CN116999445A - 熊果酸与澳洲茄胺联合治疗结直肠癌的应用 - Google Patents
熊果酸与澳洲茄胺联合治疗结直肠癌的应用 Download PDFInfo
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Abstract
熊果酸与澳洲茄胺联合治疗结直肠癌的应用，属于生物技术领域，具体公开了一种熊果酸与澳洲茄胺联合用药在治疗结直肠癌中的应用。该药物组合物抗癌疗效好，毒副作用低，两者联合用药产生了协同作用。二者通过诱导癌细胞凋亡，抑制其增殖与转移，在体内外发挥协同抗癌活性。本发明中熊果酸与澳洲茄胺的联合用药方案在结直肠癌的防治和研究方面具有重要的意义和广泛的应用前景。
Description
技术领域
本发明属于生物技术领域，具体涉及熊果酸和澳洲茄胺联合用药在治疗结直肠癌中的应用。
背景技术
结直肠癌(colorectal cancer,CRC)是继肺癌和乳腺癌之后，世界上第三常见的癌症类型，也是第四致命的癌症类型。随着现代医学的发展，CRC的治疗不断完善,包括手术、放疗、化疗、分子靶向治疗及中医中药的综合治疗，其中化疗药物的使用在CRC治疗中占到很大比例。铂类化合物(奥沙利铂)、抗代谢药(5-氟尿嘧啶)、拓扑异构酶抑制剂(伊立替康)是最常用的化疗药物，它们阻碍了有丝分裂、DNA复制和细胞毒作用。尽管上述药物已导致CRC死亡率有所降低，但有充分证据表明，大多数接受药物治疗的患者不会完全受益，部分会发生癌症复发或者经历严重且可能致命的药物不良事件。
中药方剂多途径、多靶点的治疗方式是联合用药的典型范例，在疾病治疗中体现了巨大的优势。中草药的配伍关系研究主要为中药药材配伍、有效部位配伍以及有效成分配伍。以功效为导向的活性成分之间的配伍将传统经验与现代技术相结合，既能够发挥协同治疗的效果，也能够从分子水平上阐明作用机制，为中医药走向现代化提供了一个新的思路。在治疗结直肠癌的中药药方中，有很多传统药对，例如黄芩—黄连，女贞子—墨旱莲，山慈菇—全蝎，地榆—槐花，针对结直肠癌不同的病理分期及患者所处的不同西医常规治疗阶段，分阶段辨证论治，善用药对，在减轻西医常规治疗不良反应、增加治疗疗效、延长患者生存期、提高患者生活质量等方面疗效突出。
藤龙补中汤是以解毒、利湿、健脾立法，凝练大肠癌治疗协定处方研发的治疗大肠癌的抗癌中药复方，由藤梨根、龙葵、蛇莓、白术、茯苓、薏苡仁、槲寄生、半枝莲组成。藤梨根为猕猴桃科植物中华猕猴桃(Actinidia chinensis Planch.)或软枣猕猴桃(A.argutaPlanch.)等植物的干燥根，作为清热解毒类传统中药，可用于解毒消肿、散瘀通络，具有清热解毒、祛风除湿、利尿止血等功效。其中重要的活性成分熊果酸可以通过抑制IL-6/STAT3信号通路调控其下游Bcl-2、Cyclin D1、CDK4、Bax、p15等因子的表达，进而有效抑制肠细胞的增殖、促进其凋亡。龙葵是茄科植物茄属植物龙葵(Solanum ni-grum Linne.)的干燥地上部分，具有清热解毒、消炎利尿等功效，可用于治疗疔疮、痈肿、丹毒，跌打扭伤，现代药理学研究表明龙葵提取物具有抗肿瘤作用。龙葵中主要活性成分澳洲茄胺已被研究能有效抑制人肠癌细胞增殖，通过下调MMP抑制细胞转移，并通过抑制AKT/GSK3β/β-catenin信号通路的激活，增加Bax/Bcl-2比例、活化Caspase-3、Caspase-8、Caspase-9、PARP诱导细胞发生凋亡。目前尚无关于熊果酸(Ursolic Acid,UA)和澳洲茄胺(Solasodine,Sol)联合应用的相关报道。
