CN115006538A - Sdcbp抑制剂在制备抗食管癌药物中的应用 - Google Patents
Sdcbp抑制剂在制备抗食管癌药物中的应用 Download PDFInfo
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Abstract
本发明公开了SDCBP抑制剂在制备抗食管癌药物中的应用，属于生物医药技术领域。本发明经试验发现，SDCBP抑制剂能够有效抑制食管癌细胞和食管癌耐药细胞的增殖和生长。本发明的SDCBP抑制剂通过AKT通路介导抑制食管癌生长，另外，在10～40μM浓度范围内，SDCBP抑制剂呈浓度、时间依赖性显著抑制食管癌细胞增殖。本发明的SDCBP抑制剂作为潜在的抗肿瘤药物具有一定的安全性。此外，发明人经研究发现：SDCBP抑制剂和5‑FU联合用药在抑制食管癌，尤其是食管鳞癌方面具有显著的协同增效作用。
Description
技术领域
本发明属于生物医药技术领域，特别涉及SDCBP抑制剂在制备抗食管癌药物中的应用。
背景技术
SDCBP(多配体聚糖结合蛋白)是一种将多配体聚糖介导的信号与细胞骨架联系起来的分子，该蛋白含有串联重复的PDZ结构域，在细胞质中可以与多种跨膜蛋白C-末端的结构域结合，影响细胞膜和细胞骨架的组成、细胞黏附、蛋白质的转运和转录因子的激活。SDCBP除在黑色素瘤中特异性表达外，还发现其与多种恶性肿瘤的进展密切相关。但迄今为止，关于SDCBP抑制剂在食管癌治疗中的应用尚未见报道，其分子机制在很大程度上也不清楚。
食管癌在我国是一种比较常见的消化道肿瘤，是最常见的恶性肿瘤之一，具有较高的发病率和致死率，总体生存率较低。食管癌有两种组织学亚型：食管鳞癌(ESCC)和食管腺癌(EA)。然而，包括中国在内的亚太地区绝大多数病例都为ESCC。目前，食管癌的首选治疗方法是手术完全切除病变和局部淋巴结。然而，由于该病早期无明显异常症状，因此在患者确诊时，多已发展至中晚期，此时为患者实施外科根治性手术治疗，不仅达不到理想的治疗效果，且会严重创伤患者机体。针对该类患者，临床上采用同步化疗法进行治疗，常用化疗药物为5-氟尿嘧啶，顺铂及多烯紫杉醇，但临床经验表明该治疗方法常无法达到预期效果，同时伴有严重的副作用。另外，化疗和放疗的失败会导致肿瘤复发和预后不良，这主要是由于疗效有限和副作用，如传统的化疗既杀伤癌细胞也杀伤正常细胞，这对机体产生了严重的毒副作用。因此寻找更稳定、有效、安全的抗癌药物已成为当务之急。
近年来，随着肿瘤新理论的不断升级，以及肿瘤耐药等临床用药问题的不断涌现，创新的抗癌药物研发始终是肿瘤研究的热点和重点。其中，随着分子生物学机制的不断发展及生物技术产业的不断推动和支持，人们对肿瘤的探索也不断深入，越来越多的肿瘤特异性分子靶点已为人们所认识，随之而来的抗肿瘤小分子靶向药物亦发展壮大。小分子靶向药物正以其高疗效，低毒副反应以及高度特异性等优势成为肿瘤治疗研究的热点。目前临床广泛应用的小分子靶向抗肿瘤药主要为酪氨酸激酶抑制剂包括吉非替尼、厄洛替尼、伊马替尼、舒尼替尼、拉帕替尼、索拉非尼等。然而，尚未见SDCBP小分子抑制剂在抗癌活性方面的报道。
发明内容
本发明的首要目的在于克服现有技术的缺点与不足，提供SDCBP抑制剂在制备抗食管癌药物中的应用。
本发明的上述目的通过以下技术方案予以实现：
SDCBP抑制剂在制备抗食管癌药物中的应用。
所述的SDCBP抑制剂的结构式如式(Ⅰ)所示：
所述的SDCBP抑制剂的有效浓度优选为5～40μM；更优选浓度为10～40μM。
所述的抗食管癌药物是指能够抑制食管癌细胞生长和/或增殖的药物。
SDCBP抑制剂通过AKT通路介导抑制食管癌生长。
SDCBP抑制剂呈浓度、时间依赖性显著抑制食管癌细胞增殖。
所述的食管癌优选为食管鳞癌。
一种抗食管癌药物，包括SDCBP抑制剂。
所述的抗食管癌药物还包括其他与SDCBP抑制剂具有协同增效作用的药物。
