CN112641949A - 一种含有pi3k抑制剂的药物组合物及其应用 - Google Patents
一种含有pi3k抑制剂的药物组合物及其应用 Download PDFInfo
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Abstract
本发明属于生物医药领域，具体涉及一种含有PI3K抑制剂的药物组合物及其应用，所述组合物包含有效量的PI3K抑制剂、有效量的HSP90抑制剂和药物上可接受的载体。本发明含有PI3K抑制剂的药物组合物对食管癌、肺癌、胃癌及肝癌细胞具有显著的治疗作用，同时对正常细胞毒性较小，本发明PI3K抑制剂组合物对食管癌细胞增殖和迁移具有显著抑制作用，同时能够显著升高Cleaved‑PARP的表达，促进凋亡效果。本发明含有PI3K抑制剂的药物组合物使药物的生物利用度提高，同时能够使药效产生协同增效的作用，对肿瘤耐药治疗效果明显优于单药使用。
Description
技术领域
本发明属于生物医药领域，具体涉及一种含有PI3K抑制剂的药物组合物及其应用。
背景技术
全球癌症状况日益严重，癌症而死亡的人数将由每年的600万增加至1000万。随着生活水平的提高，饮食结构的改变，食管癌的发病率呈逐年上升趋势；原发性肝癌是人类最常见的恶性肿瘤之一；肺癌为常见的恶性肿瘤，分为细胞肺癌和非小细胞肺癌。这些癌症的治疗虽然以手术为主，但由于早期患者一般无明显症状，在首次被确诊的癌症患者中，很多已为中晚期，故非手术治疗(如化疗)在肿瘤的综合治疗中有着十分重要的地位。化疗是利用化学药物阻止癌细胞的增殖、浸润、转移，直至最终杀灭癌细胞的一种治疗方式。
目前已上市的抗肿瘤药物较多，如烷化剂药物、抗代谢药物、抗肿瘤抗生素、免疫调节剂等，但是大多药物普遍存在选择性低，毒性较大，病人不耐受等缺点。随着对肿瘤的发生发展的分子机制研究越来越清楚，分子靶向治疗多种恶性肿瘤受到了广泛的关注和高度重视。分子靶向药物选择性高、广谱有效，其安全性优于细胞毒性化疗药物，是目前肿瘤治疗领域发展的新方向。
磷脂酰肌醇3激酶(PI3K)/丝氨酸苏氨酸激酶(AKT)信号通路不仅调节肿瘤细胞的增殖与活化，还影响肿瘤细胞的侵袭、迁移、细胞外基质的降解以及肿瘤血管生成等。PI3K/AKT轴的扰动直接与各种疾病有关，最显著的是癌症、免疫疾病、炎性疾病和糖尿病。LY294002是首个合成的已知抑制PI3Kα/δ/β的小分子，是选择性的可渗透细胞的特定PI3K抑制剂，它不仅能够结合class I PI3Ks和其他PI3K相关的激酶，还能够结合一些与PI3K家族无关的新型靶点，可作用于酶的ATP结合位点，且抑制自体吞噬的螯合作用。Dactolisib(BEZ235)，一种双重的pan-class I PI3K和mTOR抑制剂，作用于p110α/γ/δ/β和mTOR。Pictilisib(GDC-0941)是目前口服生物可利用的I类PI3激酶(PI3K)抑制剂，可竞争性地与PI3K的ATP结合口袋相结合，阻止传递PI3K下游信号的第二信使磷脂酰肌醇3，4，5-三磷酸(PIP 3)的形成。
热休克蛋白(Heat Shock Protein,HSP)是在从细菌到哺乳动物中广泛存在一类热应激蛋白质。HSP90是一种普遍存在的分子伴侣，在真核和原核细胞中广泛存在，负责许多致癌蛋白的稳定和成熟。当传统疗法由于肿瘤基因改变导致肿瘤细胞通过分支信号通路来减少对原有药物抑制通路的依赖性时，数量众多的HSP90往往都直接或间接参与这些新的通路的调节。SNX-2112是目前在临床试验中具有抗癌特性的HSP90抑制剂，SNX-2112能够选择性结合到HSP90α和HSP90β的ATP结合袋中。17-AAG，是一种有效的HSP90抑制剂，抑制许多蛋白的表达，包括雄激素受体(AR)，HER2和AKT。
目前，大部分肿瘤的生物学行为并非由单一信号传导通路所支配，而是多个信号传导通路共同起作用的，因此联合用药针对多靶点进行治疗将不仅旨在减少或延缓耐药性的出现、降低毒性，而且还通过多种药物对癌细胞杀伤的协同作用取得更好的疗效。目前，没有关于PI3K抑制剂和HSP抑制剂联合用药用于抗肿瘤耐药的相关研究报道。
发明内容
