CN113116925A - 通关藤苷h与顺铂组合物及其应用 - Google Patents
通关藤苷h与顺铂组合物及其应用 Download PDFInfo
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- CN113116925A CN113116925A CN202110443956.9A CN202110443956A CN113116925A CN 113116925 A CN113116925 A CN 113116925A CN 202110443956 A CN202110443956 A CN 202110443956A CN 113116925 A CN113116925 A CN 113116925A
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- cisplatin
- marsdenia tenacissima
- glycoside
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- tenacissima
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Abstract
本发明涉及医药技术领域，具体是通关藤苷H与顺铂组合物及其应用，所述通关藤苷H和顺铂的摩尔浓度比为：通关藤苷H：顺铂＝1:2。本发明通过以人肺癌细胞A549、食管癌细胞KYSE70和卵巢癌细胞SK‑OV‑3作为体外实验模型，观察通关藤苷H和顺铂联合用药对细胞增殖抑制效果。本发明实验结果表明，与对照组相比(单一用药组)，联合用药组对细胞增殖抑制明显，可显著加强化疗药物在肿瘤治疗中的效果，具备开发成临床联合用药的前景。
Description
技术领域
本发明涉及技术医药领域，具体地说，是通关藤苷H与顺铂组合物及其应用。
背景技术
恶性肿瘤——癌症已成为常见且严重威胁人类生命和生活质量的主要疾病之一。近年来随着经济社会的发展，虽然人们生活水平在不断提高，但癌症的发病率和死亡率却在不断上升。
目前临床使用的治疗肿瘤的西药毒副作用大，在治疗的同时对肿瘤患者的身体造成极大的伤害，此外，也出现了恶性肿瘤细胞对西药的敏感性降低等问题。使得疾病越来越难治疗，患者生存质量下降。
细胞凋亡是指体内外因素触发细胞内预存的死亡程序，在基因的调控下自主地启动细胞的死亡程序，有序地结束生命的过程，即程序性细胞死亡。正常机体利用细胞凋亡清除多余、衰老和受损伤的细胞，以保持机体的内环境平衡，维持正常生理活动。一旦凋亡发生失衡就可能引起癌症、自身免疫性疾病等多种疾病的发生。肿瘤细胞对化疗药物的敏感度降低使得化疗难以取得良好进展进而导致化疗失败，因此提高肿瘤细胞对化疗药物敏感度的机制研究和应用迫在眉睫。而联合用药是指为了达到治疗目的而采用的两种或两种以上药物同时或先后应用，其结果主要是为了增加药物的疗效或为了减轻药物的毒副作用。有研究证实，中药单体与化疗药物联合用药可显著降低化疗药物使用剂量，减轻患者不良反应。本发明针对现有技术的缺陷，首次提出了将通关藤苷H与顺铂联用，用于抗癌，且实验结果表明二者协同作用，可大大降低恶性肿瘤的增值率以及大大提高恶性肿瘤对化疗药物的敏感性。关于本发明通关藤苷H与顺铂组合物及其应用目前还未见报道。
发明内容
本发明的目的是针对现有技术的不足，提供一种通关藤苷H与顺铂组合物及其应用。
