CN107058233A - 一种减小肿瘤细胞对抗肿瘤药物的耐药性的方法 - Google Patents

一种减小肿瘤细胞对抗肿瘤药物的耐药性的方法 Download PDF

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CN107058233A
CN107058233A CN201710305119.3A CN201710305119A CN107058233A CN 107058233 A CN107058233 A CN 107058233A CN 201710305119 A CN201710305119 A CN 201710305119A CN 107058233 A CN107058233 A CN 107058233A
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antineoplastic
chek2
drug resistance
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王然
王一然
王宁
王雅杰
刘传
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Abstract

本发明提供一种减小肿瘤细胞对抗肿瘤药物的耐药性的方法，其特征在于，包括：步骤一，对具有抗肿瘤药物耐药性的肿瘤细胞进行基因检测的步骤，检测该肿瘤细胞是否有Chek2基因Y390C位点的突变，若检测结果为“有”，则进入步骤二；步骤二，将野生型Chek2基因转入到具有抗肿瘤药物耐药性的细胞中。本发明提供的减小肿瘤细胞对抗肿瘤药物的耐药性的方法，能够使肿瘤细胞减小对抗肿瘤药物的耐药性，具有帮助研究肿瘤抗药性的机制和指导临床上进一步扩展现有抗肿瘤药物的应用范围的重要意义。

