CN107320486A - 穿心莲内酯与顺铂联合用药在制备治疗顺铂耐药性肺癌药物中的应用 - Google Patents
穿心莲内酯与顺铂联合用药在制备治疗顺铂耐药性肺癌药物中的应用 Download PDFInfo
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Abstract
本发明属于药学领域，特别涉及穿心莲内酯与顺铂联合用药在制备治疗顺铂耐药性肺癌药物中的应用。本发明首次分析穿心莲内酯与顺铂联合用药在治疗顺铂耐药性肺癌的效果，拓展了该化合物的新用途。
Description
一、技术领域
本发明属于药学领域。特别涉及穿心莲内酯增敏顺铂在制备治疗耐药性肺癌药物中的应用。
二、背景技术
近年来根据国家卫生部报告的数据表明，肺癌已替代肝癌成为我国恶性肿瘤死亡原因第一位(约占全部恶性肿瘤致死的22.7％)。在全球，肺癌的发病率和死亡率也是居各种癌症之首。化疗是治疗肺癌的主要手段之一，尽管取得了一定的进展，但在过去25年其5年生存率仍未见显著提高，耐药成为化疗失败的主要原因。顺铂(cis-dichlorodiamine platinum，CDDP)是临床肺癌化疗的一线药物，病人在顺铂化疗初期通常可以获得良好的疗效，但是耐药性往往严重限制了顺铂的进一步治疗。国际癌症组织推荐以顺铂为基础的联合化疗作为肺癌的一线标准化疗方案，现已取得了一定的疗效。
穿心莲内酯(Andrographolide)，是天然植物穿心莲(Andrographis Paniculata(Burm.f)Ness)的主要有效成份，具有祛热解毒，消炎止痛之功效，对肿瘤生长也有一定的抑制作用。关于穿心莲内酯与顺铂协同作用治疗耐药性肺癌的报导尚未出现。本发明研究了穿心莲内酯在增敏顺铂治疗耐药性肺癌中的作用。
三、发明内容
本发明的目的是研究穿心莲内酯与顺铂联合用药在治疗顺铂耐药性肺癌的效果，增加该化合物的适应症，为老药新用提供依据。
本发明的技术方案：
1.穿心莲内酯的结构
本发明所研究的穿心莲内酯(Andrographolide)的结构式如下：
2.穿心莲内酯与顺铂联合用药的药理试验
1、细胞培养
人源顺铂耐药性NSCLC细胞株A549/DPP来自中国科学上海细胞生物研究所，用DMEM完全培养基(含10％FBS)培养于37℃、5％CO2饱和湿度的培养箱中。
2、裸鼠肺癌异种移植模型建立及给药
将对数生长期的A549/DPP细胞用预冷的PBS洗涤和重悬。将重悬好的细胞稀释成4×107个/mL，以每只裸鼠100μL的体积进行皮下注射。待肿瘤长出后，每隔两天用游标卡尺测量肿瘤大小。肿瘤体积计算公式：V＝0.5*L1*(L2)2，L1代表肿瘤长度，L2代表肿瘤宽度。植瘤两周后，把裸鼠(肿瘤平均大小约为50mm3)随机分为4组，对照组(PBS)，顺铂组(0.75mg/kg)，穿心莲内酯组(水溶性穿心莲内酯磺化物5mg/kg)，顺铂组与穿心莲内酯联用组(顺铂0.75mg/kg和穿心莲内酯磺化物5mg/kg)，每组8-10只。腹腔注射给药，每天一次，持续30天。
3、免疫印迹
取适量肿瘤组织(约10mg)，用300μL RIPA裂解液进行匀浆。冰浴0.5h，4℃离心12000g，10min，取上清。用BCA测定蛋白含量。制备10％的SDS-PAGE胶，以20μg蛋白量上样电泳。恒压条件下，积层胶内电泳电压为80V，分离胶电压为100V。电泳结束后，用湿法转膜转至PVDF膜(350mA，90min)。膜用5％脱脂奶粉封闭，室温1h，膜与一抗共孵，室温2h，PBST洗涤三次，与适当稀释的二抗共孵，室温1h，膜同法洗涤三次，与底物共孵1min。膜与X-光胶片在暗盒曝光。
4、AnnexinV/PI染色
采用流式细胞术检测A549/DPP细胞凋亡率。分别单用顺铂(10μg/mL)，单用穿心莲内酯(30μM)或二者合用刺激A549/DPP细胞，48h后用预冷的PBS洗涤2次，以结合缓冲液调整细胞浓度至1×106个/mL，吸取100μL细胞悬液(1×105个细胞)于流式细胞检测管中，分别加入5μL FITC-Annexin V和5μL碘化丙啶(Propidiumiodide，PI)溶液，轻轻震荡混匀，室温避光孵育15min后，再加入400μL结合缓冲液，并立即流式检测。每个样品收集1×104个细胞，使用FACScan软件(Becton Dickinson，USA)进行分析。
5、统计分析
