CN116098911B - 一种人参皂苷Rg6在制备抗顺铂耐药型卵巢癌药物中的应用 - Google Patents
一种人参皂苷Rg6在制备抗顺铂耐药型卵巢癌药物中的应用 Download PDFInfo
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- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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Abstract
本发明公开一种人参皂苷Rg6的新用途,具体是发现了人参皂苷Rg6在抑制顺铂耐药型卵巢癌细胞活力方面具有独特作用,可逆转卵巢癌细胞的铂耐药,使得人参皂苷Rg6可单独或与顺铂联合用于制备抗顺铂耐药型卵巢癌的药物,为顺铂耐药型卵巢癌的治疗提供新的用药策略。
Description
技术领域
本发明涉及一种人参皂苷Rg6的新用途,尤其是一种人参皂苷Rg6在制备抗顺铂耐药型卵巢癌药物中的应用。
背景技术
顺铂(Cisplatin,DDP)是临床治疗恶性肿瘤常用的化疗药物,其主要作用靶点是细胞内DNA,可阻断DNA复制和转录,产生DNA改变并增加细胞的氧化水平,以此达到杀伤肿瘤细胞的作用。然而,顺铂在使用过程中会出现毒副作用、原发性耐药和继发性耐药,使顺伯的临床应用受到限制。有研究发现,中药与顺伯联用能够提高顺铂对肿瘤细胞的增殖毒副作用,诱导细胞凋亡从而提高肿瘤细胞对顺铂的敏感性,同时还可降低顺铂的毒副作用,但并未报道存在单个药物能够调解特定的耐药相关的靶点而完全逆转顺铂耐药。
人参(Panax ginseng C.A. Meyer.)为五加科人参属植物的干燥根及根茎,是一种名贵中草药,其主要活性成分是人参皂苷、人参多糖、人参甲苷等,具有抗肿瘤、抗衰老及提高机体免疫力等多种药理功效,已有关于人参皂苷Rg3、Rh2、Rg5等具有抗肿瘤作用的相关报道。
人参皂苷Rg3可显著抑制肝癌小鼠模型体内肿瘤的生长,与药物顺铂联合使用能增强化疗效果,并一定程度上抑制顺铂毒性。同时,人参皂苷Rg3可通过下调PD-L1基因增加胃癌细胞株对顺铂的敏感性,从而抑制胃癌细胞增殖。
人参皂苷Rh2与顺铂联合应用于前列腺癌小鼠模型中,不但可以减少副作用而且可以通过明显增强caspase-3 mRNA表达而诱导癌细胞凋亡。体外低剂量人参皂苷Rh2可能通过降低细胞内p53表达增加人食管癌细胞的胞内顺铂浓度,增强顺铂的杀伤作用。
人参皂苷Rg5可与顺铂协同抑制食管癌细胞生长并促进细胞凋亡,其机制可能与下调 Bcl-2和p-AKT蛋白表达有关。
但是,以上对于人参皂苷抗癌作用的研究,均体现在抑制肿瘤细胞增殖及降低顺铂的毒副作用方面,目前还没有专门针对顺铂耐药型癌细胞进行治疗的报道。
卵巢癌是一种严重威胁女性健康的恶性肿瘤,已成为全球女性妇科癌症死亡的第二大病因。其中上皮卵巢癌是最常见的病理类型,占所有卵巢癌的50~70%,该类患者约80%对铂类为基础的化疗敏感,临床上常以肿瘤细胞减灭术联合紫杉醇、铂类化疗为主要治疗方案,但多数患者会出现复发和铂耐药。由于目前没有逆转卵巢癌铂耐药的有效药物,使得上皮性卵巢癌的治疗效果一直无法完善,5年生存率一直徘徊在30~40%,且 90% 以上患者死于原发性或继发性化疗耐药。
人参皂苷Rg6是由 20(R、S)-Rg2 热裂解产生的稀有人参皂苷,然而,迄今为止,并没有关于人参皂苷Rg6在治疗卵巢癌研究方面的相关报道。
发明内容
本发明是为了解决现有技术所存在的上述技术问题,提供一种人参皂苷Rg6在制备抗顺铂耐药型卵巢癌药物中的应用。
本发明的技术解决方案是:一种人参皂苷Rg6在制备抗顺铂耐药型卵巢癌药物中的应用。
所述的人参皂苷Rg6在制备抗顺铂耐药型卵巢癌药物中的应用,是将人参皂苷Rg6与顺铂联合在制备抗顺铂耐药型卵巢癌药物中的应用,所述人参皂苷Rg6与顺铂的浓度配比为55.66uM:20uM。
本发明发现了人参皂苷Rg6在抑制顺铂耐药型卵巢癌细胞活力方面具有独特作用,可逆转卵巢癌细胞的顺铂耐药,使得人参皂苷Rg6可单独或与顺铂联用于制备抗顺铂耐药型卵巢癌的药物,为顺铂耐药型卵巢癌的治疗提供新的用药策略。
附图说明
图1是本发明实施例所提取的人参皂苷Rg6的质谱图。
图2是本发明实施例所提取的人参皂苷Rg6的氢谱图。