为实现上述目的，本发明采取的技术方案是：
第一方面，本发明提供了通关藤苷H合并顺铂组合物，所述通关藤苷H和顺铂摩尔浓度比例为：通关藤苷H：顺铂＝1:(2～4)。
优选地，所述通关藤苷H和顺铂摩尔浓度比例为：通关藤苷H：顺铂＝1:(2～3)。
优选地，所述通关藤苷H和顺铂摩尔浓度比例为：通关藤苷H：顺铂＝1:2。
进一步地，所述组合物包括药学上可接受的载体，所述药学上可接受的载体和通关藤苷H共同加工。
进一步地，所述通关藤苷H的剂型包括注射剂、片剂、胶囊剂或颗粒剂。
第二方面，本发明提供了如上所述的组合物的制备方法，包含按照摩尔浓度配比称取各原料药的步骤。
第三方面，本发明提供了如上所述组合物在制备治疗恶性肿瘤的药物中的应用。
优选地，所述恶性肿瘤包括人肺癌恶性肿瘤、人食管癌恶性肿瘤、人卵巢癌恶性肿瘤。
进一步地，所述的组合物能抑制恶性肿瘤细胞增殖、促进恶性肿瘤细胞凋亡、降低顺铂用药量、提高恶性肿瘤对顺铂的敏感性。
术语
如本文所用，术语“药学上可接受的”的成分是适用于人和/或动物而无过度不良副反应(如毒性、刺激和变态反应)的，即有合理的效益/风险比的物质。
如本文所用，术语“药学上可接受的载体”指用于治疗剂给药的载体，包括各种赋形剂和稀释剂等。该术语指这样一些药剂载体：它们本身并不是必要的活性成分，且施用后没有过分的毒性。合适的载体是本领域普通技术人员所熟知的。在Remington’sPharmaceutical Sciences(MackPub.Co.，N.J.1991)中可找到关于药学上可接受的赋形剂的充分讨论。在组合物中药学上可接受的载体可含有液体，如水、盐水、甘油和乙醇。另外，这些载体中还可能存在辅助性的物质，如乳化剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、调味剂、着色剂、助溶剂等。以上，所述的乳化剂诸如乙酰化单甘油脂肪酸酯、乙酰化双甘油脂肪酸酯、蔗糖酯、山梨糖醇脂、大豆磷脂、月桂酸单甘油酯、丙二醇脂肪酸酯、硬脂酰乳酸钙、双乙酰酒石酸、单硬脂酸甘油酯、改性大豆磷脂等。所述的赋形剂诸如硬脂酸镁、微晶纤维素、乳糖、奶糖、高分子量的聚乙二醇等。所述的填充剂诸如淀粉、甘露醇、硅酸、糊精、磷酸氢钙、纤维素等。所述的粘合剂诸如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、阿拉伯胶、淀粉浆、羟丙基淀粉、改良淀粉、预胶化淀粉、糊精、微晶纤维素、聚乙烯吡咯烷酮胶浆、明胶浆。所述的湿润剂诸如甘油等。所述的崩解剂诸如琼脂、碳酸钙、马铃薯淀粉、木薯淀粉、海藻酸、羟丙基淀粉、改良淀粉、羧甲基淀粉钠、微晶纤维素、瓜耳胶、苍耳胶、黄原胶等。所述的吸收促进剂诸如季铵化合物、泡腾剂、环糊精、维生素D及其衍生物、胡椒碱等。所述的调味剂可以是酸味剂、甜味剂，诸如磷酸、乳酸、酒石酸、偏酒石酸、苹果酸、延胡索酸、乙酸、琥珀酸、木糖醇、甜菊糖、甜蜜素、天门冬酰苯丙氨酸甲酯、薄荷油等。所述的着色剂可以是植物着色剂、动物着色剂或微生物着色剂，诸如甜菜红、姜黄、叶绿素、紫胶红、胭脂虫红、红曲着色剂等。所述的助溶剂诸如β-环糊精、麦芽糊精、吐温、乙醇、司盘类、十二烷基硫酸钠、丙二醇、聚乙二醇、甘油等。但对于本领域技术人员而言，还知晓可用于本发明的药用载体不仅限于上述类型。
剂型
对于本发明所述的通关藤苷H的剂型没有特别的限制，可以是任何适用于哺乳动物服用的剂型；优选的，所述的剂型为注射剂、片剂、胶囊剂或颗粒剂。从易于制备、给药或服用的立场看，优选的通关藤苷H是注射剂。
