CN112843238B - 包含微管蛋白抑制剂和Notch抑制剂的药物组合物及其应用 - Google Patents
包含微管蛋白抑制剂和Notch抑制剂的药物组合物及其应用 Download PDFInfo
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Abstract
本发明属于医药技术领域,具体涉及一种药物组合物及其应用,所述药物组合物包含Notch抑制剂和微管蛋白抑制剂。本发明的药物组合物可以提高肿瘤患者,尤其是非小细胞肺癌、卵巢癌和乳腺癌患者对微管蛋白抑制剂的化疗敏感性。此外,建立了新的预测肿瘤对微管蛋白抑制剂化疗敏感性的标记物。
Description
技术领域
本发明属于医药领域,涉及包含微管蛋白抑制剂和Notch抑制剂的药物组合物及其应用,还涉及建立新的预测肿瘤对微管蛋白抑制剂化疗敏感性的标记物。
背景技术
在全球,癌症仍然是严重威胁人类生命健康的主要因素,世界卫生组织下属的国际癌症研究机构发布最新数据显示,2020年全球新增癌症病例约1930万、死亡人数约1000万,中国分部约占23.7%和30%。
目前,针对恶性肿瘤的主要治疗手段包括手术、放疗和化疗等。由于很多恶性肿瘤被确诊时已经为晚期肿瘤,如非小细胞肺癌、卵巢癌和乳腺癌等,化疗仍然是恶性肿瘤的主要治疗手段。然而,尽管大部分患者在治疗初期对化疗敏感,但由于原发性和获得性耐药,最终导致恶性肿瘤的耐药复发。耐药复发仍然是恶性肿瘤临床治疗的主要瓶颈之一。因此,寻找可以有效预测恶性肿瘤化疗敏感性的组织病理学标志物,以及新的治疗方案尤为重要。
Notch是重要的膜受体蛋白,通过与相邻细胞膜上的配体直接结合,响应细胞外的特定信号,开启细胞内信号连锁反应。Notch信号通路是一条保守的通路,在哺乳动物中包含了Notch1-4四个受体成员和DLL1,3,4以及JAG1,2五个配体成员。当与其配体结合后,Notch受体胞内段经过γ-分泌酶介导的切割,产生有活性的Notch胞内结构域(NICD),活化的NICD易位至细胞核,最终激活Notch信号通路下游分子如Hes1的转录,进而在细胞分化、增殖、存活、细胞命运的决定及肿瘤的发生、发展中发挥重要功能。尽管针对Notch信号通路的多个抑制剂已经进入临床试验,但是结果显示单独用药对于多种类型肿瘤患者没有明显效果。
目前,对于Notch信号通路抑制剂是否能够有效提高肿瘤患者对微管蛋白抑制剂的化疗效果,鲜有报道。
发明内容
为了提高肿瘤患者,尤其是非小细胞肺癌、卵巢癌和乳腺癌患者的化疗敏感性,本发明提出一种Notch抑制剂和微管蛋白抑制剂(尤其是紫杉类药物)的联合治疗方案。同时,本发明还提出将Notch2、NICD2和Hes1作为肿瘤患者对化疗药物敏感性的分子标志物,可以用于预测肿瘤患者,尤其是非小细胞肺癌、卵巢癌和乳腺癌,对微管蛋白抑制剂的化疗敏感性,为临床医生快速准确了解患者对化疗药物的疗效,及时采取更具个体化的治疗方案,从而避免患者接受过度、无效的化疗。
为了达到上述目的,一方面,本发明提出一种药物组合物,包含Notch抑制剂和微管蛋白抑制剂。
在一些实施例中,所述Notch抑制剂为RO4929097、LY3039478、MRK-003、PF-03084014、BMS-906024中的一种或多种。
在一些实施例中,所述微管蛋白抑制剂为紫杉类药物,优选为紫杉醇、多西他赛、长春瑞滨中的一种或多种。
在一些实施例中,所述Notch抑制剂和微管蛋白抑制剂的摩尔比为:200∶1-3∶10,例如100∶1、50∶1、10∶1或1∶1。
另一方面,本发明还提出一种所述药物组合物在制备治疗肿瘤的药物中的应用。
在一些实施例中,所述肿瘤为非小细胞肺癌、卵巢癌和乳腺癌中的一种或多种。