图3是本发明实施例所提取的人参皂苷Rg6的碳谱图。
图4是本发明实施例人参皂苷Rg6对普通卵巢癌细胞A2780S和顺铂耐药型卵巢癌细胞A2780CP的活力抑制作用效果对比示意图。
图5是本发明实施例人参皂苷Rg6对普通卵巢癌细胞SKOV3和顺铂耐药型卵巢癌细胞SKOV3-DDP的活力抑制作用效果对比示意图。
图6是本发明实施例人参皂苷Rg6和顺铂联用药与单独使用顺铂对顺铂耐药型卵巢癌细胞A2780CP的活力抑制作用效果对比示意图。
实施方式
人参皂苷Rg6对卵巢癌细胞活力抑制的实验:
1. 材料与试剂来源
人源性卵巢癌细胞系A2780(简称A2780S)及其顺铂耐药株(简称A2780CP)均为本实验室储存,购于中国科学院细胞库。人源性卵巢癌细胞株SKOV3及其顺铂耐药株(简称SKOV3-DDP),购自湖南丰晖生物科技有限公司。
DMEM培养基购自美国Hyclone公司,胎牛血清购自美国Gibco公司,顺铂(cDDP)购自美国Sigma公司,胰酶购自美国Hyclone公司,DMSO购自美国Sigma公司,CCK8试剂盒购自北京维百奥生物公司。
人参皂苷Rg6的制备方法如下:
1)取100 kg鲜西洋参果实,加入适量的乙醇浸泡提取三次,合并乙醇提取液,40℃下减压浓缩得浸膏;
2)将浸膏(3005 g)用适量水稀释,依次用乙酸乙酯和水饱和正丁醇萃取三次,分别得到乙酸乙酯层,水饱和正丁醇萃取层和水层;
3)水层过AB-8大孔吸附树脂柱色谱,依次用水、30%、50%、70%和95%乙醇梯度洗脱,得到30%、50%、70%和95%乙醇组分;
4)正丁醇萃取层经硅胶柱层析,二氯甲烷:甲醇:水梯度洗脱(50:1:0.1→20:10:1→ 10:1:0.1→5:1:0.1→1:1:0.1→0:1:0.1,V/V),共得到13个洗脱组分(Fr. 1~Fr.13);
5)取组分Fr. 7经硅胶柱层析,二氯甲烷:甲醇:水(15:1:0.1→10:1:0.1→5:1:0.1→1:1:0.1→0:1:0,V/V)进行梯度洗脱,得7个洗脱组分(Fr. 7A~Fr. 7G);
6)取组分Fr. 7C经RP-C18柱色谱,甲醇:水梯度洗脱(30:70~80:20,V/V),得到化合物(8 mg);
7)对化合物经浓缩、冻干得到白色粉末进行鉴定:Liebermann-Burchard和Molish反应均呈阳性;ESI-MS m/z质谱图如图1所示: 811.5 [M+HCOO]-,765.5 [M-H]-,619.4 [M-H-146]-,457. 4 [M-H-162-146]- ,提示其分子结构可能为含1个葡萄糖和1个鼠李糖的PPD型人参皂苷;
8)1H-NMR(600 MHz,C5D5N)谱图如图2所示:在高场区显示有7个甲基质子信号分别为,δ 0.95(3H,s,CH3-30),0.96(3H,s,CH3-19),1.23(3H,s,CH3-29),1.35(3H,s,CH3-18),1.58(3H,s,CH3-27),1.65(3H,s,CH3-26),2.11(3H,s,CH3-28)以及1个鼠李糖的6位甲基质子信号,δ 1.77(3H,d,J = 6.0 Hz);在低场区显示有3个烯氢质子信号,δ 4.87(1H,br s,Hb-21),5.09(1H,br s,Ha-21)和5.25(1H,m,H-24),2个糖端基质子信号,δ 5.22(1H,d,J =7.8 Hz,H-1')和6.48(1H,br s,H-1'')。依据糖端基质子的偶合常数,并结合碳谱核磁数据,初步确定葡萄糖基的连接构型为β构型。13C-NMR(150 MHz,C5D5N)谱图如图3所示,显示有42个碳信号,其中包括4个烯碳信号分别为,δ 107.9,125.1,131.0和155.3,2个糖端基碳信号δ 101.6和101.7,除2组糖基的碳信号之外,母核上还显示有3个连氧碳信号分别为,δ 72.1,74.1和78.2 ;
9)将质谱裂解规律与核磁数据相结合,并与人参皂苷Rg6标准分子式比对,鉴定化合物2为人参皂苷Rg6,其纯度大于98%。
2. 实验药物配制
1)以DMSO作为溶剂充分溶解人参皂苷Rg6,配制成 200 mg/mL母液;
2)在配置好母液的基础上,再使用DMEM培养液稀释上述母液至所需的工作浓度,对不同类型的上皮卵巢癌细胞进行活力抑制实验。
3.实验方法