针对现有技术存在的不足，提供了一种含有PI3K抑制剂的药物组合物，本发明含有PI3K抑制剂的药物组合物显示出对食管癌、肺癌、乳腺癌及结直肠癌细胞具有显著的治疗作用，同时对正常细胞毒性较小。本发明含有PI3K抑制剂的药物组合物对食管癌细胞增殖、迁移和对食管癌细胞克隆形成具有显著抑制作用，显著升高Cleaved-PARP的表达，促进凋亡效果，使药物的生物利用度提高。同时，本发明含有PI3K抑制剂的药物组合物中的LY294002和SNX-2112联用能够使药效产生协同增效的作用，扩大抗肿瘤范围，对食管癌、肺癌、肝癌及胃癌细胞具有显著的治疗作用，且对正常细胞毒性较小，对肿瘤耐药治疗效果明显优于单药使用。
本发明的上述发明目的是通过以下技术方案得以实现的：
本发明提供了一种含有PI3K抑制剂的药物组合物，所述组合物包含有效量的PI3K抑制剂、有效量的HSP90抑制剂和药物上可接受的载体。
优选的，所述的PI3K抑制剂为BEZ235、GDC-0941和LY294002的一种，所述HSP90抑制剂为17-AAG和SNX-2112中的一种。
优选的，所述PI3K抑制剂为LY294002，所述HSP90抑制剂为SNX-2112。
优选的，所述LY294002和SNX-2112的摩尔浓度比为10～50∶0.025～0.4。
优选的，所述药物组合物中LY294002和SNX-2112的摩尔浓度比为30∶0.05。
优选的，可将本发明中所述药物组合物按照本领域常规技术制备成注射制剂或口服制剂，本发明优选将本发明中所述药物组合物制备成口服制剂，所述口服制剂优选为口服胶囊。所述药物组合物的剂型为注射制剂或口服制剂。根据制剂形式，本发明所述药物组合物在制剂中的含量以质量分数计，可以为1～99％，优选为5～90％；制剂使用的辅料可采用本领域常规的辅料，以不和本发明药物组合物发生反应或不影响本发明药物的疗效为前提，制剂的制备方法可以采用本领域常规的制备方法进行制备。
本发明另外一个目的是提供上述药物在制备预防和/或治疗肿瘤耐药药物中的用途。
优选的，所述肿瘤选自食管癌、肺癌和肝癌的至少一种。
优选的，所述肿瘤为食管癌。
与现有技术相比，本发明药物组合物具有以下优势：
本发明药物组合物在治疗食管癌、肺癌及肝癌方面具有显著的积极效果，尤其是在治疗食管癌方面，取得了协同增效的作用，明显优于它们中的单组份药物，且经试验表明，本发明药物组合物与现有抗肿瘤药物相比，疗效有提升，且毒性明显偏低，并且能够逆转肿瘤多药耐药，减少了副作用的发生，取得了预料不到的技术效果。
附图说明
图1为LY294002单独作用对食管癌细胞迁移的影响。
图2为LY294002和SNX-2112联合作用对肿瘤细胞和正常细胞存活率影响。
图3为LY294002和SNX-2112联合作用对耐药食管癌细胞迁移的影响。
图4为LY294002和SNX-2112联合作用对食管癌和耐药食管癌细胞克隆形成的影响。
图5为LY294002和SNX-2112联合作用对食管癌和耐药食管癌细胞凋亡的影响。
具体实施方式
以下通过具体实施方式的描述对本发明作进一步说明，但这并非是对本发明的限制，本领域技术人员根据本发明的基本思想，可以做出各种修改或改进，但是只要不脱离本发明的基本思想，均在本发明的范围之内。
实施例1、LY294002单独作用对食管癌细胞迁移的影响
将食管癌细胞株KYSE30、KYSE450以每孔12000个细胞的数量接种到96孔板，待细胞贴壁后，同步化12h，用划痕仪进行划痕，PBS洗两遍后，换含2％胎牛血清培养基，进行拍照，此时为0h，然后加入空白对照组和剂量分别为0、30、15、7.5、3.25μM的LY294002实验组，培养24h后进行拍照，量取宽度，计算迁移率。按照细胞迁移比率＝宽度(实验组0h-实验组24h)/宽度(空白组0h-空白组24h)ⅹ100％，结果详见图1和表1。
表1各细胞迁移率测定结果
由表1和图1可知，30、15、7.5、3.25μM的LY294002可以显著性抑制食管癌细胞株KYSE30和KYSE450的迁移。这表明，LY294002具有一定抑制食管癌细胞迁移的能力。
实施例2、LY294002和SNX-2112联合作用对肿瘤细胞及正常细胞的影响
将KYSE30食管癌细胞株、ECA-109食管癌细胞株、耐顺铂的ECA-109食管癌细胞、A549肺癌细胞株、HepG2肝癌细胞株和HUVEC正常血管内皮细胞以每孔3000-6000个细胞的数量接种到96孔板，待细胞贴壁后，分别将细胞分为对照组、LY294002单药组、SNX-2112单药组及LY294002和SNX-2112药物联合用药组；培养48h后，每孔加入10μL CCK-8溶液，继续培养1h，在酶标仪上读取OD值(波长450nm)，读取每孔的吸光值，计算细胞存活率。按照细胞存活率(％)＝(OD实验组-OD空白)/(OD对照组-OD空白)×100％的公式，计算得到细胞存活率，结果见图2。