所述的其他与SDCBP抑制剂具有协同增效作用的药物优选包括但不限于5-FU。
SDCBP抑制剂和5-FU联合用药在抑制食管癌，尤其是食管鳞癌方面具有显著的协同增效作用。
所述的抗食管癌药物还包含药学上可接受的辅料。
所述的药学上可接受的辅料优选为缓释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、吸附载体、表面活性剂和润滑剂中的至少一种。
所述的抗肿瘤药物的给药形式优选包括但不限于口服给药和灌胃给药中的至少一种。
本发明相对于现有技术具有如下的优点及效果：
本发明经试验发现，SDCBP抑制剂能够有效抑制食管癌细胞和食管癌耐药细胞的增殖和生长。本发明的SDCBP抑制剂通过AKT通路介导抑制食管癌生长。另外，在10～40μM浓度范围内，SDCBP抑制剂呈浓度、时间依赖性显著抑制食管癌细胞增殖。本发明的SDCBP抑制剂作为潜在的抗肿瘤药物具有一定的安全性。此外，发明人经研究发现：SDCBP抑制剂和5-FU联合用药在抑制食管癌，尤其是食管鳞癌方面具有显著的协同增效作用。
附图说明
图1为SDCBP抑制剂的筛选流程图及结构式图；其中，图A为SDCBP抑制剂的筛选流程图；图B为SDCBP抑制剂的结构式图。
图2为体外细胞实验结果图；其中，图A为CCK-8实验结果图；图B为单克隆形成实验结果图；图C为不同浓度的SDCBP抑制剂处理食管癌细胞后活化的半胱氨酸天冬氨酸蛋白酶3(Cleaved caspase 3)、活化半胱氨酸天冬氨酸蛋白酶-9(Cleaved caspase 9)和p-Akt的变化结果图。
图3为裸鼠体内实验结果图；其中，图A为不同浓度的SDCBP抑制剂处理裸鼠体内皮下瘤体积变化的实验结果图；图B为不同浓度SDCBP抑制剂处理的裸鼠血常规检测的ALT水平变化图；图C为不同浓度SDCBP抑制剂处理的裸鼠血常规检测的AST水平变化结果图；图D为不同浓度SDCBP抑制剂处理的裸鼠的体重变化结果图；图E为不同浓度SDCBP抑制剂处理的裸鼠的肺、肝、肾脏的形态变化结果图，图F为SDCBP抑制剂和5-FU处理裸鼠体内人食管癌耐药株移植瘤的结果图，图G为SDCBP抑制剂和5-FU处理的裸鼠的肺、肝、肾脏的形态变化结果图。
具体实施方式
下面结合实施例及附图对本发明作进一步详细的描述，但本发明的实施方式不限于此。
SDCBP抑制剂的筛选：
基于SDCBP的PDZ2结构域，从ChemDiv小分子数据库中筛选SDCBP抑制剂，通过二轮筛选人工挑选得到150个小分子化合物，选择排名前30的小分子化合物进行生物学实验，最终通过体外实验筛选到最佳的SDCBP抑制剂。筛选流程如图1A所示。
实施例1：体外试验
(1)实验材料
人食管鳞癌细胞KYSE150和KYSE410细胞购自于ATCC；SDCBP抑制剂购自于上海陶素生化科技有限公司，结构式如图1B所示；CCK-8试剂购自于日本同仁化学研究所；雌性裸鼠(BALB/C-nu/nu)购自于南京大学模式动物研究所；DMEM培养基购自于美国Gibco；DMSO购自于美国sigma；SDCBP抑制剂溶于DMSO，储存浓度10mM于-80℃冰箱；5-氟尿嘧啶购自于美国sigma。
(2)CCK-8实验：
以每孔50μL/1000个细胞的数量接种人食管鳞癌细胞KYSE150、KYSE410细胞于96孔板中，12h细胞贴壁后，用10mM的SDCBP抑制剂溶于DMEM培养基分别稀释得到10μM、20μM和40μM含SDCBP抑制剂的培养基，按照不同的浓度梯度每孔加入50μL含SDCBP抑制剂的培养基，同时以不含SDCBP抑制剂的培养基作为对照，即得SDCBP抑制剂的浓度分别为0、10μM、20μM和40μM的细胞处理组。于0、1天(24h)、2天(48h)、3天(72h)、4天(96h)和5天(120h)按照CCK-8试剂盒说明书每孔加10μL CCK-8试剂于37℃、5％CO2培养箱中孵育2h，用酶联免疫检测仪在450nm波长处检测。