制备方法
在得知本发明的通关藤苷H与顺铂组合物的配方以后，本领域技术人员可采用多种常规方法来将所述通关藤苷H加工成药物。
制备过程中，还可选择性地加入其它一些药学上(或食品学上或保健品学上)可接受的载体。
用途及使用方法
本发明的组合物可直接用于治疗恶性肿瘤，包括人肺癌恶性肿瘤、人食管癌恶性肿瘤、人卵巢癌恶性肿瘤。
本发明的组合物的用量可随给药的模式、剂型和待治疗的疾病的严重程度而变化。例如，由治疗状况的需要，可每天分开给予若干次的单一剂量，或将剂量按比例地减少。当然，具体剂量还应考虑施用方式、施用对象的身体状况等因素，这些都是本领域技能范围之内的。
本发明优点在于：
首次提出将通关藤苷H与顺铂组合使用，且限定了二者合用的最佳摩尔浓度比，实验以人肺癌恶性肿瘤、人食管癌恶性肿瘤、人卵巢癌恶性肿瘤作为体外实验模型，观察通关藤苷H和顺铂联合用药对细胞增殖抑制效果。本发明实验结果表明，与对照组相比(单一用药组)，联合用药组对细胞增殖抑制明显，可显著加强化疗药物在肿瘤治疗中的效果，且能显著提高肿瘤细胞对化疗药物的敏感性、显著提高恶性肿瘤细胞的凋亡率，进而提高患者的生存质量，具备开发成临床联合用药的前景。
附图说明
附图1是通关藤苷H与顺铂联合用药对肺癌细胞A549增殖抑制的协同作用。
附图2是通关藤苷H与顺铂联合用药对人食管癌KYSE70增殖抑制的协同作用。
附图3是通关藤苷H与顺铂联合用药对人卵巢癌细胞SKOV3增殖抑制的协同作用。
附图4是通关藤苷H、顺铂单用及联合使用对肺癌细胞A549凋亡程度的影响。
附图5是通关藤苷H、顺铂单用及联合使用对人食管癌细胞KYSE70凋亡程度的影响。
附图6是通关藤苷H、CDDP单用及联合使用对人卵巢癌细胞SKOV3凋亡程度的影响。
具体实施方式
下面结合具体实施方式，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明记载的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1效果实施例
1实验材料
通关藤苷H购自宝鸡市辰光生物科技有限公司；二甲亚砜(DMSO)购自Sigma公司；顺铂(Cisplatin,CDDP)购自MCE公司；DMEM高糖培养基，胎牛血清，双抗，PBS均购自Gibco公司；BCA试剂盒均购自索莱宝公司；CCK-8试剂盒购自Dojindo公司；Annexin V-FITC/PI凋亡试剂盒购自美国BD公司。
2实验方法
2.1细胞培养
从液氮罐中取出装有细胞的冻存管，快速放入事先准备好的37℃水浴锅中，轻轻摇晃，使其快速溶解。随后，用酒精棉球擦拭后，移入超净工作台。用移液枪将吸出的细胞混合液置入离心管中，离心后，去上清，培养基重悬，将细胞团块吹散、吹匀，并将其移至培养皿中，培养基为含10％胎牛血清和1％双抗的DMEM高糖培养基。在37℃，5％CO2，饱和湿度条件下培养。
2.2通关藤苷H对人肺癌、食管癌、卵巢癌细胞株活性的影响
取对数期细胞A549、KYSE70和SKOV3，用新鲜的培养液重悬，调整细胞浓度为8×104个/mL，按每孔100μL接种于96孔板，在孵育箱中孵育12h，等待贴壁。贴壁后，弃去细胞培养液，设置对照组(不加药)和不同给药浓度的通关藤苷H组(通关藤苷H浓度为5，10，15，20和25μM)。每组均设6复孔，对每孔进行不同处理以保证最终液体体积为100μL，培养48h。于结束前，吸去药液，每孔加入10μL CCK-8和90μLDMEM，混匀，分别培养2h后置于酶标仪上，于450nm波长处检测吸光度。计算通关藤苷I对三种肿瘤细胞的抑制率。
