的表型的细胞,诸如癌细胞。
本发明的术语“端粒酶”是指催化端粒重复序列添加至端粒的末端的核糖核酸蛋白。端粒是涵盖染色体的末端且被认为稳定染色体的一段长重复序列。在人类中,端粒通常长7kb至10kb,包含序列-TTAGGG-的多个重复序列。在大多数成人细胞中,端粒酶不表达,并且端粒长度减少了原始的连续复制。当细胞复制达到一定数量的次数或更多时,端粒逐渐缩小,使得细胞进入终末崩溃期,其引起细胞衰老。在体细胞中,端粒酶无活性,但是在90%的癌细胞中具有活性,并且端粒酶抑制剂可用于抑制癌症。
在本发明的一种示例实施方式中,在正常细胞中通过luterion处理增加端粒酶表达和活性,而癌细胞系的luterion处理揭示端粒酶表达和活性降低。换句话说,可证实luterion仅抑制癌细胞的端粒酶活性。
根据本发明的第一方面,本发明涉及一种用于抑制癌细胞的端粒酶活性的组合物,所述组合物包含luterion作为活性成分。
根据本发明,证实当使用luterion处理正常细胞时对于细胞活力无作用,而当使用不同来源的luteiron处理癌细胞系时对于其增殖具有强抑制作用。换句话说,证实luterion抑制癌细胞的增殖而不影响正常细胞。
根据本发明的第二方面,本发明涉及一种用于预防或治疗癌症的药物组合物,所述组合物包含luterion作为活性成分。
本发明的luterion可源自漆树(Rhus verniciflua),但是不限于此。例如,luterion可作为源于表1至4中所描述的药用植物的luterion使用。luterion存在于所有植物和动物中,并且由此不限于表1至4中所描述的药用植物。
[表1]
[表2]
[表3]
[表4]
此外,用于本发明的luterion具有但不限于1或更低的密度,高于脂肪和脂质的密度,低于蛋白质的密度,并且由此可通过蒸汽蒸馏从植物分离。
用于本发明的luterion可通过如下的蒸汽蒸馏方法从植物分离:
(a)将溶剂添加至植物中,在50℃至90℃使用空气或氧气间歇鼓泡的同时振荡;
(b)收集通过振荡蒸发的蒸汽或气体,然后冷却以获得冷凝液;
(c)使用具有0.8μm至1.2μm孔的过滤器;
(d)对所过滤的冷凝液进行离心;以及
(e)从所离心的上清液分离源于植物的luterion。
用于本发明的luterion可通过添加水至luterion并在红外线(IR)光辐射下于18℃至30℃培养而使用。
在本发明的一种实施方案中,提供了通过抑制哺乳动物癌细胞的端粒酶和抑制端粒酶阳性细胞而治疗癌症的方法和组合物。本发明的组合物包含于药学上可接受的载体或盐中的治疗有效量的luterion。
本发明的组合物还可用于治疗其他端粒酶相关疾病或病症,诸如其他过度增殖性疾病,诸如银屑病或自身免疫性疾病,类风湿性关节炎,需要免疫系统抑制的免疫系统疾病,对于毒藤(poison ivy)或毒葛(poison oak)的免疫系统应答。
此外,应该理解,癌症治疗的治疗益处通过将本发明的端粒酶抑制剂以及US 5,656,638、US 5,760,062、US 5,767,278、US 5,770,613和US 5,863,936中所描述的其他端粒酶抑制剂与其他抗癌剂组合实施。此类组合的选择可根据疾病的类型、患者的年龄和一般健康状态、疾病进展的侵袭性、TRF长度和待治疗的患病细胞的端粒酶活性以及患者对于包含所述组合的药剂的耐受性而变化,但不限于此。例如,当癌症进展达到晚期时,本发明的端粒酶抑制性化合物可与其他有效减小癌症尺寸的药剂和治疗方案(例如,放射治疗、手术、化学治疗和/或激素治疗)联合使用。此外,在某些情况下,可推荐本发明的端粒酶抑制剂与一种或多种治疗疾病的副作用的药剂组合使用,诸如镇痛药,或有效刺激患者的免疫应答的药剂(例如,集落刺激因子)。
本发明的luterion组合物可通过任何合适的途径施用于人或动物受试者。
所述组合物可口服或胃肠外、肌内、脑内、血管内(包括静脉内)、皮下、鼻内、心内、脑内、腹腔内或经皮施用于人或动物受试者。
通常,所述组合物可通过注射施用,并且可优选以血管注射(例如,静脉内)或肌内注射的形式施用,并且施用所需的途径可根据患者的特性而调整。
本发明的组合物可被配制用于任何合适的途径,包括胃肠外、肌内、脑内、血管内(包括静脉内)、心内、脑内、腹腔内、皮下、鼻内或经皮施用。胃肠外施用的组合物还可包含缓冲液、稀释剂或其他合适的添加剂,并且可包含无菌水溶液。
除了luterion,本发明的组合物还可包含药学上可接受的载体、增稠剂、稀释剂、缓冲剂、防腐剂及其他药学上可接受的载体或赋形剂,并且可配制成药物组合物。
“药学上可接受的载体”是用于递送一种或多种核酸至患者的试剂或者可用于本发明的药物组合物的药理学上可接受的且无其他药理学活性的载体,并且包括但不限于离子交换剂、铝、硬脂酸铝、卵磷脂、血清蛋白(诸如人血清白蛋白)、缓冲物质(诸如不同磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的部分甘油酯混合物)、水、盐、或者电解质(诸如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠和锌盐)、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的基质、聚乙二醇、羧甲基纤维素钠、聚芳酯、蜡、聚乙烯-聚氧丙烯阻透组合物、聚乙二醇、羊毛脂等。