发明内容
本发明的目的是针对现有肿瘤治疗技术中的不足，提供一种熊果酸联合澳洲茄胺在抗肿瘤药物中的应用。
本发明还提供了熊果酸和澳洲茄胺在抑制结直肠癌细胞增殖药物中的应用。
本发明还提供了熊果酸和澳洲茄胺在诱导结直肠癌细胞凋亡药物中的应用。
本发明还提供了熊果酸和澳洲茄胺在抑制结直肠癌细胞迁移和/或侵袭药物中的应用。
所述熊果酸和澳洲茄胺的优选摩尔浓度比为1:4。
更优选地，最佳配伍方案为6μM的熊果酸配伍24μM的澳洲茄胺。
上述应用中，所述结肠癌细胞为HCT-116细胞和MC38细胞；
本发明还提供了熊果酸和澳洲茄胺在抑制小鼠异种移植瘤增殖方面的应用。
所述小鼠异种移植瘤增殖实验中熊果酸和澳洲茄胺的优选质量比为1:4。
上述应用中，所述小鼠为Balb/c免疫缺陷型小鼠，异种移植瘤为MC38结肠癌细胞所接种。
本发明的有益效果：
本发明将熊果酸和澳洲茄胺低剂量联合用药抗结直肠癌，与熊果酸、澳洲茄胺单药治疗比较，药物协同作用，药效显著提升，表现出更低的药物毒性，更佳的抑癌效果。
附图说明
图1为MTT探究药对比例及时间实验结果。
图2为细胞划痕实验结果。
图3为Transwell侵袭实验结果。
图4为小鼠异种移植瘤抑制实验(n＝4)。
具体实施方式
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂，如无特殊说明，均可从商业途径得到。
实施例1
熊果酸-澳洲茄胺抑制结直肠癌细胞增殖的协同效应实验
1.熊果酸-澳洲茄胺抑制结直肠癌细胞增殖的比例及时间探究
固定抗癌药物熊果酸的浓度(6μM)，联合以1:0.1、1:0.25、1:0.5、1:1、1:4、1:7、1:10七个比例浓度梯度的澳洲茄胺处理结肠癌HCT-116细胞和MC38细胞24、48、72h，用MTT比色法计算细胞在不同给药比例及时间的药物处理模式下的增殖抑制强度。如附图1所示，综合不同浓度比例和给药时间下的细胞活性，得出优选给药比例和给药时间分别为1:4和48h。
2.熊果酸-澳洲茄胺联合用药研究
以1:4的联合用药比例，选用一定浓度梯度的熊果酸与澳洲茄胺分别处理结肠癌HCT-116细胞和MC38细胞48h，同时，联合使用不同梯度浓度的熊果酸与澳洲茄胺处理结肠癌HCT-116细胞和MC38细胞48h，用MTT比色法计算细胞在三种不同的药物处理模式下各自的增殖抑制强度，根据计算出联合指数(Combination Index,CI)来反应两药配伍的效应，结果见表1。熊果酸-澳洲茄胺联合用药在体外表现出中强于单体药物的抑制效应，具体为中高浓度协同(CI<1)，低浓度拮抗(CI>1)。
表1熊果酸联合澳洲茄胺对结肠癌细胞增殖的抑制效应及联合指数
*p<0.05vs单药组，nsp>0.05
实施例2
熊果酸联合澳洲茄胺诱导结肠细胞凋亡具有协同效应
根据实施例1的结果，采用析因设计，观察两药联用对结肠癌细胞凋亡的影响。
1.流式细胞术检测熊果酸联合澳洲茄胺诱导结肠癌细胞凋亡的效应
选择6μM熊果酸和24μM澳洲茄胺分别处理结肠癌HCT-116细胞和MC38细胞48h，同时设置联合用药处理组。收集细胞并调节细胞浓度，加入适量标记了荧光染料的Annexin V和适量PI，孵育后用流式细胞仪检测。结果见表2，经UA+Sol组刺激后的HCT-116和MC38结肠癌细胞凋亡率高于对照组和单药组。