2.3通关藤苷H联合顺铂对肿瘤细胞株活性的影响
取对数生长期肺癌A549细胞、食管癌KYSE70细胞和卵巢癌SKOV3细胞，分别用新鲜的培养液重悬，调整细胞浓度为8×104个/mL，按每孔100μL接种于96孔板，在孵育箱中孵育12h，等待贴壁。贴壁后，弃去细胞培养液，设置对照组(不加药)、通关藤苷H组(通关藤苷H浓度为5，10，15，20和25μM)、顺铂组(给药浓度均为10，20，30，40和50μM)、联合用药组(顺铂：通关藤苷H药物浓度2：1配比)。每组均设6复孔，对每孔进行不同处理以保证最终液体体积为100μL，培养48h。于结束前，吸去药液，每孔加入10μL CCK-8和90μLDMEM，混匀，分别培养2h后置于酶标仪上，于450nm波长处检测吸光度。分别计算通关藤苷H，顺铂和通关藤苷H联合顺铂对三种肿瘤细胞A549、KYSE70和SKOV3的抑制率。
2.4通关藤苷H与顺铂联合使用诱导肿瘤细胞凋亡作用
取对数生长期细胞，接种于6孔板中，每孔加入新鲜培养液2mL，放入孵育箱中培养。12h后，弃去培养基，进行药物处理。继续培养48h，弃去药液，PBS冲洗2遍，胰酶消化，收集细胞悬液，离心操作(4℃，1000rpm，3min),100μL 1×Binding Buffer重悬于1.5mL EP管，加入5μLAnnexin V-FITC和5μL PI染液，室温放置15min，半小时内流式仪上机检测。
2.5数据处理及分析
使用SPSS21.0进行数据分析，计量资料以
表示，多组间均数比较采用单因素方差分析(onewayANOVA)，两两比较采用LSD-t检验；方差不齐采用秩和检验。P<0.05为差异具有统计学意义。
3实验结果
各组药物对肺癌A549细胞、食管癌KYSE70细胞和卵巢癌SKOV3细胞进行处理48h后，与空白对照组相比，各组药物均可抑制A549、KYSE70和SKOV3细胞的增殖(**P<0.01)，抑制率呈浓度依赖性。结果见表1、2和3。
3.1通关藤苷H、顺铂单独及联合使用对人肺癌A549细胞的增殖抑制作用
表1通关藤苷H、顺铂单独及联合使用对人肺癌A549细胞的增殖抑制作用(
n＝3)
表2通关藤苷H、顺铂单独及联合使用对人食管癌KYSE70细胞的增殖抑制作用(
n＝3)
表3通关藤苷H、顺铂单独及联合使用对人卵巢癌SKOV3细胞的增殖抑制作用(
n＝3)
3.2通关藤苷H与顺铂联合用药的协同作用研究
为了验证通关藤苷H与顺铂对肿瘤细胞的增殖抑制存在协同作用，我们利用CompuSyn软件计算3组联合用药的Combination Index(CI)值，结果见表4、5和6，图1、2和3。CI值作用判断协同作用存在与否的量化指标，CI值<1代表具有协同效应，数值越小协同效应越强。计算结果表明，两药物联合对肺癌A549细胞、食管癌KYSE70细胞和卵巢癌SKOV3细胞均存在协同效应。
表4通关藤苷H与顺铂联合使用对肺癌细胞A549增殖抑制的联合指数(
n＝3)
表5通关藤苷H与顺铂联合使用对人食管癌KYSE70增殖抑制的联合指数(
n＝3)
表6通关藤苷H与顺铂联合使用对人卵巢癌细胞SKOV3增殖抑制的联合指数(
n＝3)