此外,发明人还发现肿瘤组织中Notch2、NICD2和Hes1可以作为预测肿瘤患者对微管蛋白抑制剂化疗敏感性的分子标志物,尤其是针对紫杉醇类药物,从而避免患者接受过度、无效的化疗。一方面,如果患者本身就高表达Notch2,那么暗示其对紫杉醇化疗不敏感,施用紫杉醇难以取得理想的治疗效果;另一方面,如果紫杉类药物化疗过程中,Notch2表达水平升高,信号通路被激活,NICD2/Hes1表达水平升高,暗示患者开始对紫杉醇类药物产生化疗抵抗,继续施用紫杉醇的治疗效果较差。
因此,又一方面,本发明还提出一种检测Notch信号通路分子如Notch2、NICD2和/或Hes1的表达水平的试剂在制备预测肿瘤患者对微管蛋白抑制剂治疗敏感性的预测剂或选择适合进行微管蛋白抑制剂治疗的肿瘤患者的选择剂中的应用,其中检测到Notch信号通路分子如Notch2、NICD2和/或Hes1的表达水平升高,则判断肿瘤患者对所述微管蛋白抑制剂不敏感。
又一方面,本发明还提出一种检测Notch信号通路分子如Notch2、NICD2和/或Hes1的表达水平的试剂在制备监测接受微管蛋白抑制剂治疗的肿瘤患者的治疗效果的监测剂中的应用,其中检测到所述患者中Notch信号通路分子如Notch2、NICD2和/或Hes1的表达水平升高,则判断肿瘤患者对微管蛋白抑制剂治疗产生抵抗。
在一些实施例中,所述微管蛋白抑制剂为紫杉类药物,优选为紫杉醇、多西他赛、长春瑞滨中的一种或多种,任选地所述肿瘤为非小细胞肺癌、卵巢癌和乳腺癌中的一种或多种。
在一些实施例中,Notch信号通路分子包括Notch信号通路基因和/或蛋白,任选地检测Notch信号通路分子的试剂包括Notch信号通路基因的特异性引物和/或Notch信号通路蛋白的特异性抗体。
与现有技术相比,本发明具有以下有益效果:
(1)Notch抑制剂和微管蛋白抑制剂类化疗药物,尤其是紫杉类药物的联合治疗方案,可以显著抑制非小细胞肺癌和卵巢癌细胞、裸鼠移植瘤肿瘤的生长,促进肿瘤细胞的对微管蛋白抑制剂化疗敏感性,可以用于指导临床试验及后期的临床应用。
(2)Notch2、NICD2和Hes1作为分子标志物,经过临床样本验证,能较好预测肿瘤患者,尤其是非小细胞肺癌和卵巢癌细胞患者对微管蛋白抑制剂化疗药物的敏感性,任一所述分子标记物可以应用于化疗药物的敏感性检测试剂盒开发,可用于指导临床个体化治疗,并提高治疗的精准性。
附图说明
以下附图仅旨在于对本发明做示意性说明和解释,并不限定本发明的范围。其中:
图1:卵巢癌患者在接受紫杉醇依赖的治疗方案后,肿瘤组织中Notch2的表达水平显著上调。左图是卵巢癌患者治疗前后临床标本的Notch2免疫组化染色结果;右图是对Notch2表达水平进行定量的结果;
图2:卵巢癌患者在接受紫杉醇依赖的治疗方案后,Notch2的表达上调导致患者化疗后无进展期缩短;
图3:过表达Notch2活化片段-NICD2导致肿瘤细胞对Paclitaxel化疗敏感性降低,同时伴随着Hes1表达水平的上调;
图4:Notch抑制剂RO4929097联合Paclitaxel抑制非小细胞肺癌和卵巢癌细胞增殖,促进细胞的化疗敏感性,A是克隆形成的结果图;B是细胞活力实验的结果图;
图5:Notch抑制剂RO4929097联合Paclitaxel抑制卵巢癌移植瘤的生长;A是最终牺牲小鼠时肿瘤的大小图;B是实验过程中肿瘤的生长曲线;C是最终牺牲小鼠时肿瘤重量的统计图;
以上图示中,*(p<0.05),**(p<0.01),***(p<0.001)表示与对照相比,有显著差异。
具体实施方式
结合本发明的一般性描述,通过下述实施例将更容易理解本发明,以下描述的目的仅在于阐述本发明的某些方面的实施例,不旨在于限制本发明。需要说明的是,实施例所用的实验方法或实验条件,如无特殊说明均按常规方法或厂家说明书进行,实施例所用材料、试剂,如无特殊说明均可从商业途径获得。
一、实验方法
