CN111228272B - 药物混合物及在制备逆转肝癌索拉非尼耐药性药物中应用 - Google Patents
药物混合物及在制备逆转肝癌索拉非尼耐药性药物中应用 Download PDFInfo
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Abstract
本发明涉及一种与蛋白稳定性相关的蛋白HSP90抑制剂NVP‑HSP990、AT13387、NVP‑AUY922协同瑞戈非尼在低浓度时能够逆转肝癌细胞对索拉非尼的耐药性。具体方法采用HSP90抑制剂NVP‑HSP990、AT13387、NVP‑AUY922和低浓度的瑞戈非尼共同作用索拉非尼耐药的HepG2和HuH7肝癌细胞株、能够明显的抑制索拉非尼耐药的HepG2和HuH7细胞的生长，从而为克服索拉非尼耐药性提供了有效的方法。
Description
技术领域
本发明发现了逆转肝癌细胞耐药性的新方法，属于细胞生物学和医疗技术领域。
背景技术
肝癌是我国最常见的恶性肿瘤之一，发病率在恶性肿瘤中居第5位，在肿瘤致死率中居第二位。目前在临床肝癌诊疗中，严重存在着早期诊断难、手术切除率低(15％～25％)、复发转移率高(20％～60％)、治疗缺乏针对性等问题。因此，分子靶向治疗成为了近年来肝癌综合治疗的重要方法之一。瑞戈非尼(regorafenib)是一类有效的RAF激酶抑制剂，可通过对丝裂原活化蛋白激酶通路和信号转导与转录激活因子3通路的调控抑制HCC细胞增殖、诱导细胞凋亡。但在三期临床实验中，瑞戈非尼仅提高耐药肝癌患者3个月的生存时间。
HSP90是是热休克蛋白家族中的成员，通过与其他伴侣分子形成复合体，结合靶蛋白，促进其折叠装配，从而使蛋白达到其活性构想，并能够增强其稳定性。HSP90的靶蛋白中有很多在肿瘤转移的信号通路中起重要作用的蛋白激酶和转录因子，例如跨膜酪氨酸集美受体，血管内皮生长因子受体等，同时HSP90参与肿瘤细胞的代谢重编程，故而HSP90在肿瘤的侵袭、迁移、增殖、死亡调节和能量代谢等各个关键环节起到了重要的调节作用。
发明内容
本发明涉及逆转肝癌细胞对索拉非尼的耐药性，实验结果表明，通过联合抑制剂和瑞戈非尼处理，肝癌细胞活力明显降低，从而达到治疗肿瘤的作用。
本发明涉及一种与蛋白稳定性相关的蛋白HSP90抑制剂NVP-HSP990、AT13387、NVP-AUY922协同瑞戈非尼在低浓度时能够逆转肝癌细胞对索拉非尼的耐药性。具体方法采用HSP90抑制剂NVP-HSP990、AT13387、NVP-AUY922和低浓度的瑞戈非尼共同作用索拉非尼耐药的HepG2和HuH7肝癌细胞株、能够明显的抑制索拉非尼耐药的HepG2和HuH7细胞的生长，从而为克服索拉非尼耐药性提供了有效的方法。
一种药物混合物，包含热激蛋白90(HSP90)的抑制剂NVP-HSP990或AT13387或NVP-AUY922中的一种或二种或三种，以及瑞戈非尼。
所述药物混合物，热激蛋白90(HSP90)抑制剂NVP-HSP990(a)其化合物的结构式为(a)；热激蛋白90(HSP90)抑制剂AT13387(b)其化合物的结构式为(b)；热激蛋白90(HSP90)抑制剂NVP-AUY922(c)其化合物的结构式为(c)；
所述药物混合物，药物混合物中NVP-HSP990或AT13387或NVP-AUY922中的一种或二种或三种与瑞戈非尼的摩尔比为5000～500，优选为1000。
所述药物混合物，药物混合物包含热激蛋白90(HSP90)的抑制剂NVP-HSP990或AT13387或NVP-AUY922和瑞戈非尼；
瑞戈非尼与NVP-HSP990的摩尔比为5000～500，优选为1000；
瑞戈非尼与AT13387的摩尔比为5000～500，优选为1000；
瑞戈非尼与NVP-AUY922的摩尔比为5000～500，优选为1000。
所述药物混合物在制备逆转肝癌索拉非尼耐药性药物中应用。
所述的应用，NVP-HSP990协同瑞戈非尼能够明显的降低HepG2耐药细胞的活细胞数目；
AT13387协同瑞戈非尼能够明显的降低HepG2耐药细胞的活细胞数目；
NVP-AUY922协同瑞戈非尼能够明显的降低HepG2耐药细胞的活细胞数目；
从而逆转肝癌细胞对索拉非尼的耐药性。
所述的应用，所述药物为注射或口服药物，瑞戈非尼的注射或口服药物浓度为30-60mg/kg，NVP-HSP990的注射或口服药物浓度为0.1-0.01mg/kg，AT13387的注射或口服药物浓度为0.11-0.011mg/kg，NVP-AUY922的注射或口服药物浓度为0.12-0.012mg/kg。