所述药物组合物可呈无菌注射水性或油性悬浮液的无菌注射制剂的形式。可根据本领域已知的技术使用合适的分散剂或湿润剂(例如,吐温80)和悬浮剂配制悬浮液。无菌注射制剂还可以是于非毒性胃肠外可接受的稀释剂或溶剂中的无菌注射溶液或悬浮液(例如,于1,3-丁二醇中的溶液)。可接受使用的媒介物和溶剂包括甘露醇、水、林格氏溶液和等渗氯化钠溶液。此外,非挥发性油通常用作溶剂或悬浮介质。对于此目的,可使用任何具有低刺激性的非挥发性油,包括合成的甘油一酯或者甘油二酯。脂肪酸诸如油酸及其甘油酯衍生物以及药学上可接受的天然油(例如,橄榄油或蓖麻油)可用于注射制剂,尤其是那些聚氧乙烯化的天然油。
本发明的组合物以治疗有效量施用。施用途径和所需的用药剂量可根据多个参数来确定,特别是根据疾病的严重性、待治疗的患者的年龄和体重。最佳剂量可根据个体构造的相对效力而变化,并且可基于EC50,EC50被发现通常推断在体外和体内动物模型中有效。通常,剂量为0.01mg/kg至100mg/kg。根据年龄、重量、疾病的严重性、待治疗的疾病的频率和施用途径,结构的其他剂量可通过施用、待施用的肌内注射或组织(静脉内或皮下)注射而调整。
本发明的组合物还可配制成用于口服施用的膳食添加剂或功能性食物。对于功能性食物制剂或口服药物组合物,合适的赋形剂包括药用级载体,例如甘露醇、乳糖、葡萄糖、蔗糖、淀粉、纤维素、明胶、硬脂酸镁、糖精钠和/或碳酸镁。对于口服液体制剂使用,所述组合物可配制成溶液、悬浮液、乳液或糖浆,其以适于水合的固体或液体形式于水性载体中制备,诸如盐水、葡萄糖水、甘油或乙醇,优选水或生理盐水。优选地,所述组合物可含有少量无毒性辅助材料,诸如湿润剂、乳化剂或缓冲剂。本发明的luterion可掺入功能性食物制剂中或可包含药用植物提取物。
根据第三方面,本发明涉及一种用于预防或缓解癌症的食物组合物,所述组合物包含luterion作为活性成分。
根据第四方面,本发明涉及一种用于预防或缓解癌症的方法,所述方法包括施用包含luterion作为活性成分的组合物。
根据第五方面,本发明涉及一种抑制癌组织、癌细胞或癌症患者中端粒酶活性的方法,所述方法包括施用包含luterion作为活性成分的组合物。
根据第六方面,本发明涉及一种用于抑制癌细胞的增殖的方法,所述方法包括施用包含luterion作为活性成分的组合物。
根据第七方面,本发明涉及包含luterion作为活性成分的组合物用于预防或治疗癌症的用途。
根据第八方面,本发明涉及包含luterion作为活性成分的组合物用于抑制癌组织、癌细胞或癌症患者中端粒酶活性的用途。
根据第九方面,本发明涉及用于制备包含luterion作为活性成分的组合物的抗癌组合物的用途。
实施例
下文中,将参考实施例更详细地描述本发明。本领域技术人员应该理解的是,这些实施例仅用于更详细地描述本发明,并且根据本发明的概念,本发明的范围不限于这些实施方案。
实施例1:luterion的分离
将100g药用植物漆树(Rhus verniciflua stokes)切割成适合尺寸为20倍至30倍(即,2升至3升尺寸)的容器,并置于容器中。将5至8倍植物量的500g至800g蒸馏水(优选植物的6倍,即600g)添加至容器中,然后在80℃或更低进行水浴。每间隔约3小时使用氧气进行鼓泡20至30分钟,持续8小时水浴,从而使得植物的luterion不会缠绕。在烧瓶中收集鼓泡之后提取时蒸发的蒸汽。使用IR光(波长:约3μm至约1000μm,优选200μm至600μm)辐射通过冷却和冷凝所收集的蒸汽而获得的冷凝液1小时至2小时,以防止luterion的突变。之后,使用具有0.8μm或更大直径的孔的过滤器过滤冷凝液,在1200rpm至5000rpm仅将已穿过过滤器的冷凝液重复离心5分钟至10分钟。使用IR光辐射通过离心获得的上清液,从而使得luterion颗粒随运动性(motility)聚集,并使用移液管分离。将所分离的luterion穿过具有50nm直径的孔的过滤器,由此洗涤未过滤的luterion以获得源自漆树的luterion。通过此过程,获得具有50nm至800nm长直径的luteiron,这能够通过暗视野显微镜或共聚焦显微镜观察。根据其尺寸,将所获得的luterion分成50nm至200nm(产生期)/200nm至400nm(成熟期)/400nm至600nm(分裂期)/600nm至800nm(过分裂期)。
以相同的方式,从表1至4中描述的药用植物获得luterion。
实施例2:通过使用luterion处理的癌细胞的端粒酶活性
