CN116850295A - 一种治疗肿瘤的药物组合物、药物及应用 - Google Patents
一种治疗肿瘤的药物组合物、药物及应用 Download PDFInfo
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Abstract
本发明公开了一种治疗肿瘤的药物组合物、药物及应用,属于联合用药技术领域。本发明提供了一种治疗肿瘤的药物组合物,将抗血管生成药物和HIF‑1a抑制剂联合用药。本发明证实抗血管生成治疗诱导的胃癌缺氧微环境促进细胞内HIF‑1a累积,HIF‑1a通过增强葡萄糖代谢重编程提高细胞的缺氧耐受性,使胃癌细胞在缺氧微环境中保持活力。本发明将抗血管生成药物apatinib与HIF‑1a抑制剂CAY10585通过联合治疗的方式能够产生协同互补效应:加剧胃癌肿瘤内缺氧,阻断胃癌细胞葡萄糖代谢重编程,进而增强抗肿瘤效应,抑制胃癌的进展。
Description
技术领域
本发明属于联合用药技术领域,具体涉及一种治疗肿瘤的药物组合物、药物及应用。
背景技术
apatinib是我国自主研发的一种新型小分子酪氨酸激酶抑制剂(TKI),靶向结合血管内皮生长因子受体2(VEGFR-2),可强效抑制肿瘤内新生血管生成,抑制肿瘤进展,有效延长晚期肿瘤及转移性肿瘤患者无进展生存期和总生存期。apatinib是第一个被中国食品药品监督管理局批准用于治疗转移性胃癌的抗血管生成剂。目前apatinib已被推荐为晚期胃癌及转移性胃癌患者的三线治疗,通过抑制肿瘤新生血管形成有效提高肿瘤患者生存预后。然而,抗血管生成治疗导致肿瘤内部血供减少,加剧了肿瘤内部缺氧,而选择性肿瘤细胞亚群通过葡萄糖代谢重编程增强细胞的缺氧耐受性,导致抗血管生成治疗失败。
发明内容
本发明的目的在于提供一种治疗肿瘤的药物组合物、药物及应用,所述药物组合物或药物能够克服临床上抗血管生成治疗抵抗问题,抗血管生成的同时削弱肿瘤细胞的缺氧耐受性,增强抗肿瘤效应。
本发明提供了一种治疗肿瘤的药物组合物,包括抗血管生成药物和HIF-1a抑制剂。
优选的,所述抗血管生成药物包括以下至少一种:apatinib、Bevacizumab和ramucirumab。
优选的,所述HIF-1a抑制剂包括以下至少一种:CAY10585和Lificiguat(YC-1)。
优选的,所述apatinib和CAY10585的工作浓度比为120mg/kg:10mg/kg。
本发明还提供了上述药物组合物在制备治疗肿瘤的药物中的应用。
优选的,所述治疗包括以下至少一项:
(1)抑制肿瘤内新生血管形成;
(2)促进缺氧微环境形成;
(3)抑制肿瘤的生长;
(4)抑制肿瘤的转移。
本发明还提供了一种治疗肿瘤的药物,活性成分包括上述药物组合物,还包括药学上可接受的辅料。
优选的,所述活性成分的质量百分含量为0.1~99%。
优选的,所述药物的剂型包括口服剂、静脉注射剂或腹腔注射剂。
优选的,所述肿瘤包括胃癌。
有益效果:本发明提供了一种治疗肿瘤的药物组合物,将抗血管生成药物和HIF-1a抑制剂联合用药。本发明实施例中证实了抗血管生成治疗诱导的肿瘤缺氧微环境促进缺氧诱导因子HIF-1a累积,肿瘤内缺氧程度越高,HIF-1a表达则越高,HIF-1a通过增强葡萄糖代谢重编程提高细胞的缺氧耐受性,使肿瘤细胞在缺氧微环境中保持活力。