数据以mean±SD表示。肿瘤体积两组间的比较，用Mann-Whitney test，其他数据两组间比较用Student’s two-tailed t-test来检验各组间的差异。***代表P＜0.001，**代表P＜0.01，*代表P＜0.05。
3.穿心莲内酯与顺铂联合用药的药理试验结果及分析
从图1、2、3可以看出，单用顺铂(0.75mg/kg)或单用穿心莲内酯(5mg/kg)对顺铂耐药性肺癌细胞的体内生长无显著抑制作用，但是二者联用对肿瘤生长的抑制作用明显增强。在治疗终点(给药第30天)，联合用药组肿瘤大小与PBS对照组相比，肿瘤抑制率达到59.22％(肿瘤抑制率＝1-实验组肿瘤体积/对照组肿癌体积；P＜0.01，Mann-Whitney test)。与单用顺铂组相比，肿瘤抑制率提高了41.71％(59.22％vs 17.51％，P＜0.05，Mann-Whitney test)。联用组与单用穿心莲内酯组平均肿瘤重量分别为(0.134±0.056)vs(0.290±0.043)g(P＜0.05，Students’t test)，减少0.156g；联用组与PBS对照组平均肿瘤重量分别为(0.134±0.056)vs(0.350±0.114)g(P＜0.01，Students’t test)，减少0.216g。
如图4所示，与PBS对照组相比，联用组肿瘤组织总蛋白中细胞凋亡相关蛋白PARP的剪切形式明显增加，表明联合用药可能促进顺铂耐药性肺癌细胞的凋亡。
从图5可以看出，顺铂(10μg/mL)与穿心莲内酯(30μM)联用与顺铂单用相比，明显提高了体外培养的耐药性肺癌细胞的凋亡能力。这一结果佐证了图4的在体结果。
四、附图说明
图1、小鼠移植瘤体积变化。
穿心莲内酯5mg/kg单用或顺0.75mg/kg单用对顺铂耐药肺癌细胞株A549/DDP体内生长没有明显影响，但联合给药时，能够有效抑制小鼠移植瘤的生长，穿心莲内酯联合顺铂组与PBS对照组相比，肿瘤抑制率达到59.22％(P＜0.01，Mann-Whitney test)(肿瘤抑制率＝1-实验组肿瘤体积/对照组肿瘤体积)。
图2、给药终止后剥除的小鼠移植肿瘤。
给药30天，处死小鼠，剥离小鼠移植肿瘤，进行拍照。
图3、肿瘤重量。
称量肿瘤重量，联用组与单用穿心莲内酯组平均肿瘤重量分别为(0.134±0.056)vs(0.290±0.043)g(P＜0.05，Students’t test)，联用组与PBS对照组平均肿瘤重量分别为(0.134±0.056)vs(0.350±0.114)g(P＜0.01，Students’t test)。
图4、肿瘤组织蛋白印迹。
提取肿瘤组织总蛋白，蛋白印迹考察了凋亡相关指标PARP的剪切变化，可以看出，与PBS对照组相比，联用组PARP的剪切显著增强。
图5、顺铂耐药肺癌细胞株凋亡检测
Annexin V-PI双染流式技术检测了顺铂耐药肺癌细胞株的凋亡，可以看出，顺铂10μg/mL与穿心莲内酯30μM联用与顺铂单用相比，明显提高了细胞凋亡能力(P＜0.001，Students’t test)。
五、具体实施方式
本发明采用穿心莲内酯与顺铂联合用药治疗耐药性肺癌。通过裸鼠异种移植实验发现二者联用与单用顺铂或单用穿心莲内酯相比，肿瘤生长抑制率显著提高，平均肿瘤重量也明显下降。联用组肿瘤组织中细胞凋亡相关蛋白PARP的剪切增强，表明肿瘤细胞发生明显的凋亡。体外实验也表明穿心莲内酯与顺铂联用可明显增加耐药性肺癌细胞株的凋亡。
以上结果表明穿心莲内酯与顺铂联合用药能通过促进肿瘤细胞凋亡从而抑制顺铂耐药性肺癌的发展，为制备治疗耐药性肺癌的药物提供依据。
Claims (1)
1.穿心莲内酯与顺铂联合用药在制备治疗顺铂耐药性肺癌药物中的应用。
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| Title |
|---|
| LIN ET AL.: "Andrographolide Sensitizes the Cytotoxicity of Human Colorectal Carcinoma Cells Toward Cisplatin via Enhancing Apoptosis Pathways In Vitro and In Vivo", 《TOXICOLOGICAL SCIENCES》 * |
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