将1×106个细胞/ml的正常细胞(成纤维细胞)和癌细胞(NCl-H1975,MDA-MA-468,WiDr)分别接种于60mm培养板。然后,在约12小时之后,以50μg/ml处理实施例1中分离的luterion,待培养。在5%CO2培养箱中于37℃使用不含抗生素-抗真菌剂(PSF)的1%FBSDMEM培养基进行细胞培养。在接种之后48小时收获细胞,并测量端粒酶活性。
通过使用端粒酶检测试剂盒(Millipore)的TRAP分析进行端粒酶活性分析。结果,证实使用luterion处理降低癌细胞(NCl-H1975,MDA-MA-468,WiDr)的端粒酶表达和活性(参见图11B)。
此外,由于对于正常细胞即成纤维细胞进行相同实验和分析,证实与对照组(未经luterion处理的组)相比,人正常细胞的端粒酶表达和活性增加(参见图11A)。
实施例3:通过luterion处理的癌细胞增殖的抑制
在几种类型人癌细胞系(肺癌(NCl-H1975)、结肠癌(WiDr)、乳腺癌(MDA-MB-486)、肝癌(HCC38)和白血病(AGH-77))和正常细胞系(成纤维细胞)进行MTT分析以测量luterion针对癌细胞的细胞毒性。
将100μl的细胞悬浮液(5×104个细胞/ml)接种至具有平底的96孔微量滴定板的各孔,并且培养24小时。然后,替换培养基以具有不同浓度的luterion,并且将所得物再培养48小时。
然后,将使用培养基稀释10倍的100μl非水性黄色MTT(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑鎓溴化物)溶液添加至各孔。将细胞储存在37℃和5%CO2浓度的培养箱中以在细胞中产生甲臜(formazan)晶体。在约4小时之后,去除额外的培养基,并且将200μl DMSO添加至各孔以溶解细胞中形成的水不溶性甲臜,然后使用微孔板读数仪分析在595nm的吸光度。
作为测量各浓度的癌细胞的存活率(其以未使用luterion处理的对照组的吸光度为100%进行测定)的结果,癌细胞的存活率以浓度依赖性方式降低。而在正常细胞中未观察到细胞毒性(参见图12)。
此外,除了上述癌细胞系以外,还证实了在AsPC-1胰腺癌细胞系、A549肺癌细胞系和BT-20乳腺癌细胞系中不同来源的luterion有效抑制癌细胞增殖。以与上述MTT分析相同的方式测量细胞活力,并且通过实施例1的方法分离的不同来源的luterion显示对于癌细胞的增殖具有抑制作用(参见图13至15)。
因此,发现包含本发明的luterion作为活性成分的组合物可抑制癌细胞的增殖以预防或治疗癌症。
工业实用性
包含本发明的luteiron的组合物抑制癌细胞中的端粒酶活性,并且对于正常细胞无作用或促进正常细胞中的端粒酶活性。由此,所述组合物仅有效抑制癌细胞的增殖而具有抗癌作用。
如上所述,详细描述了本发明的特定部分。对于本领域技术人员显而易见的是,这些描述用于优选的实施方案,但本发明并非受限于此。因此,本发明的实际范围将由所附权利要求及其等同物来限定。
Claims (11)
1.一种用于预防或治疗癌症的药物组合物,所述组合物包含luterion作为活性成分。
2.一种用于抑制癌细胞中端粒酶活性的组合物,所述组合物包含luterion作为活性成分。
3.权利要求1或2的组合物,其中,所述luterion源自选自由如下组成的组的药用植物:羌活(Ostericum koreanum Maximowicz)、独活(Aralia continentalis Kitagawa)、荆芥(Schizonepeta tenuifolia Briquet)、防风(Saposhnikovia divaricata Schischki)、生地黄(Rehmannia glutinosa Liboschitz ex Steudel)、茯苓(Poria cocos Wolf)、前胡(Angelica decursiva Franchet et Savatier)、车前子(车前草(Plantago asiaticaLinne))、地骨皮(枸杞子(Lycium chinense Miller))、柴胡(Bupleurum falcatumLinne)、泽泻(Alisma orientale Juzepzuk)、木通(Akebia quinata Decaisne)、玄参(Scrophularia ningpoensis Hemsley)、栝楼(Trichosanthes kirilowii Maximowicz)、猪苓(Polyporus umbellatus Fries)、黄连(Coptis japonica Makino)、苦参(Sophoraflavescens Solander ex Aiton)、黄柏(Phellodendron amurense Ruprecht)、知母(Anemarrhena asphodeloides Bunge)、熟地黄(Rehmannia glutinosa Liboschitz exSteudel)、山茱萸(Cornus officinalis Siebold et Zuccarini)、牡丹皮(Paeoniasuffruticosa Andrews)、覆盆子(Rubus coreanus