本发明实施例中还将抗血管生成药物apatinib与HIF-1a抑制剂CAY10585通过联合治疗的方式能够产生协同互补效应:apatinib抑制肿瘤新生血管形成,其所诱导的缺氧微环境促进HIF-a表达,增强了HIF-a抑制剂CAY10585的靶向性;CAY10585阻断胃癌细胞葡萄糖代谢重编程,削弱肿瘤细胞的缺氧耐受性。apatinib与CAY10585的联合治疗有助于克服临床上抗血管生成治疗抵抗问题,抗血管生成的同时削弱肿瘤细胞的缺氧耐受性,增强抗肿瘤效应。本发明还通过小鼠体内实验证实:apatinib有效抑制肿瘤内新生血管形成,减少肿瘤血供,促进缺氧微环境形成。apatinib与CAY10585的联合治疗有效抑制肿瘤的生长及转移,增强抗肿瘤效应,抑制肿瘤的进展。
附图说明
图1为本发明体内治疗实验的流程图;
图2为抗血管生成治疗诱导的缺氧微环境与HIF-1a的关联结果图;
图3为HIF-1a与细胞葡萄糖代谢重编程及细胞缺氧耐受的关联结果图;
图4为HIF-1a抑制剂CAY10585抑制胃癌细胞葡萄糖代谢重编程及缺氧耐受性的关联结果图;
图5为apatinib与CAY10585的联合治疗与抗肿瘤效应的作用图。
具体实施方式
本发明提供了一种治疗肿瘤的药物组合物,包括抗血管生成药物和HIF-1a抑制剂。
本发明所述抗血管生成药物优选包括所述抗血管生成药物包括以下至少一种:apatinib、Bevacizumab和ramucirumab;所述HIF-1a抑制剂包括以下至少一种:CAY10585和Lificiguat(YC-1);实施例中以apatinib和CAY10585联合用药为例进行说明,且构建胃癌原位种植瘤模型成功的第10天开始给予抗血管药物apatinib(口服灌胃,120mg/kg,每天),第24天开始给予CAY10585(口服灌胃,10mg/kg,每天)。本发明对所述apatinib和CAY10585的来源并没有特殊限定,利用本领域逇常见市售产品即可。
本发明还提供了上述药物组合物在制备治疗肿瘤的药物中的应用。
本发明所述CAY10585是一种有效的缺氧诱导因子HIF-1a抑制剂,可抑制缺氧状态下细胞内HIF-1a的积累。作为细胞感应外界氧气变化的关键转录因子,HIF-1a负责激活参与低氧稳态的相关基因的转录。本研究发现胃癌缺氧微环境中HIF-1a高度富集,并HIF-1a通过调控胃癌细胞葡萄糖代谢重编程,提高胃癌细胞的缺氧耐受性,使胃癌细胞在缺氧微环境保持活力,逃避凋亡或死亡。进而导致胃癌抗血管生成治疗抵抗。基于这一分子机制,使用apatinib与CAY10585进行联合治疗,抑制肿瘤血管生成同时阻断肿瘤细胞的葡萄糖代谢重编程,克服抗血管生成治疗抵抗,抑制肿瘤进展。
本发明所述治疗,优选包括以下至少一项:
(1)抑制肿瘤内新生血管形成;
(2)促进缺氧微环境形成;
(3)抑制肿瘤的生长;
(4)抑制肿瘤的转移。
本发明还提供了一种治疗肿瘤的药物,活性成分包括上述药物组合物,还包括药学上可接受的辅料。
本发明所述活性成分的质量百分含量优选为0.1~99%。本发明所述药物的剂型优选包括口服剂、静脉注射剂或腹腔注射剂。
为了进一步说明本发明,下面结合实施例对本发明提供的一种治疗肿瘤的药物组合物、药物及应用进行详细地描述,但不能将它们理解为对本发明保护范围的限定。
实施例1
一、实验方法
1.体外治疗实验:
材料来源:HIF-1a抑制剂CAY10585采购自Selleck公司(产品编号S8441)实验步骤:
(1)细胞培养:调整细胞至良好状态,当细胞处于对数生长期时,使用0.25%EDTA胰酶将细胞消化下来,并接种至24孔板中,并放置于37℃,含5%CO2的细胞培养箱中继续培养;待细胞贴壁后更换含氯化钴CoCl2(100μM)完全培养基,模拟体外缺氧环境;
(2)药物治疗:向孔中上清加入HIF-1a抑制剂CAY10585(0.7μM)刺激胃癌细胞