3.3通关藤苷H和顺铂单独及联合使用诱导肿瘤细胞凋亡作用
给药后48h，通关藤苷H组，顺铂组以及联合用药组对肺癌细胞A549凋亡水平均显著上升(**P<0.01)，分别为(8.29±1.46)％、(16.12±1.33)％和(33.29±3.52)％。与单药给药组相比，联合用药组可显著升高细胞的凋亡水平(**P<0.01)。结果见表7、图4。
表7通关藤苷H、顺铂单用及联合使用对肺癌细胞A549凋亡程度的影响(
n＝3)
给药后48h，通关藤苷H组，顺铂组以及联合用药组对人食管癌细胞KYSE70凋亡水平均显著上升(**P<0.01)，分别为(10.39±1.33)％、(15.39±2.17)％和(34.29±4.04)％。与单药给药组相比，联合用药组可显著升高细胞的凋亡水平(**P<0.01)。结果见表8、图5。
表8通关藤苷H、顺铂单用及联合使用对人食管癌细胞KYSE70凋亡程度的影响(
n＝3)
给药后48h，通关藤苷H组，顺铂组以及联合用药组对人卵巢癌细胞SKOV3凋亡水平均显著上升(**P<0.01)，分别为(7.36±0.82)％、(13.91±2.87)％和(30.89±5.03)％。与单药给药组相比，联合用药组可显著升高细胞的凋亡水平(**P<0.01)。结果见表9、图6。
表9通关藤苷H、顺铂单用及联合使用对人卵巢癌细胞SKOV3凋亡程度的影响(
n＝3)
4讨论
顺铂是临床癌症治疗的一线药物，然而肿瘤细胞对其敏感度的降低使治疗效果变差。临床数据表明，与传统单用化疗药物相比，联合用药可以提高疗效。因此，寻找可与常用化疗药物协同增效的天然成分对于结直肠癌治疗具有重要临床意义。
本发明中，采用通关藤苷H(15μM)和顺铂(30μM)联合用药，体外实验证明能有效抑制肺癌A549细胞，人食管癌细胞KYSE70和人卵巢癌细胞SKOV3的增殖，使癌细胞对化疗药物的敏感性增强，促进肿瘤细胞凋亡。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员，在不脱离本发明原理的前提下，还可以做出若干改进和补充，这些改进和补充也应视为本发明的保护范围。
Claims (9)
1.通关藤苷H合并顺铂组合物，其特征在于，所述通关藤苷H和顺铂摩尔浓度比例为：通关藤苷H：顺铂＝1:(2～4)。
2.通关藤苷H合并顺铂组合物，其特征在于，所述通关藤苷H和顺铂摩尔浓度比例为：通关藤苷H：顺铂＝1:(2～3)。
3.通关藤苷H合并顺铂组合物，其特征在于，所述通关藤苷H和顺铂摩尔浓度比例为：通关藤苷H：顺铂＝1:2。
4.根据权利要求1-3任一所述的组合物，其特征在于，所述组合物包括药学上可接受的载体，所述药学上可接受的载体和通关藤苷H共同加工。
5.根据权利要求1-3任一所述的组合物，其特征在于，所述通关藤苷H的剂型包括注射剂、片剂、颗粒剂或胶囊剂。
6.权利要求1-5任一所述的组合物的制备方法，其特征在于，包含按照摩尔浓度配比称取各原料药的步骤。
7.权利要求1-3任一所述组合物在制备治疗恶性肿瘤的药物中的应用。
8.根据权利要求7所述的应用，其特征在于，所述恶性肿瘤包括人肺癌恶性肿瘤、人食管癌恶性肿瘤、人卵巢癌恶性肿瘤。
9.根据权利要求7所述的应用，其特征在于，所述的组合物能抑制恶性肿瘤细胞增殖、促进恶性肿瘤细胞凋亡、降低顺铂用药量、提高恶性肿瘤对顺铂的敏感性。
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