Miquel)、忍冬藤(Lonicera japonicaThunberg)、薄荷(Mentha arvensis Linne var.piperascens Malinvaud ex Holmes)、栀子(Gardenia jasminoides Ellis)、连翘(金钟花(Forsythia viridissima Lindley))、牛蒡子(Arctium lappa Linne)、猕猴桃藤(猕猴桃(Actinidia arguta PLANCH))、猕猴桃(Actinidia arguta Fructus)、木瓜(Chaenomelis Fructus)、葡萄根(Vitis viniferaRadix)、芦根(Phragmitis Rhizoma)、樱桃(Prunus tomentosa Thunb)、五加皮(Acanthopanax sessiliflorum SEEM)、松花粉(Pinus densiflora S.et Z)、杵头糠(ricebran on a mallet head)、青松节(Pinus tabulaeformis)、荞麦米(Semen Fagopyri)、漆树(Rhus verniciflua)、川芎(Cnidium officinale Makino)、当归(Angelica GigasNakai)、柑皮(Citri Unshius Pericarpium)、何首乌(Polygonum multiflorumThunberg)、白首乌(Cynanchum wilfordii Hemsley)、人参(Panax ginseng C.A.Meyer)、白术(Atractylodes japonica Koidzumi)、苍术(Atractylodes lancea De Candlle)、干姜(生姜(Zingiber officinale Roscoe))、肉桂(桂皮(Cinnamomum cassia Presl))、陈皮(柑橘树(Citrus unshiu Markovich))、藿香(Agastache rugosa O.Kuntze)、紫苏叶(Perilla frutescens Britton var.acuta Kudo)、枣(Zizyphus jujuba Millervar.inermis Rehder)、甘草(Glycyrrhiza uralensis Fischer)、乌头(Aconitumcarmichaeli Debeaux)、香附子(Cyperus rotundus Linne)、黄芪(Astragalusmembranaceus Bunge)、白芍药(Paeonia lactiflora Pallas)、茴香(Foeniculum vulgareMiller)、高良姜(Alpinia officinarum Hance)、大腹皮(Areca catechu Linne)、半夏(Pinellia ternata Breitenbach)、南星(Arisaema amurense Maximowicz var.serratumNakai)、益智(Alpinia oxyphylla Miquel)、枳实(酸橙树(Poncirus trifoliataRafinesque))、厚朴(Magnolia ovobata Thunberg)、木香(Aucklandia lappa Decne)、吴茱萸(Evodiae rutaecarpa Bentham)、补骨脂(Psoralea corylifolia Linn)、大葱(青葱根(Allium fistulosum Linn))、砂仁(Amomum villosum Loureiro)、山楂(Crataeguspinnatifida Bunge)、麻黄(Ephedra sinica Staph)、甘菊(chrysanthemum indicumLinne)、桔梗(桔梗花(Platycodon grandiflorum))、杏仁(杏树(Prunus armeniacavar.ansu Max.))、白芷(Angelica dahurica BENTH.et HOOK)、麦门冬(Liriope muscariBALL)、天门冬(Asparagus cochinchinensis Merr)、山药(薯蓣(Dioscorea japonicaTHUNB))、酸枣仁(Zizyphus jujube)、龙眼肉(Dimocarpus longan Lour)、远志(Polygalatenuifolia)、石菖蒲(Acorus graminens SOLAND)、五味子(Schizandra chinensisBAALL)、茅栗(Castanea crenata S.et Z.)、薏苡仁(Coix lachryma-jobi var.ma-yuen)、莱菔子(白萝(Raphanus sativus L))、葛根(野葛(Pueraria thunbergiana))、黄芩(Scutellaria baicalensis GEORG)、藁本(Angelica tenuissima NAKAI)、鹿茸(CerviParvum Cornu)、大黄(Rheum palmatum)、升麻(Cimicifuga heracleifolia KOM)、柏子仁(Biota orientalis ENDL)、桑白皮(椹树(Morus alba L))、款冬花(Tussilago farfara)、白果(Gingko biloba L)、麝香草(Thymus vulgaris)和皂角(Gleditsia japonica Miquelvar.koraiensis Nakai)。