3.1细胞的培养
A2780CP/A2780S、SKOV3/SKOV3-DDP细胞使用含10%胎牛血清、1%青霉素、1%链霉素及1%两性霉素B的DMEM培养基,放置于37 ℃、5% CO2条件的细胞培养箱中培养。至细胞达到70~80%融合度时用胰蛋白酶消化传代,取处于对数生长期、状态良好的细胞用于后续实验。
3.2细胞单独加入人参皂苷Rg6的活力抑制实验
分别选取对数生长期的A2780CP/A2780S细胞,或SKOV3/SKOV3-DDP细胞,经0.25%胰酶消化后,1000 rpm离心5 min,弃掉上清液,加入上述培养基,吹打均匀,调整细胞浓度为1000个/孔,将其均匀接种于96孔板中,放入培养箱中培养24h后,弃掉完全培养基并更换加药培养基。对照组为DMEM培养基和细胞,实验组为含不同浓度人参皂苷的完全培养基,人参皂苷Rg6设置6个浓度梯度,空白组为相同体积的完全培养基。分别培养72 h后,每孔加入10 μL CCK8避光孵育1 h,采用酶标仪测定孔板在450 nm 波长的吸光度(OD)值。细胞活力抑制率(Inhibition Rate)=1-[A(加药)-A(空白)]/[A(对照)-A(空白)]。细胞活力半数抑制浓度(Half maximal inhibitory concentration,IC50)利用GRAPHPAD Prism 5.02 软件(GraphPad Software, San Diego CA, USA)进行计算。
3.3人参皂苷Rg6与顺铂联合用药对卵巢癌细胞活力的抑制实验
分别选取对数生长期的A2780CP或A2780S细胞,经0.25%胰酶消化后,1000 rpm离心5 min,弃掉上清液,加入上述培养基,吹打均匀,调整细胞浓度为1000个/孔,将其均匀接种于96孔板中,放入培养箱中培养24 h后,弃掉完全培养基并更换加药培养基。将细胞分为空白组、对照组、顺铂组(cDDP)、和人参皂苷联合顺铂组(cDDP+G-Rg6),每组各设5个副孔。空白组为相同体积的完全培养基,对照组为DMEM培养基和细胞,顺铂组为含一定浓度顺铂(20uM)的完全培养基,人参皂苷联合顺铂组为使用细胞活力半数抑制的人参皂苷Rg6药物浓度(55.66uM)和含上述顺铂浓度(20uM)的完全培养基。分别培养0 h、24 h、48 h、72 h后,每孔加入10 μL CCK8避光孵育1 h,采用酶标仪测定孔板在450 nm 波长的吸光度(OD)值。细胞活力(Cell viability)= [A(加药)-A(空白)]/[A(对照)-A(空白)]。
4.实验结果
如图4所示:人参皂苷Rg6对于顺铂耐药型上皮卵巢癌细胞A2780CP的活力抑制作用(IC50=55.66uM)要高于其对同种来源的普通上皮卵巢癌细胞A2780S的活力抑制作用(IC50=59.54uM)。平行实验结果如图5所示:人参皂苷Rg6对于另一种顺铂耐药型上皮卵巢癌细胞SKOV3-DDP的活力抑制作用(IC50=48.31uM)要高于其对同种来源的普通上皮卵巢癌细胞SKOV3的活力抑制作用(IC50=64.85uM)。结果表明:单独使用人参皂苷Rg6,其抗顺铂耐药型卵巢癌细胞的活力抑制作用高于其对同种来源的普通卵巢癌细胞的活力抑制作用。
实验结果如图6所示。结果表明:与单独加入顺铂的实验组相比,人参皂苷Rg6的加入显著增强了对于顺铂耐药型上皮卵巢癌细胞的活力抑制作用,抑制率可以达到80%以上。
综上,本发明的实验结果表明:
人参皂苷Rg6抗顺铂耐药型上皮卵巢癌细胞的活力抑制作用高于其对同种来源的普通上皮卵巢癌细胞的活力抑制作用;同时与顺铂联用显著增强了对于顺铂耐药型上皮卵巢癌细胞的活力抑制作用。提示人参皂苷Rg6具有逆转上皮卵巢癌细胞顺铂耐药的作用,人参皂苷Rg6可作为抗顺铂耐药型卵巢癌的药物。
Claims (3)
1.一种人参皂苷Rg6在制备抗顺铂耐药型卵巢癌药物中的应用。
2.根据权利要求1所述的人参皂苷Rg6在制备抗顺铂耐药型卵巢癌药物中的应用,其特征在于人参皂苷Rg6与顺铂联合在制备抗顺铂耐药型卵巢癌药物中的应用。
3.根据权利要求2所述的人参皂苷Rg6在制备抗顺铂耐药型卵巢癌药物中的应用,其特征在于所述人参皂苷Rg6与顺铂的浓度配比为55.66μM:20μM。
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