(3)单克隆形成实验
以每孔1000个细胞的数量接种人食管鳞癌细胞KYSE150、KYSE410细胞于6孔板中，隔夜细胞贴壁，配制含SDCBP抑制剂的培养基，其中SDCBP抑制剂的浓度分别为0、5μM、10μM、20μM，将2mL不同SDCBP抑制剂浓度的含SDCBP抑制剂的培养基分别加入到上述细胞中于37℃、5％CO2培养箱中孵育。14天后，取出细胞培养板，PBS缓冲液(pH 7.4，购于Sigma-Aldrich公司；下同)洗3次，75％(v/v)甲醇固定15min，0.4％结晶紫染色10min，肉眼计数单克隆数目。
(4)Western blot实验
以每孔2×105个细胞的数量接种人食管鳞癌细胞KYSE150、KYSE410细胞于6孔板中，隔夜细胞贴壁，配制含SDCBP抑制剂的培养基，其中SDCBP抑制剂的浓度分别为0、5μM、10μM、20μM，将2mL不同SDCBP抑制剂浓度的含SDCBP抑制剂的培养基分别加入到上述细胞中于37℃、5％CO2培养箱中孵育。48h后，取出细胞培养板，按照细胞培养及传代方法，收集细胞于1.5mL离心管中，加入适量蛋白裂解液(预先按体积比1:100加入蛋白酶抑制剂PMSF)，在漩涡振荡器上间歇震荡裂解细胞40min，至细胞完全裂解，4℃12000rpm离心30min。转移上清于新的离心管中。
使用BCA(二喹啉甲酸)法检测裂解样品中的蛋白浓度。根据BCA试剂盒(购自于美国Thermo Fisher Scientific)说明书，操作过程如下：
1)用超纯水进行蛋白标准品的梯度稀释，配制如下浓度的蛋白标准液：2.0mg/mL、1.0mg/mL、0.5mg/mL、0.25mg/mL、0.125mg/mL、0.0625mg/mL、0.03125mg/mL。
2)用超纯水进行蛋白待测样品的稀释，根据预测蛋白浓度稀释待测蛋白(将待测蛋白浓度尽量稀释到标准品的测量范围内)，设置3个复孔。
3)按照BCA试剂盒说明书配制工作液(每孔90μL反应液)：A:B＝50:1，充分震荡混匀。
4)实验设空白孔、标准孔和待测样品孔，并设置3个复孔。
5)按照空白孔加入10μL超纯水，标准孔加入10μL各不同浓度的标准品，待测样本孔加入10μL稀释号的待测样本。
6)每孔加90μL BCA工作液，在37℃恒温培养箱中反应30min。
7)将96孔板置于多功能酶标仪中测定562nm波长下的吸光值。根据标准品绘制标准曲线，并根据拟合的方程计算待测样品的蛋白浓度。
根据BCA法所测得的蛋白浓度，制备合适浓度的蛋白上样缓冲液，使用超纯水和loading buffer调整样本浓度至同一水平进行电泳。配制相应浓度的SDS-PAGE胶(浓缩胶5％)，安装好电泳装置，向电泳槽内添加新鲜配置的电泳缓冲液。将制备好的蛋白样品煮沸5min使蛋白进一步变性。用微量移液器吸取10-20μL的蛋白样品(总蛋白量约为30μg)加至上样孔内；70V电压进行样本的浓缩，待样品进入分离胶后将电压调至120V，电泳至上样缓冲液距胶下沿约0.5cm处停止电泳。电泳完成后取下玻璃板，切去上层浓缩胶，在干转仪器上分别叠放下层海绵垫，待转SDS-PAGE胶，滤纸及上层海绵垫，设置转膜程序转膜7min(可根据就目的蛋白分子量适量延长或缩短转膜时间)。转膜结束后，小心取下PVDF膜，标记并置于含有5％脱脂奶粉的封闭液中室温封闭lh。TBST缓冲液(购于北京华越洋生物科技有限公司)洗去封闭液，加入相应的一抗(抗体稀释于一抗二抗稀释液中，稀释比例一般为1:1000～1:2000)，4℃孵育过夜。次日回收一抗，TBST缓冲液洗涤5次，每次5min。加入HRP标记的相应二抗(抗体稀释于5％脱脂奶粉中，稀释比例1∶2000)，室温摇床孵育l h。二抗孵育后用TBST缓冲液洗涤5次，每次5min。将ECL化学发光法检测试剂盒(购于美国Bio-RadLaboratories)中的两种发光底物A液和B液按照体积比1:1混合后覆盖PVDF膜，在凝胶成像系统，根据蛋白表达丰度，调整机器曝光时间，用Image Lab软件分析目的蛋白条带。