1.临床肿瘤样本的免疫组化
临床肿瘤样本来自中国科学技术大学第一附属医院(安徽省立医院),所有样本均在患者知情同意的情况下获取,本研究经中国科学技术大学伦理委员会批准(批准号:2019-N(H)-212)。通过对病案进行检索,获得了同一患者化疗前后配对的石蜡标本,然后使用Notch2抗体进行免疫组化染色。根据Notch2的着色程度及着色细胞的比例对样本进行打分,根据程度将样本分成0-3四个等级,依次逐渐增强,根据着色细胞的比例分成1-4四个等级,分别对应0-25%,26%-50%,51%-75%,76%-100%,最后二者相乘,获得最终的免疫组化指数(IHC Score)。
2.患者生存曲线绘制
通过阅读患者的病例信息获得患者化疗后的无进展期时长(Progress freesurvival),然后根据Notch2染色的免疫组化指数,将患者分成Notch2高表达和低表达的两群,利用Graphpad绘制患者的生存曲线。
3.蛋白质免疫印迹实验(Western blot)
构建过表达Notch2活化片段-NICD2的稳定细胞系,将2×105个细胞均匀接种于6孔培养板中,一天后待细胞贴壁后,分别加入DMSO,100nM Paclitaxel(Sigma-Aldrich,T7191),1uM RO4929097(Selleck,S1575)及Paclitaxel联合RO4929097处理细胞,处理48小时后,用预冷的PBS洗涤3次,然后加入细胞裂解液((50mM Tris-HCl,250mM NaCl,1mMEDTA,50mM NaF and 0.5%Triton X-100,pH 7.4)使用前加1mM DTT,1mM PMSF和Cocktail(Sigma,1∶100)),裂解30分钟后,用细胞刮收取细胞裂解液,4℃,12000rpm离心5分钟后,收取上清。根据Bradford法蛋白浓度测定试剂盒(生工生物,SK3031)说明书进行操作,对蛋白液体进行定量。然后进行SDS-PAGE电泳及转模,再按照传统流程对对PVDF膜进行封闭及抗体孵育,最后进行曝光。
4.细胞培养
人非小细胞肺癌细胞系A549和卵巢癌细胞系OVCAR8购自ATCC(美国典型培养物保藏中心,美国),将细胞接种在60mm培养皿中,37℃、5%CO2中培养,使用DMEM培养基(Gibco,美国)补充有10%胎牛血清(Gibco,美国)、100单位/ml青霉素(碧云天,中国)和100mg/ml链霉素(碧云天,中国),取对数生长期细胞进行试验。
5.克隆形成
将2万个A549和OVCAR8细胞种植到24孔细胞培养板中,一天后分别利用DMSO,100nM(A549)Paclitaxel(Sigma-Aldrich,T7191),10nM(OVCAR8)Paclitaxel,1uMRO4929097(Selleck,S1575)及Paclitaxel联合RO4929097处理细胞,72小时后4%PFA固定细胞,并利用0.1%结晶紫进行染色。
6.肿瘤细胞存活实验
将5千个A549和OVCAR8细胞种植到96孔细胞培养板中,一天后加入不同浓度的Paclitaxel(Sigma-Aldrich,T7191)进行处理,同时联合用药组分别加入1uM RO4929097进行处理,72小时后,利用细胞活力检测试剂盒(CellTiter-Glo Luminescent ViabilityAssay kit,Promega)检测细胞的活力,然后利用Graphpad绘制存活曲线。
7.裸鼠移植瘤实验