4.权利要求3的组合物,其中所述药用植物是漆树(Rhus verniciflua stokes)。
5.一种用于预防或缓解癌症的食物组合物,所述组合物包含luterion作为活性成分。
6.一种预防或治疗癌症的方法,所述方法包括施用包含luterion作为活性成分的组合物。
7.一种抑制癌组织、癌细胞或癌症患者中端粒酶活性的方法,所述方法包括施用包含luterion作为活性成分的组合物。
8.一种用于抑制癌细胞的增殖的方法,所述方法包括施用包含luterion作为活性成分的组合物。
9.luterion用于预防或治疗癌症的用途,所述用途包括施用包含luterion作为活性成分的组合物。
10.包含luterion作为活性成分的组合物用于抑制癌组织、癌细胞或癌症患者中端粒酶活性的用途。
11.luterion用于制备包含luterion作为活性成分的抗癌组合物的用途。
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EP3096141A4 (en) * | 2014-01-14 | 2017-09-06 | Won Cheol Choi | Method for screening cancer prevention agent or anticancer agent using morphological characteristics of luterial |
EP3243902A4 (en) * | 2015-01-06 | 2018-05-30 | Luterion Co., Ltd. | Luterion and separating and culturing methods for same |
KR101885648B1 (ko) * | 2018-01-31 | 2018-08-06 | 신보현 | 백하수오, 황정, 머위 및 다시마의 혼합추출물을 포함하는 위암의 예방 또는 치료용 조성물 |
KR102350039B1 (ko) * | 2019-08-28 | 2022-01-11 | 경희대학교 산학협력단 | 당귀, 포부자 및 건강 혼합 추출물을 유효성분으로 포함하는 암 예방 또는 치료용 조성물 |
KR102633488B1 (ko) | 2020-06-21 | 2024-02-06 | (주)파이토메디 | 배초향 추출물 또는 틸리아닌를 유효성분으로 함유하는 근육 질환 개선, 치료 또는 예방용, 또는 근 기능 개선용 조성물 |
CN113317205B (zh) * | 2021-07-15 | 2022-10-18 | 云南中医药大学 | 一种阳春砂利用基茎丛生芽和“节繁殖”培养的高效人工育苗方法 |
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JPS55111422A (en) * | 1979-02-22 | 1980-08-28 | Japan Synthetic Rubber Co Ltd | Antitumorigenic agent |
US5583016A (en) | 1994-07-07 | 1996-12-10 | Geron Corporation | Mammalian telomerase |
US5958680A (en) | 1994-07-07 | 1999-09-28 | Geron Corporation | Mammalian telomerase |
US5760062A (en) | 1995-04-18 | 1998-06-02 | Geron Corporation | Telomerase inhibitors |
US5863936A (en) | 1995-04-18 | 1999-01-26 | Geron Corporation | Telomerase inhibitors |
US5656638A (en) | 1995-04-18 | 1997-08-12 | Geron Corporation | Telomerase inhibitors |
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US5767278A (en) | 1995-10-06 | 1998-06-16 | Geron Corporation | Telomerase inhibitors |