Description

一种减小肿瘤细胞对抗肿瘤药物的耐药性的方法
技术领域
本发明涉及一种化疗药物表柔比星耐药细胞株的建立方法，本发明还涉及表柔比星耐药细胞株的应用，属于细胞模型领域。
背景技术
乳腺癌的药物治疗已经进入了分子分型指导下的精准化治疗时代。通过组化四要素(ER、PR、HER2和Ki67)而代替基因芯片检测的简易分子分型，已广泛应用于指导临床药物治疗方案的制定。但三阴型乳腺癌(TNBC)因其ER、PR以及HER2均阴性，对靶向激素受体的内分泌治疗和靶向HER2的系列药物治疗无效。曾被列为靶向治疗的弃儿。而三阴型乳腺癌又较其他分子类型发病更年轻化，遗传倾向更明显，有更强的侵袭性，2年内局部复发和内脏转移的风险更高。传统的化疗虽然显示出较高的近期有效率，但缓解时间较短，总体生存差，亟待开发针对性强的靶向治疗药物。
相对于乳腺癌的其他分子分型，三阴型乳腺癌中BRCA1/2突变型(BRCAness)患者比例明显增高，约占15％。BRCA1/2基因不仅是目前发现的外显率最高的乳腺癌遗传易感基因，而且还是DNA损伤修复的重要基因。在DNA损伤发生后，BRCA1蛋白能够迅速招募到DNA损伤位点上，通过蛋白激酶ATM(Ataxiatelangiectasia mutated)等磷酸化过程，激活其下游的细胞周期检查点激酶2(cell-cycle checkpoint kinase 2，CHEK2或者Chk2)等蛋白，通过同源重组(homologous recombination，HR)和非同源重组通路实现对DNA损伤的修复。因此理论上伴有BRCAl/2基因突变的乳腺癌对致DNA损伤的药物更为敏感。大量的临床研究也证实了以DNA损伤为主要作用机制的药物，如顺铂、卡铂等能明确提高三阴型乳腺癌，特别是BRCA1/2型乳腺癌的疗效。基于合成致死理论(synthetic lethality)，在BRCA1/2型乳腺癌的治疗中，加入另外一个DNA损伤修复关键酶PARP1(polyADP-ribose polymerasefamily member 1,聚腺苷二磷酸-核糖转移酶1)的抑制剂，能更有效抑制肿瘤细胞的损伤修复，提示对化疗药物敏感。PARP1可与修复途径中的多种蛋白相互作用，并募集它们到DNA损伤位点。在碱基切除修复途径中PARP1可募集另一个DNA损伤修复元件XRCC1至单链损伤部位，而在DNA双链损伤修复途径中可募集DNA依赖的蛋白激酶。PARP1抑制剂通过抑制PARP1活性导致单链DNA不能被修复，经DNA复制，单链损伤变成双链损伤。BRCA1和BRCA2都是DNA双链损伤后同源重组修复过程中发挥关键作用。一旦BRCA1/2缺失后，依赖于此的同源重组途径修复异常，进而影响细胞周期阻滞和细胞凋亡。基于此理论，应用PARP1抑制剂联合DNA损伤化疗药物卡铂治疗BRCA1/2突变率相对较高的三阴型乳腺癌理论上应该具有更好的疗效。然而，O’Shaughnessy教授牵头开展的国际多中心III期临床研究，并未显示出PARP1抑制剂iniparib联合致DNA损伤化疗药物卡铂及吉西他滨治疗三阴型乳腺癌的优势。随后Astra Zeneca公布的另一个PARP1抑制剂olaparib治疗三阴型乳腺癌II期临床结果，也未达到预期的疗效。之后的多个PARP1抑制剂治疗三阴型乳腺癌的临床试验结果均为阴性。为何对于BRCAness型比例较高的三阴型乳腺癌，化疗基础上联合PARP1抑制剂没有发挥合成致死效应，是目前亟待解决的问题，然而目前并没有一个合适的细胞模型来进行相关机制的研究。
发明内容
本发明的目的在于提供一种减小肿瘤细胞对抗肿瘤药物的耐药性的方法。
本发明采用了如下技术方案：
一种减小肿瘤细胞对抗肿瘤药物的耐药性的方法，其特征在于，包括：步骤一，对具有抗肿瘤药物耐药性的肿瘤细胞进行基因检测的步骤，检测该肿瘤细胞是否有Chek2基因Y390C位点的突变，若检测结果为“有”，则进入步骤二；步骤二，将野生型Chek2基因转入到具有抗肿瘤药物耐药性的细胞中。
进一步，本发明的减小肿瘤细胞对抗肿瘤药物的耐药性的方法，还可以具有这样的特征：若对抗肿瘤药物耐药的细胞为小鼠细胞，则步骤一中检测小鼠细胞中是否有Chek2基因Y394C位点的突变。
进一步，本发明的减小肿瘤细胞对抗肿瘤药物的耐药性的方法，还可以具有这样的特征，还包括：步骤三，使用抗肿瘤药物对步骤二中得到的细胞进行处理，验证细胞是否仍然对该抗肿瘤药物敏感。
进一步，本发明的减小肿瘤细胞对抗肿瘤药物的耐药性的方法，还可以具有这样的特征：步骤二中，使用逆转录病毒载体将野生型Chek2基因转入到目的细胞中。
进一步，本发明的减小肿瘤细胞对抗肿瘤药物的耐药性的方法，还可以具有这样的特征：步骤二中，转入野生型Chek2基因的同时，应当同时转入GFP基因。
进一步，本发明的减小肿瘤细胞对抗肿瘤药物的耐药性的方法，还可以具有这样的特征：步骤二中，转入野生型Chek2基因的同时，同时转入嘌呤霉素的抗性基因。
进一步，本发明的减小肿瘤细胞对抗肿瘤药物的耐药性的方法，还可以具有这样的特征：步骤一中，肿瘤细胞为Eμ-Myc p19Arf-/-B细胞。
进一步，本发明的减小肿瘤细胞对抗肿瘤药物的耐药性的方法，还可以具有这样的特征：步骤一中，肿瘤细胞为三阴型乳腺癌细胞。
进一步，本发明的减小肿瘤细胞对抗肿瘤药物的耐药性的方法，还可以具有这样的特征：其中，抗肿瘤药物的浓度设置为5个浓度梯度。
进一步，本发明的减小肿瘤细胞对抗肿瘤药物的耐药性的方法，还可以具有这样的特征：其中，抗肿瘤药物为表柔比星或者顺铂。
发明的有益效果
本发明的方法能够使肿瘤细胞减小对抗肿瘤药物的耐药性，具有帮助研究肿瘤抗药性的机制和指导临床上进一步扩展现有抗肿瘤药物的应用范围的重要意义。
附图说明
图1是Chek2表达的real-time PCR的检测结果图；
图2是不同浓度的表柔比星对细胞的杀伤结果图；
图3是Chek2基因的表达情况；
图4是Ser的磷酸化情况；
图5是puma的mRNA的表达情况；
图6是p21的表达量；
图7是Noxa的mRNA的表达情况。
具体实施方式
以下结合附图来说明本发明的具体实施方式。需要说明的是，本发明中未详细描述的实验，均按照生物化学的标准操作规程或者相应试剂盒的说明书进行操作。
1.Chek2基因被沉默后，会对表柔比星产生耐药性。
构建CHEK2的shRNA，进行药物实验，选择DNA损伤的化疗药物表柔比星DOX。具体流程如下：DOX分2个梯度，用48孔板进行试验，每孔加100ul BCM(B细胞培养基)，0.2M B细胞和100ulL表柔比星：10ug/ml。
表1：药物结果
Log Dox1 Dox2 mock
Chk2-shRNA 2.03 1.92 0.00
MLP -0.06 0.01 0.00
其中负值表示耐药，正值表示敏感，Log绝对值大于1说明表型明显。
对感染的shRNA进行嘌呤霉素筛选后，抽提RNA反转录成cDNA，进行real-time PCR结果如图1所示：说明CHEK2确实有下调。
2.表柔比星耐药细胞株的建立过程
人的Chek2 Y390位点在鼠中对应的为Y394位点，构建chek2cDNA，对394位点酪氨酸碱基进行突变为半胱氨酸(TAT→TGT)；得到chek2 Y394C的cDNA。
对Eμ-Myc p19Arf-/-B细胞感染行puro-chek2的shRNA，载体中只含嘌呤霉素抗性，不含GFP。感染后进行嘌呤霉素筛选，筛选后得到chek2-null的B细胞。
对chek2-null的B细胞感染Chek2cDNA分别为:Chek2WT，Chek2Y394C，Chek2VEC，使GFP在20-50％之间，然后进行药物实验。具体流程如前，另由于chek2-null B细胞经过嘌呤霉素筛选，对其他药物也产生一定耐药，这次实验药物浓度表柔比星(DOX)：20ug/ml。
表2：药物实验结果
Log Dox-2 Dox-3 Mock
Chek2-Y394C 0.41 0.34 0.00
Chek2-WT -1.41 -1.76 0.00
Chek2-Vec -0.27 -0.04 0.00
以上结果说明CHEK2表达下降的细胞对表柔比星表现出不同程度的耐药。
3.表达CHEK2 Y390C的细胞对化疗药物产生最大杀伤需要的药物浓度远远大于野生型CHEK2细胞
对前面感染的Chek2WT，Chek2Y394C和Chek2VEC进行流式细胞分选，含GFP的细胞被筛选出来。进行DOX药物实验，分5个梯度，每个梯度做3个副孔，每个梯度递增0.7nM，观察48小时最大杀伤，结果如表3所示：
表3：各个浓度的表柔比星对Chek2表达状态的杀伤情况
如图3所示，虽然Y394C具有表达产物，但是如图2所示：Chek2Y394C和Chek2VEC对DOX48h最大杀伤需要的药物浓度远远大于Chek2WT，说明Y394的表达产物却没有相应的生物学功能。图2中表柔比星的浓度分别是：0mM、0.7mM、2.1mM、3.5mM、4.9mM、7mM。
4.CHEK2 Y390C通过细胞周期检测点以及凋亡影响CHEK2的功能
如图4所示，DOX处理6小时后，Y394C细胞对底物P53Ser20的磷酸化大大降低。如图5、图6和图7所示，表柔比星处理后，Y394C的细胞表达P53下游P21，Puma以及Noxa均明显低于WT，提示Y394C细胞的凋亡功能异常。图5、图6和图7中的图例，未处理指未加入表柔比星，已处理指加入表柔比星处理。
5.利用上述实验，形成减小肿瘤细胞对抗肿瘤药物的耐药性的方法：
步骤一，对具有抗肿瘤药物耐药性的肿瘤细胞进行基因检测的步骤，检测该肿瘤细胞是否有Chek2基因Y390C位点的突变，若检测结果为“有”，则进入步骤二；
步骤二，将野生型Chek2基因转入到所述具有抗肿瘤药物耐药性的细胞中。肿瘤细胞可以采用Eμ-Myc p19Arf-/-B细胞，也可以采用三阴型乳腺癌细胞。
若对抗肿瘤药物耐药的细胞为小鼠细胞，则步骤一中检测小鼠细胞中是否有Chek2基因Y394C位点的突变。
步骤三，使用抗肿瘤药物对步骤二中得到的细胞进行处理，验证细胞是否仍然对该抗肿瘤药物敏感。
步骤二中，使用逆转录病毒载体将野生型Chek2基因转入到目的细胞中。转入野生型Chek2基因的同时，应当同时转入GFP基因或者转入嘌呤霉素的抗性基因，便于后续分辨成功转入野生型Chek2基因的细胞。表柔比星或者顺铂的浓度设置为5个浓度梯度。