如图2所示，LY294002和SNX-2112在肿瘤细胞中组合使用具有很好的联合效果，而对正常细胞的毒性较小。
实施例3、LY294002和SNX-2112联合作用对耐药食管癌细胞迁移的影响
将人耐顺铂的ECA-109食管癌细胞以每孔12000个细胞的数量接种到96孔板，待细胞贴壁后，同步化12h，用划痕仪进行划痕，PBS洗两遍后，换含2％胎牛血清培养基，进行拍照，此时为0h，将细胞分为对照组、LY294002单药组、SNX-2112单药组及LY294002和SNX-2112药物联合用药组，分别加入对应的培养基或者药物溶液，培养24h后进行拍照，量取宽度，计算迁移率。按照细胞迁移比率＝宽度(实验组0h-实验组24h)/宽度(空白组0h-空白组24h)×100％，结果详见图3。
从图3可看出，与对照组以及单药组相比，联合用药后显著性抑制食管癌耐药细胞株的迁移。
实施例4、LY294002和SNX-2112联合作用对食管癌细胞和耐药食管癌细胞克隆形成的影响
将人食管癌细胞Kyse30细胞和耐顺铂的ECA-109食管癌细胞接种到6孔板，待细胞贴壁过夜后，分为对照组、LY294002单药组、SNX-2112单药组及LY294002和SNX-2112药物联合用药组，分别加入对应的培养基或者药物溶液，孵育7天，检测细胞平板克隆形成情况。结果如图4所示。
从图4可看出，与对照组以及单药组相比，联合用药组细胞克隆数量和体积最小，说明LY294002和SNX-2112联合用药，能够协同抑制食管癌细胞和耐药食管癌细胞的克隆。
实施例5、LY294002和SNX-2112联合作用对食管癌细胞和耐药食管癌细胞凋亡的影响
先将食管癌细胞KYSE30和耐顺铂的ECA-109食管癌细胞以每孔3.5×105个细胞的密度接种至6孔板。待细胞贴壁后，不同浓度处理24h后，分别收取各组细胞全蛋白。先经SDS电泳后，将蛋白转移至PVDF膜上，5％脱脂奶粉室温封闭1h，孵育所需检测的蛋白相对应的一抗，4℃孵育过夜。24h回收一抗，用TBST清洗3次，每次5min，之后孵育二抗，室温孵育1h。然后用TBST清洗3次，每次5min，之后ECL显影，检测经药物处理后食管癌细胞KYSE30和耐顺铂的ECA-109食管癌细胞内凋亡通路相关蛋白PARP和Cleaved-PARP蛋白的表达情况。结果见图5。
从图5可以看出，与对照组以及单药组相比，联用组Cleaved-PARP的表达显著升高，说明LY294002和SNX-2112联合用药，能够协同促进食管癌细胞和耐药食管癌细胞的凋亡。
以上仅是本发明的优选实施方式，应当指出的是，上述优选实施方式不应视为对本发明的限制，本发明的保护范围应当以权利要求所限定的范围为准。对于本技术领域的普通技术人员来说，在不脱离本发明的精神和范围内，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (9)
1.一种含有PI3K抑制剂的药物组合物，其特征在于，所述组合物包含有效量的PI3K抑制剂、有效量的HSP90抑制剂和药物上可接受的载体。
2.如权利要求1所述的药物组合物，其特征在于，所述的PI3K抑制剂为BEZ235、GDC-0941和LY294002的一种，所述HSP90抑制剂为17-AAG和SNX-2112中的一种。
3.如权利要求2所述的药物组合物，其特征在于，所述PI3K抑制剂为LY294002，所述HSP90抑制剂为SNX-2112。
4.如权利要求3所述的药物组合物，其特征在于，所述LY294002和SNX-2112的摩尔浓度比为10～50∶0.025～0.4。
5.如权利要求4所述的药物组合物，其特征在于，所述药物组合物中LY294002和SNX-2112的摩尔浓度比为30∶0.05。
6.如权利要求1～5任一项所述的药物组合物，其特征在于，所述药物组合物的剂型为注射制剂或口服制剂。
7.如权利要求1～5任一项所述的药物组合物在制备预防和/或治疗肿瘤耐药药物中的用途。
8.如权利要求7所述的用途，其特征在于，所述肿瘤为食管癌、肺癌或肝癌的至少一种。
9.如权利要求8所述的用途，其特征在于，所述肿瘤为食管癌。
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