(3)使用比色法检测胃癌细胞葡萄糖摄取率、乳酸生成率变化,反映细胞葡萄糖代谢重编程变化
2.体内治疗实验(胃癌原位种植瘤模型治疗实验):
材料来源:HIF-1a抑制剂CAY10585采购自Selleck公司(产品编号S8441)、apatinib采购自Selleck公司(产品编号S5248)
实验步骤:
(1)胃癌原位种植瘤模型构建:
(a)准备4-6周龄的无胸腺裸鼠,雄性,体重18-20g,于SPF级环境中饲养;
(b)裸鼠皮下成瘤模型构建:将状态良好的胃癌细胞制备为单细胞悬液(5×107个/ml)。使用75%酒精消毒后,向裸鼠右侧腹股沟处注射细胞悬液(皮下注射,200μl/只),接种胃癌细胞后定期观察肿瘤生长情况;
(c)待皮下肿瘤长至1.0-1.5cm时,予以裸鼠脱臼处死,剥离肿瘤瘤块并用无菌刀片均匀切成若干份(大小约1mm3),置于Hanks缓冲液中备用;
(d)原位种植:使用乙醚吸入麻醉并酒精消毒手术区域皮肤后,沿左侧正中旁线切开裸鼠腹壁并小心轻柔暴露其腹膜、胃壁;使用可吸收缝线将肿瘤块缝合至胃壁,并缝合关腹;
(2)分组设计及药物治疗:
将构建成功的裸鼠随机分为对照组(Control)、apatinib治疗组、apatinib+CAY10585治疗组,6只/组;原位种植术后第10天予以裸鼠apatinib(120mg/kg.daily,灌胃;apatinib治疗组及apatinib+CAY10585治疗组)进行治疗,对照组(Control)裸鼠予以等体积DMSO溶液治疗;术后第24天予以裸鼠CAY10585(10mg/kg.daily,灌胃;apatinib+CAY10585治疗组)进行治疗,对照组(Control)及apatinib治疗组裸鼠予以等体积DMSO溶液治疗;
(3)观察原位种植瘤生长及转移情况:术后第8周予以裸鼠脱臼处死,全面探查胸腹腔、取出腹腔原位种植瘤,测量瘤块大小,并使用福尔马林固定后进行苏木精-伊红染色以及免疫组化检测;同时,观察裸鼠胸腹腔的肿瘤转移情况(邻近脏器的转移情况等)。
二、实验结果
1、抗血管生成治疗诱导的缺氧微环境促进HIF-积累(图2)。
通过氯化钴(CoCl2)体外缺氧模型分析可见,细胞缺氧程度(CoCl2浓度)越高,HIF-1a胞内表达水平则越高(图2中A)。经免疫荧光检测人体胃癌组织发现,缺氧区域胃癌组织缺氧诱导因子HIF-1a显著富集(图2中B)。进一步使用apatinib构建抗血管生成治疗抵抗模型,诱导小鼠皮下肿瘤内的缺氧微环境(图2中C),免疫荧光结果显示,经apatinib治疗的小鼠皮下肿瘤内新生血管显著减少,并且皮下肿瘤内显著缺氧,HIF-1a表达显著提高(图2中D)。
2、缺氧诱导因子HIF-1a通过增强细胞葡萄糖代谢重编程提高细胞缺氧耐受性(图3)
葡萄糖代谢重编程是肿瘤进展的重要内在机制,是肿瘤的特征性代谢改变。正常细胞中葡萄糖代谢处于平衡状态,主要通过线粒体氧化磷酸化过程合成三磷酸腺苷(ATP)供能;但是肿瘤细胞则处于葡萄糖高代谢状态,通过“Warburg效应”调整细胞供能模式,葡萄糖代谢模式从依赖线粒体氧化磷酸化转变为依赖糖酵解,即为葡萄糖代谢重编程。
通过CoCl2体外缺氧模型,细胞缺氧后HIF-1a的胞内水平显著上调(图3中A),胃癌细胞的葡萄糖摄取率及乳酸生成水平显著上调;而且缺氧程度越高,胃癌细胞的糖酵解水平则越高(图3中B)。同时,缺氧状态下胃癌细胞线粒体膜电位显著下降,线粒体功能受抑制(图3中C)。通过使用ATPase抑制剂OligomycinA抑制胃癌细胞的线粒体功能并增强细胞糖酵解,可见胃癌细胞缺氧状态下的增殖及迁移能力增强(图3中D和E)。以上实验结果提示缺氧状态下HIF-1a的表达上调促进胃癌细胞的葡萄糖代谢重编程,胃癌细胞产能模式从线粒体的氧化磷酸化转变为依赖于糖酵解,使胃癌细胞在缺氧微环境中具有更好的活力,提高胃癌细胞的缺氧耐受性。