结果如图2所示，从图2可以看出，CCK-8实验和单克隆形成实验结果证实SDCBP抑制剂呈浓度、时间依赖性显著抑制食管癌细胞增殖。Western blot实验结果中活化的半胱氨酸天冬氨酸蛋白酶3(Cleaved caspase 3)、活化半胱氨酸天冬氨酸蛋白酶-9(Cleavedcaspase 9)，p-AKT的变化表明SDCBP抑制剂是通过AKT通路介导对食管癌生长的抑制作用。
实施例2：体内试验
(1)皮下模型的构建以及不同药物浓度处理裸鼠
选取18只6-8周龄、雌性裸鼠(BALB/C-nu/nu)，其中，对照组6只、实验组12只，构建肿瘤皮下瘤模型。
1)按照每只裸鼠皮下注射5×106个人食管鳞癌耐药株KYSE150FR(人食管鳞癌耐药株KYSE150FR已在Li B et al.Competitive Binding Between Id1 and E2F1 to Cdc20Regulates E2F1Degradation and Thymidylate Synthase Expression to PromoteEsophageal Cancer Chemoresistance.Clin Cancer Res.2016Mar 1；22(5):1243-55.doi:10.1158/1078-0432.CCR-15-1196.中公开；下同)：首先将细胞KYSE150FR重悬于50μL PBS缓冲液中，然后混入等体积50μL Matrigel基质胶，得到100μL混合液(混合液中含有5×106个人食管鳞癌耐药株KYSE150FR)；用无菌注射器在每只裸鼠皮下注射100μL混合液；
2)在实验之前对裸鼠进行麻醉，通过无痛及有痛刺激来评估麻醉程度，确定裸鼠处于麻醉状态；
3)用25G针头的微注射器对18只裸鼠进行皮下注射重悬细胞：
SDCBP抑制剂处理：裸鼠皮下注射人食管鳞癌耐药株KYSE150FR一周，瘤体直径达到5mm左右时，随机分组，灌胃给药。SDCBP抑制剂的灌胃量分别为0mg/kg、10mg/kg和20mg/kg，100μL/只，每隔2天给一次药，并测量裸鼠体重和瘤体体积。
4)裸鼠血液生化常规检测和裸鼠组织器官形态检测
抽取裸鼠血液，离心得到血浆，然后将得到的血浆样品送至武汉谷歌生物科技有限公司进行血液生化分析(检测丙氨酸转氨酶ALT、天冬氨酸转氨酶AST水平)，取0mg/kg组的裸鼠的血液离心后得到的血浆作为对照。取裸鼠肝、肺和肾等器官送至武汉谷歌生物科技有限公司进行裸鼠组织器官形态检测。
(2)药物联用皮下模型的构建以及药物联用处理裸鼠
选取18只6-8周龄、雌性裸鼠(BALB/C-nu/nu)，其中，对照组6只、实验组12只，构建肿瘤皮下瘤模型。
1)按照每只裸鼠皮下注射5×106个人食管鳞癌耐药株KYSE150FR：首先将细胞KYSE150FR重悬于50μL PBS缓冲液中，然后混入等体积50μL Matrigel基质胶，得到100μL混合液(混合液中含有5×106个人食管鳞癌耐药株KYSE150FR)；用无菌注射器在每只裸鼠皮下注射100μL混合液；
2)在实验之前对裸鼠进行麻醉，通过无痛及有痛刺激来评估麻醉程度，确定裸鼠处于麻醉状态；
3)用25G针头的微注射器对18只裸鼠进行皮下注射重悬细胞：
SDCBP抑制剂及5-FU药物处理：裸鼠皮下注射人食管鳞癌耐药株KYSE150FR一周，瘤体直径达到5mm左右时，随机分组，灌胃给药。SDCBP抑制剂和5-FU的灌胃量分别为10mg/kg和20mg/kg，药物联用即两种药物联合使用(10mg/kg SDCBP抑制剂+20mg/kg 5-FU)，100μL/只，每隔2天给一次药，并测量裸鼠体重和瘤体体积。