US6444650B1 (en) | 1996-10-01 | 2002-09-03 | Geron Corporation | Antisense compositions for detecting and inhibiting telomerase reverse transcriptase |
US6261836B1 (en) | 1996-10-01 | 2001-07-17 | Geron Corporation | Telomerase |
JP2003061615A (ja) * | 2001-08-27 | 2003-03-04 | Niigata Prefecture | テロメラーゼ阻害剤及び食品組成物 |
CN100393209C (zh) * | 2003-09-09 | 2008-06-11 | 杰龙公司 | 用于端粒酶抑制的改性寡核苷酸 |
KR20050107352A (ko) * | 2005-10-25 | 2005-11-11 | (주)에이지아이 | 옻나무 추출물을 이용한 신규의 천연물 항암제 |
KR20070077154A (ko) * | 2007-06-20 | 2007-07-25 | (주)에이지아이 | 칠피, 건칠, 칠목 유래 알러지를 유발하지 않는 추출물 및이를 함유하는 약리학적 조성물 |
KR20110099538A (ko) * | 2010-03-02 | 2011-09-08 | (주)에이지아이 | 옻나무의 알러지를 제거하는 방법 및 그 조성물 |
EP2604274B1 (en) * | 2010-08-11 | 2016-07-13 | AZI Company Ltd. | Rhus verniciflua stokes extract having increased content of active flavonoid compound and method for preparing same |
SG189438A1 (en) * | 2010-10-18 | 2013-05-31 | Agency Science Tech & Res | Use of exosomes to promote or enhance hair growth |
JP2015524849A (ja) * | 2012-08-15 | 2015-08-27 | ザ・ユニバーシティ・オブ・シカゴThe University Of Chicago | 神経変性疾患に対するエキソソームに基づく治療法 |
JP2016526688A (ja) | 2013-07-12 | 2016-09-05 | クォン ヨンアKWON, Young Ah | ルテリアルの形態学的特性を用いた疾病の診断方法 |
EP3096141A4 (en) * | 2014-01-14 | 2017-09-06 | Won Cheol Choi | Method for screening cancer prevention agent or anticancer agent using morphological characteristics of luterial |
EP3095875A4 (en) * | 2014-01-14 | 2018-01-03 | Won Cheol Choi | Luterial and method for isolating and culturing same |
US10590384B2 (en) * | 2014-01-14 | 2020-03-17 | Luterion Co., Ltd. | Luterial and method for isolating and culturing the same |
EP3243902A4 (en) | 2015-01-06 | 2018-05-30 | Luterion Co., Ltd. | Luterion and separating and culturing methods for same |
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HK1247104A1 (zh) | 2018-09-21 |
KR101766373B1 (ko) | 2017-08-09 |
WO2016111530A1 (ko) | 2016-07-14 |
KR20160084322A (ko) | 2016-07-13 |
JP2018502152A (ja) | 2018-01-25 |
EP3243528A4 (en) | 2018-08-01 |
CN113633669A (zh) | 2021-11-12 |
EP3243528A1 (en) | 2017-11-15 |
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