3.CAY10585有效抑制葡萄糖代谢重编程,削弱胃癌细胞的缺氧耐受性(图4)
本研究使用CAY10585(0.7M)刺激胃癌细胞,发现缺氧状态下,经CAY10585刺激后,胃癌细胞的葡萄糖摄取率及乳酸生成率显著下调,提示糖酵解水平受抑制(图4中A)。进一步通过CCK8及划痕实验分别检测胃癌细胞增殖与迁移能力变化(图4中B和C)。实验结果显示,经CAY10585刺激后(缺氧状态),胃癌细胞的增殖能力、迁移能力显著减弱,提示经CAY10585刺激后胃癌细胞葡萄糖重编程受阻,细胞缺氧耐受性下降,导致胃癌细胞在缺氧环境中活力受损。
4.apatinib与CAY10585的联合治疗增强抗肿瘤效应并克服抗血管生成治疗抵抗(图5)
通过细胞体外治疗实验显示,CAY10585有效抑制了胃癌细胞葡萄糖酵解,抑制缺氧状态下胃癌细胞的增殖与迁移能力。进一步构建小鼠胃癌原位种植瘤模型(图1中A)进行药物体内治疗实验。分别设立对照组(Control)、apatinib组及apatinib与CAY10585的联合治疗组,检测抗血管生成药物联合HIF-1a抑制剂的治疗效果(图1中B)。实验结果显示,抗血管生成药物apatinib可有效抑制胃癌的进展,而apatinib与CAY10585联合治疗组展现出更强的抗肿瘤作用,可见胃癌的腹腔转移情况显著减少,肿瘤生长受抑制(图5中A);经苏木素-伊红染色法(HE)染色进一步证实胃癌原位种植瘤及肠道转移的肿块性质(图5中B)。综上所述,动物实验证实,apatinib与CAY10585的联合治疗可有效抑制胃癌原位种植瘤生长与转移,增强抗肿瘤效应。
尽管上述实施例对本发明做出了详尽的描述,但它仅仅是本发明一部分实施例,而不是全部实施例,人们还可以根据本实施例在不经创造性前提下获得其他实施例,这些实施例都属于本发明保护范围。
Claims (10)
1.一种治疗肿瘤的药物组合物,其特征在于,包括抗血管生成药物和HIF-1a抑制剂。
2.根据权利要求1所述药物组合物,其特征在于,所述抗血管生成药物包括以下至少一种:apatinib、Bevacizumab和ramucirumab。
3.根据权利要求1或2所述药物组合物,其特征在于,所述HIF-1a抑制剂包括以下至少一种:CAY10585和Lificiguat(YC-1)。
4.根据权利要求3所述药物组合物,其特征在于,所述apatinib和CAY10585的工作浓度比为120mg/kg:10mg/kg。
5.权利要求1~4任一项所述药物组合物在制备治疗肿瘤的药物中的应用。
6.根据权利要求5所述应用,其特征在于,所述治疗包括以下至少一项:
(1)抑制肿瘤内新生血管形成;
(2)促进缺氧微环境形成;
(3)抑制肿瘤的生长;
(4)抑制肿瘤的转移。
7.一种治疗肿瘤的药物,其特征在于,活性成分包括权利要求1~4任一项所述药物组合物,还包括药学上可接受的辅料。
8.根据权利要求7所述药物,其特征在于,所述活性成分的质量百分含量为0.1~99%。
9.根据权利要求7所述药物,其特征在于,所述药物的剂型包括口服剂、静脉注射剂或腹腔注射剂。
10.根据权利要求7所述药物,其特征在于,所述肿瘤包括胃癌。
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