表2熊果酸联合澳洲茄胺诱导结肠癌细胞凋亡的效应
*p<0.05vs Control
实施例3
熊果酸联合澳洲茄胺诱导结肠细胞转移具有协同效应
1.划痕实验观察熊果酸联合澳洲茄胺抑制结肠癌细胞迁移的效应
分别用6μM熊果酸和24μM澳洲茄胺配伍，采用划痕实验观察其对结肠癌细胞迁移的影响。采用细胞划痕实验构建体外伤口愈合模型。结果见图2和表3所示，药物处理后，在倒置显微镜观察到对照组细胞具有明显的愈合趋势，证明模型构建成功，而熊果酸与澳洲茄胺联用处理组的HCT-116细胞和MC38细胞伤口愈合能力明显降低，与熊果酸治疗组和澳洲茄胺治疗组作用相比，熊果酸和澳洲茄胺联合治疗对抑制结肠癌细胞迁移作用明显增强。
表3熊果酸联合澳洲茄胺对结肠癌细胞迁移的抑制作用(划痕法)
*p<0.05vs Control，nsp>0.05
2.Transwell实验观察熊果酸联合澳洲茄胺抑制结肠癌细胞侵袭的效应
分别用6μM熊果酸和24μM澳洲茄胺配伍，采用Transwell实验观察其对结肠癌细胞侵袭的影响。使用Transwell小室将细胞分隔于上室中。静置4-6h贴壁后给药，培养48h后进行固定染色。见图3和表4，经熊果酸与澳洲茄胺联用处理组处理HCT-116细胞和MC38细胞后，从Transwell小室上室迁移到下室的细胞相较于对照组、熊果酸治疗组和澳洲茄胺治疗组数量明显减少，提示熊果酸和澳洲茄胺联合治疗对抑制结肠癌细胞侵袭作用明显增强。
表4熊果酸联合澳洲茄胺对结肠癌细胞侵袭的抑制作用(Transwell法)
*p<0.05vs Control，nsp>0.05
实施例4
熊果酸联合澳洲茄胺协同抑制结肠癌移植瘤生长
构建结肠癌小鼠异种移植瘤模型，熊果酸单独或联合澳洲茄胺经灌胃给药作用于移植瘤小鼠，对照组给予等体积溶剂灌胃。治疗14天后，将肿瘤组织测量和拍照。结果如附图4，肿瘤大小明显看到熊果酸单独及其联合澳洲茄胺给药组小鼠的肿瘤小于对照组，联合给药组具有最明显的肿瘤抑制效果。
Claims (10)
1.一种抗肿瘤药物组合物，其特征在于，其有效成分是熊果酸和澳洲茄胺，所述肿瘤为结直肠癌。
2.如权利要求1所述的抗肿瘤药物组合物，其特征在于，所述抗肿瘤是指抑制肿瘤细胞增殖、诱导肿瘤细胞凋亡、抑制肿瘤细胞转移。
3.如权利要求1所述的抗肿瘤药物组合物，其特征在于，所述结肠癌细胞来源于人和动物，为HCT-116细胞和MC38细胞。
4.如权利要求1所述的抗肿瘤药物组合物，其特征在于，所述熊果酸和澳洲茄胺的摩尔浓度比为1:4，具体在药物体系中的浓度为6μM和24μM。
5.如权利要求1所述的抗肿瘤药物组合物，其特征在于，所述肿瘤还包括实体肿瘤，具体为MC38细胞接种的结肠癌实体肿瘤。
6.如权利要求5所述的抗肿瘤药物组合物，其特征在于所述熊果酸和澳洲茄胺的质量比为1:4。
7.权利要求1所述抗肿瘤药物组合物在抑制结直肠癌细胞增殖药物中的应用。
8.权利要求1所述抗肿瘤药物组合物在诱导结直肠癌细胞凋亡药物中的应用。
9.权利要求1所述抗肿瘤药物组合物在抑制结直肠癌细胞迁移和/或侵袭药物中的应用。
10.权利要求1所述抗肿瘤药物组合物在抑制小鼠异种移植瘤增殖方面的应用。
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