LA-D靶向CDK4/6-Cyclin D1-Rb-E2F通路对乳腺癌细胞的抑制功能  

Inhibition of LA-D on breast cancer cells via the CDK4/6-Cyclin D1-Rb-E2F pathway

作　　者：刘媛媛 李寒雪 张思懿 左玲怡 周娇娇 姜文韬 刘志晴 张美琪 成文浩 敬爱新 袁庆 刘彬 LIU Yuanyuan;LI Hanxue;ZHANG Siyi;ZUO Lingyi;ZHOU Jiaojiao;JIANG Wentao;LIU Zhiqing;ZHANG Meiqi;CHENG Wenhao;JING Aixin;YUAN Qing;LIU Bing(School of Pharmacy,Jiangsu Ocean University,Lianyungang 222005,China;Jiangsu Key Laboratory of Marine Drug Active Molecular Screening,Jiangsu Ocean University,Lianyungang 222005,China)

机构地区：[1]江苏海洋大学药学院,江苏连云港222005 [2]江苏海洋大学江苏省海洋药物活性分子筛选重点实验室,江苏连云港222005

出　　处：《江苏海洋大学学报(自然科学版)》2025年第1期71-80,共10页Journal of Jiangsu Ocean University:Natural Science Edition

摘　　要：乳腺癌是一种常见的恶性肿瘤,发病率较高,主要发生在女性乳腺组织中。设计并合成了一种新型Abemaciclib衍生物6-((2-氯-4-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)苯氧基)甲基)吡啶腈(LA-D)。通过MTT试验分析细胞的活力,伤口愈合试验、Transwell试验分析化合物LA-D对乳腺癌细胞侵袭迁移的抑制作用。采用鸡胚绒毛尿囊膜体内试验进一步评价化合物LA-D的生物学意义以及功能作用。采用Western blot分析周期相关CDK4/6-Cyclin D1-Rb-E2F通路各蛋白的表达,进一步确定化合物LA-D抑制乳腺癌的作用机制。结果显示,化合物LA-D对CDK4具有较强的亲和力,且能够影响乳腺癌细胞的细胞形态,抑制乳腺癌细胞的增殖、迁移、侵袭、黏附。综上,LA-D对乳腺癌细胞具有较强的抗肿瘤作用,其抗肿瘤活性可能依赖于抑制CDK4/6-Cyclin D1-Rb-E2F通路相关蛋白的表达。因此,化合物LA-D可能是一种乳腺癌的潜在治疗药物。Breast cancer is a common malignancy with a high incidence,mainly occurring in female breast tissue.This study designed and synthesized a novel Abemaciclib derivative 6-((2-chlorine-4-((5-fluorine-4-(4-fluorine-1-isol-2-methyl-1H-benzene[d]imidazole-6-group)pyrimidine-2-group)amino)phenoxy)methyl)pyridine nitrile(LA-D).The viability of the cells was analyzed by MTT assay,and the wound healing assay and Transwell assay analyzed the inhibitory effect of the compound LA-D on the invasion and migration of breast cancer cells.The in vivo experiments used the membrane of chick embryo to further evaluate the biological significance and functional role of the compound LA-D.The mechanism of action of the compound LA-D in inhibiting breast cancer was further determined by Western blot by analyzing the expression of each protein of the CDK4/6-Cyclin D1-Rb-E2F pathway.The results showed that the compound LA-D had a strong affinity for CDK4 and could affect the cell morphology of breast cancer cells and inhibit the proliferation,migration,invasion and adhesion.In conclusion,LA-D has a strong anti-tumor effect on breast cancer cells,and its anti-tumor activity may depend on inhibiting the expression of proteins involved in the CDK4/6-Cyclin D1-Rb-E2F pathway.Thus,the compound LA-D may be a potential therapeutic agent for breast cancer.

关 键 词：LA-D 乳腺癌 迁移 侵袭 抗肿瘤活性 

分 类 号：R965.1[医药卫生—药理学]