CN105434438B - 一种伐诺司林二盐酸盐的药物用途 - Google Patents
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Abstract
本发明公开了一种伐诺司林二盐酸盐的药物用途，具体的为将伐诺司林二盐酸盐作为致癌因子CDK2,4,6的联合抑制剂，从而发挥抗肝癌的功效，所述伐诺司林二盐酸盐为1‑(2‑[双(4‑氟苯基)甲氧基]乙基)‑4‑(3‑苯基丙基)哌嗪二盐酸盐(Vanoxerine dihydrochloride)，诺司林二盐酸盐作为一种新型抗肝癌药物，可用于减缓肿瘤病情的发展，降低患者的痛苦，本发明也为研制能用于肝癌,大肠癌及其它恶性肿瘤治疗的药物提供了新的思路和技术储备。
Description
技术领域
本发明涉及一种伐诺司林二盐酸盐的药物用途，尤其是通过抑制致癌因子CDK2,4,6的活性发挥抗肝癌的作用。
背景技术
原发性肝癌是危害人类健康的重要疾病之一，多次被我国政府列为研究和防治的重点。肝癌的治疗长期以来一种是一个世界性的难题。肝癌发病隐匿，患者就诊时多属中、晚期，而且肝癌是一种恶性程度高、浸润和转移性强以及极易耐药的恶性肿瘤，目前临床上治疗肝癌的化疗药物治疗效果都不是很理想，且外科手术治疗后存在70-90％的复发率，复发后的患者对化疗、放疗出现抵抗作用,因此寻找新型抗肝癌药物迫在眉睫。
细胞周期紊乱是恶性肿瘤形成的一个标志，细胞周期蛋白依赖性激酶(CDKs)的激活与失活维持着细胞周期各时相有序进行。CDK2是G1过渡到S期的关键因子。抑制CDK2可以抑制肿瘤细胞的增生，为一个很好的肿瘤药物靶点。CDK4,6是G1前期的关键致癌因子，抑制CDK4,6可以抑制肿瘤细胞的增生，也为一个很好的肿瘤药物靶点，所以筛选出可抑制致癌因子CDK2,4,6活性的药物即可抑制抑制肿瘤细胞的增生，发挥抗肝癌的功效。
发明内容
本发明公开了将伐诺司林二盐酸盐作为抗肝癌药物的用途，即将伐诺司林二盐酸盐作为抗肝癌的药物；
进一步的，所述的伐诺司林二盐酸盐为1-(2-[双(4-氟苯基)甲氧基]乙基)-4-(3-苯基丙基)哌嗪二盐酸盐(Vanoxerinedihydrochloride)。
进一步的，所述肝癌的致癌因子为CDK2,4,6。
进一步的，将1-(2-[双(4-氟苯基)甲氧基]乙基)-4-(3-苯基丙基)哌嗪二盐酸盐(Vanoxerinedihydrochloride)作为致癌因子CDK2,4,6的联合抑制剂。
为了更好的说明本发明的实质，下面结合实验例对本发明的研究做详细说明。
实验例1
本发明通过计算机药物开发软件idock针对致癌因子CDK2,4,6从FDA注册过的药物数据库初筛出打分很高的9个化合物，然后通过实验室体内外实验验证其抗癌作用。实验室体内外实验包括如下几步：
1、idock软件筛选CDK2抑制剂的候选药物
从FDA认证的包括在dbap和fda目录下ZINC药物数据库中4,914个药物进行分析且依据绑定的亲和强度值进行排序。从中找出且购买到9个打分最高的化合物进行下一步的实验。它们分别是莫那匹尔、氟啶蜱脲、凯坦色林、酒石酸盐、他尼氟酯、度他雄胺、阿坦塞林、咪唑斯汀、伐诺司林二盐酸盐。
2、比较候选药物对应的IC50值
通过MTT实验首先检查了9个化合物的抗癌效果。这九个化合物分别都对肝癌细胞系QGY7703和Huh7有抗癌效果。用graphpadprime5软件计算出其IC50值，比较各化合物对应的IC50值，从而筛选出最有效的化合物伐诺司林二盐酸盐。伐诺司林二盐酸盐干扰肝癌细胞系QGY7703和Huh7及大肠癌细胞系LOVO和DLD1后,呈现时间(24,48,72小时)及剂量(3,10,30uM/L)依赖性抑制增加效果，图3。
3、观察伐诺司林二盐酸盐对肝癌细胞干扰效果
为了观察伐诺司林二盐酸盐对肝癌细胞的抑制效果,通过用流式细胞术检测在不同浓度伐诺司林二盐酸盐干扰肝癌细胞QGY7703和Huh76,12,24小时后细胞周期分布情况，与对照组相比较，伐诺司林二盐酸盐大大的增加了停滞在G1期的细胞,且呈现时间及剂量依赖性增加的趋势(P<0.05)，同时结果显示随着G1期细胞数量的增加同时伴随着S期细胞数量的减少。
4、评估伐诺司林二盐酸盐干扰肝癌细胞后引起的细胞凋亡结果
通过流式细胞技术检测伐诺司林二盐酸盐干扰肝癌细胞Huh7和QGY7703后,与对照组相比较伐诺司林二盐酸盐大大的增加了细胞的凋亡数量,且呈现时间及剂量依赖性增加的趋势(P<0.05)。
5、伐诺司林二盐酸盐干扰肝癌细胞QGY7703和Huh7细胞后，CDK2,4,6,Rb,cyclinE,cyclinD,pho-CDk2,pho-Rb，cyclinB的蛋白表达量的变化情况
通过Westernblotting实验伐诺司林二盐酸盐干扰肝癌细胞后G1期及G1期至S期转换相关蛋白CDK2,4,6,cyclinD/B,cyclinE,Rb,pho-CDk2andpho-Rb进行检测。结果显示伐诺司林二盐酸盐干扰肝癌细胞Huh7和QGY7703后其CDK2,4,6,cyclinD,cyclinE,Rb,pho-CDK2和pho-Rb蛋白表达量呈现剂量依赖性下降趋势，cyclinB蛋白表达量没有改变。
有益效果：
本发明通过体外试验验证，伐诺司林二盐酸盐可抑制致癌因子CDK2,4,6活性，具有强烈的抗肝癌的效果，伐诺司林二盐酸盐作为一种新型抗肝癌药物，可用于减缓肿瘤病情的发展，降低患者的痛苦，本发明也为研制能用于肝癌,大肠癌及其它恶性肿瘤治疗的药物提供了新的思路和技术储备。
附图说明
下面结合附图和具体实施方式对本发明的技术方案作进一步具体说明。