一种治疗肝癌的药物，包含权利要求1-4任一所述药物混合物和索拉非尼。
附图说明
图1利用Cell Titer Glo方法进行细胞活力检测结果。
图2利用western blot实验进行检测结果。
具体实施方式
现结合实例，对本发明做进一步说明。实例仅限于说明本发明，而非对本发明的限定。
实施例1 HSP90抑制剂与瑞戈非尼溶液的制备
瑞戈非尼使用DMSO溶解制备成储存溶液浓度为50mM。使用DMEM培养基稀释至5μM。NVP-HSP990、AT13387、NVP-AUY922各使用DMSO溶液制备成储存溶液浓度为10mM。使用DMEM培养基稀释至5nM。
实施例2 HSP90抑制剂和瑞戈非尼联合作用对索拉非尼耐药肝癌细胞的抑制作用
将HepG2的索拉非尼耐药细胞铺到96孔板中，分成8组，分别为HepG2耐药细胞加入DMSO处理，HepG2耐药细胞加入瑞戈非尼处理，HepG2耐药细胞加入NVP-HSP990处理，HepG2耐药细胞加入AT13387处理，HepG2耐药细胞加入NVP-AUY922处理，HepG2耐药细胞加入瑞戈非尼(1μM)和NVP-HSP990(5nM)处理，HepG2耐药细胞加入瑞戈非尼(1μM)和AT13387(5nM)处理，HepG2耐药细胞加入瑞戈非尼(1μM)和NVP-AUY922(5nM)处理，处理后细胞培养24小时和48小时后，利用Cell Titer Glo方法进行细胞活力检测，其结果如图1所示，HSP90抑制剂联合瑞戈非尼后明显抑制肝癌耐药细胞的增殖。
实施例3 HSP90抑制剂联合瑞戈非尼抑制脂肪酸合成
将HepG2耐药细胞铺到6孔板中，分成4组，分别为HepG2耐药细胞加入DMSO处理，HepG2耐药细胞加入瑞戈非尼(1μM)处理，HepG2耐药细胞加入瑞戈非尼(1μM)和HSP90抑制剂(5nM)处理，处理24小时后，收集细胞蛋白，利用western blot实验进行检测。其结果如图2所示，瑞戈非尼和HSP90抑制剂明显抑制脂肪酸合成酶的表达。
通过上述实验表明，HSP90抑制剂和瑞戈非尼处理后，可改变索拉非尼肝癌耐药细胞的脂肪酸代谢途径，抑制肝癌耐药细胞的生长，从而达到治疗肝癌的目的。
Claims (6)
1.一种药物混合物在制备抑制肝癌索拉非尼耐药性药物中的应用，其特征在于：所述药物混合物包含热激蛋白90（HSP90）的抑制剂NVP-HSP990或AT13387或NVP-AUY922中的一种或二种或三种，以及瑞戈非尼。
2.权利要求1所述的应用，其特征在于：热激蛋白90（HSP90）抑制剂NVP-HSP990（a）其化合物的结构式为（a）；热激蛋白90（HSP90）抑制剂AT13387（b）其化合物的结构式为（b）；热激蛋白90（HSP90）抑制剂NVP-AUY922（c）其化合物的结构式为（c）；
3.权利要求1所述的应用，其特征在于：
药物混合物中NVP-HSP990或AT13387或NVP-AUY922中的一种或二种或三种与瑞戈非尼的摩尔比为5000~500。
4.权利要求1所述的应用，其特征在于：
药物混合物包含热激蛋白90（HSP90）的抑制剂NVP-HSP990或AT13387或NVP-AUY922和瑞戈非尼；
瑞戈非尼与NVP-HSP990的摩尔比为5000~500；
瑞戈非尼与AT13387的摩尔比为5000~500；
瑞戈非尼与NVP-AUY922的摩尔比为5000~500。
5.权利要求1所述的应用，其特征在于：
NVP-HSP990协同瑞戈非尼能够明显的降低HepG2耐药细胞的活细胞数目；
AT13387协同瑞戈非尼能够明显的降低HepG2耐药细胞的活细胞数目；
NVP-AUY922协同瑞戈非尼能够明显的降低HepG2耐药细胞的活细胞数目；从而抑制肝癌细胞对索拉非尼的耐药性。
6.权利要求1所述的应用，其特征在于：所述药物为注射或口服药物，瑞戈非尼的注射或口服药物浓度为30-60mg/kg，NVP-HSP990的注射或口服药物浓度为0.1-0.01mg/kg，AT13387的注射或口服药物浓度为0.11-0.011mg/kg，NVP-AUY922的注射或口服药物浓度为0.12-0.012mg/kg。
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