Claims (10)

1.一种减小肿瘤细胞对抗肿瘤药物的耐药性的方法，其特征在于，包括：
步骤一，对具有抗肿瘤药物耐药性的肿瘤细胞进行基因检测的步骤，检测该肿瘤细胞是否有Chek2基因Y390C位点的突变，若检测结果为“有”，则进入步骤二；
步骤二，将野生型Chek2基因转入到所述具有抗肿瘤药物耐药性的细胞中。
2.如权利要求1所述的方法，其特征在于：
若对抗肿瘤药物耐药的细胞为小鼠细胞，则步骤一中检测小鼠细胞中是否有Chek2基因Y394C位点的突变。
3.如权利要求1所述的方法，其特征在于，还包括：
步骤三，使用抗肿瘤药物对步骤二中得到的细胞进行处理，验证细胞是否仍然对该抗肿瘤药物敏感。
4.如权利要求1所述的方法，其特征在于：
步骤二中，使用逆转录病毒载体将野生型Chek2基因转入到目的细胞中。
5.如权利要求1所述的方法，其特征在于：
步骤二中，转入野生型Chek2基因的同时，应当同时转入GFP基因。
6.如权利要求1所述的方法，其特征在于：
步骤二中，转入野生型Chek2基因的同时，同时转入嘌呤霉素的抗性基因。
7.如权利要求1所述的方法，其特征在于：
步骤一中，所述肿瘤细胞为Eμ-Myc p19Arf-/-B细胞。
8.如权利要求1所述的方法，其特征在于：
步骤一中，所述肿瘤细胞为三阴性乳腺癌细胞。
9.如权利要求3所述的方法，其特征在于：
其中，所述抗肿瘤药物的浓度设置为5个浓度梯度。
10.如权利要求1所述的方法，其特征在于：
其中，所述抗肿瘤药物为表柔比星或者顺铂。
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