图1伐诺司林二盐酸盐与其他8个化合物的干扰QGY7703和Huh7增殖率效果图；
图2伐诺司林二盐酸盐干扰肝癌细胞HepG2和Huh7呈现时间(6,12,24h)与浓度(3,10,30uM)依赖性抑制效果增加的趋势；
图3伐诺司林二盐酸盐对大肠癌细胞DLD1和LOVO呈现时间(6,12,24h)与浓度(3,10,30uM)抑制依赖性效果增加的趋势；
图4伐诺司林二盐酸盐的浓度(3,10,30uM)及作用时间(6,12,24h)与肝癌细胞QGY7703和Huh7G1期细胞阻滞效果图；
图5伐诺司林二盐酸盐处理肝癌细胞QGY7703和Huh724小时后，细胞周期分布图；
图6伐诺司林二盐酸盐浓度(3,10,30uM)及作用时间(6,12,24h)与肝癌细胞Huh7细胞凋亡数量关系图；
图7伐诺司林二盐酸盐的浓度(3,10,30uM)及作用时间(6,12,24h)与肝癌细胞QGY7703细胞凋亡数量关系图；
图8伐诺司林二盐酸盐干扰肝癌细胞Huh7和QGY7703后，其CDK2,4,6,cyclinD,cyclinE,Rb,pho-CDK2，pho-Rb及cyclinD蛋白表达量呈现下降趋势,cyclinB没有变化。
具体实施方式
实施例1
本实施例为将伐诺司林二盐酸盐，即1-(2-[双(4-氟苯基)甲氧基]乙基)-4-(3-苯基丙基)哌嗪二盐酸盐(Vanoxerinedihydrochloride)与其他辅助药品结合作为抗肝癌的药物。
实施例2
本实施例为将伐诺司林二盐酸盐，即1-(2-[双(4-氟苯基)甲氧基]乙基)-4-(3-苯基丙基)哌嗪二盐酸盐(Vanoxerinedihydrochloride)与其他辅助药品结合作为抗大肠癌的药物。
最后应当说明的是，以上实施方案仅用以说明本发明的技术方案,尽管参照较佳实例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的精神和范围，其均应涵盖在本发明的权利要求范围中。
Claims (1)
1.一种伐诺司林二盐酸盐制备药物的用途，其特征在于，将伐诺司林二盐酸盐用于制备抗肝癌的药物。
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| WO2002030422A1 (de) * | 2000-10-11 | 2002-04-18 | Merck Patent Gmbh | Verwendung bestimmter substanzen, die an den sigma-rezeptor binden, zur behandlung von sarkomen und karzinomen |
| WO2009070331A2 (en) * | 2007-11-27 | 2009-06-04 | Stc.Unm | Compounds and methods for the selective inhibition of abcb1, abcc1 and abcg2 transporters and the treatment of cancers, especially drug resistant cancers and high throughput flow cytometry assay to detect selective inhibitors |
| US20120114670A1 (en) * | 2007-10-02 | 2012-05-10 | University Of Rochester | Methods and compositions related to synergistic responses to oncogenic mutations |
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2015
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002030422A1 (de) * | 2000-10-11 | 2002-04-18 | Merck Patent Gmbh | Verwendung bestimmter substanzen, die an den sigma-rezeptor binden, zur behandlung von sarkomen und karzinomen |
| US20120114670A1 (en) * | 2007-10-02 | 2012-05-10 | University Of Rochester | Methods and compositions related to synergistic responses to oncogenic mutations |
| WO2009070331A2 (en) * | 2007-11-27 | 2009-06-04 | Stc.Unm | Compounds and methods for the selective inhibition of abcb1, abcc1 and abcg2 transporters and the treatment of cancers, especially drug resistant cancers and high throughput flow cytometry assay to detect selective inhibitors |
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