4)裸鼠组织器官形态检测
取裸鼠肝、肺和肾等器官送至武汉谷歌生物科技有限公司进行裸鼠组织器官形态检测。
结果如图3所示，从图3A可以看出：SDCBP抑制剂能够显著抑制裸鼠体内人食管鳞癌耐药株移植瘤的生长，即SDCBP抑制剂具有显著抑制食管鳞癌耐药株成瘤的能力。图3B-3E中，灌胃不同浓度SDCBP抑制剂的裸鼠血常规检测的ALT、AST水平、裸鼠体重和肺、肝、肾脏形态均无明显差异，说明SDCBP抑制剂对裸鼠没有明显的毒副作用，证明SDCBP抑制剂作为潜在的抗肿瘤药物具有一定的安全性。从图3F可以看出，SDCBP抑制剂和5-FU联用对裸鼠体内人食管鳞癌耐药株移植瘤的抑制能产生协同增效作用，分别取出小鼠的肝肺肾进行免疫组化，结果如图3G所示，SDCBP抑制剂和5-FU药物联用对小鼠肝肺肾功能无影响。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (10)
1.SDCBP抑制剂在制备抗食管癌药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述的SDCBP抑制剂的结构式如式(Ⅰ)所示：
3.根据权利要求1所述的应用，其特征在于，所述的SDCBP抑制剂的有效浓度为5～40μM。
4.根据权利要求3所述的应用，其特征在于，所述的SDCBP抑制剂的有效浓度为10～40μM。
5.根据权利要求1所述的应用，其特征在于，所述的抗食管癌药物为能够抑制食管癌细胞生长和/或增殖的药物。
6.根据权利要求1所述的应用，其特征在于，所述的食管癌为食管鳞癌。
7.一种抗食管癌药物，其特征在于，包括SDCBP抑制剂。
8.根据权利要求7所述的抗食管癌药物，其特征在于，还包括其他与SDCBP抑制剂具有协同增效作用的药物。
9.根据权利要求8所述的抗食管癌药物，其特征在于，所述的其他与SDCBP抑制剂具有协同增效作用的药物包括但不限于5-FU。
10.根据权利要求7所述的抗食管癌药物，其特征在于，所述的抗食管癌药物还包含药学上可接受的辅料；
所述的药学上可接受的辅料为缓释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、吸附载体、表面活性剂和润滑剂中的至少一种；
所述的抗肿瘤药物的给药形式包括但不限于口服给药和灌胃给药中的至少一种。
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| US20190017054A1 (en) * | 2016-01-07 | 2019-01-17 | Luni Emdad | Method of modulating survival and stemness of cancer stem cells by mda-9/syntenin (sdcbp) |
| CN111202726A (zh) * | 2020-03-11 | 2020-05-29 | 暨南大学 | 刺甘草查尔酮在制备抗食管癌药物中的应用 |
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| US20190017054A1 (en) * | 2016-01-07 | 2019-01-17 | Luni Emdad | Method of modulating survival and stemness of cancer stem cells by mda-9/syntenin (sdcbp) |
| CN111202726A (zh) * | 2020-03-11 | 2020-05-29 | 暨南大学 | 刺甘草查尔酮在制备抗食管癌药物中的应用 |
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