动物实验经中国科学技术大学伦理委员会批准(批准号:2019-N(A)-059)。Balb/c小鼠(胸腺nu/nu,6-8周龄,史莱克实验动物)皮下注射5×105A549细胞或OVCAR8细胞。待肿瘤长至100-150mm3,将小鼠随机分成四组,分别进行生理盐水(Saline)、10mg/kgPaclitaxel(紫杉醇注射液,哈药集团,国药准字H20059962)、3mg/kg RO4929097及10mg/kgPaclitaxel和3mg/kg RO4929097进行联合处理。Paclitaxel通过腹腔注射进行给药,RO4929097进行口服方式给药,每两天进行一次给药,并利用游标卡尺测量肿瘤的长度和宽度,按照公式4π/3x(宽/2)2x(长/2)计算肿瘤大小。
二、实验结果
1.临床肿瘤样本的免疫组化实验结果
收集临床卵巢癌患者化疗前后匹配的临床样本,然后进行Notch2的免疫组化染色
结果如图1所示,卵巢癌临床患者在包含紫杉醇类药物的治疗方案治疗后,约86%(24/28)的患者肿瘤组织中Notch2的蛋白表达水平显著升高,进而导致患者对紫杉醇化疗抵抗。
2.患者生存曲线绘制的结果
结果如图2所示,Notch2的蛋白表达水平越高,患者无进展期生存时间越短,尤其是在化疗后。
3.蛋白质免疫印迹实验结果
如图3所示,过表达Notch2活化片段-NICD2后,Notch信号通路下游信号分子Hes1的表达水平显著上调,同时凋亡蛋白Caspase-3的活化片段显著减少。这一结果说明,肿瘤细胞中Notch2的表达上调及活化将会抑制肿瘤细胞对Paclitaxel的敏感性。
4.细胞克隆形成和存活结果
结果如图4所示,Paclitaxel联合Notch信号通路抑制剂RO4929097可以显著抑制肿瘤细胞的克隆形成、细胞存活,促进细胞的凋亡水平。
RO4929097与Paclitaxel联合处理细胞,同时测试单用其中一种药物的组,并计算相对单用等量药物的变化幅度,变化幅度计算方式:联合用药相对细胞增殖率-单独用药相对细胞增殖率。
测试结果如下表所示,可见联合使用Paclitaxel和RO4929097能够协同高效抑制细胞存活。
联用药物 | 单药组1 | 联用组1 | 联用组2 | 联用组3 |
摩尔浓度比RO:Paclitaxel | 0 | 200 | 100 | 50 |
RO 4929097(uM) | 1 | 1 | 1 | 1 |
Paclitaxei(nM) | 0 | 5 | 10 | 20 |
相对细胞增殖率 | 99.0% | 17.3% | 14.3% | 13.0% |
相对单独用Taxol增殖率变化 | -29.8% | -12.5% | -6.8% |
5.裸鼠移植瘤实验结果
结果如图5所示,Paclitaxel联合Notch信号通路抑制剂RO4929097可以显著抑制肿瘤的大小、生长速度及最终肿瘤的重量。
RO4929097与Paclitaxel联合处理小鼠,同时测试单用其中一种药物的组,并计算相对单用等量药物的变化幅度,变化幅度计算方式:联合用药相对肿瘤生长/重量率-单独用药相对肿瘤生长/重量率。
测试结果如下表所示,可见联合使用Paclitaxel和RO4929097能够协同高效抑制肿瘤生长和最终肿瘤的重量。
综上,Notch2及其信号通路上下游分子可以作为预测肿瘤化疗敏感性的分子标志物;Notch抑制剂和紫杉类药物的联合治疗方案,提高肿瘤细胞及组织的化疗敏感性。
以上所述仅为本发明的示例性说明,本发明的保护范围不限于此,任何熟悉本领域的技术人员在本发明揭露的技术范围内,可轻易想到的变化或替代,都应涵盖在本发明保护范围之内。
Claims (1)
1.包含Notch抑制剂和微管蛋白抑制剂的药物组合物在制备治疗卵巢癌的药物中的应用,其中所述Notch抑制剂和微管蛋白抑制剂的摩尔比为:200:1-50:1,所述卵巢癌中Notch2为过表达,其中所述Notch抑制剂为RO4929097,所述微管蛋白抑制剂为紫杉醇。
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