1-脱氧野尻霉素与7-羟基香豆素耦合物诱导HCC-1937细胞凋亡的作用机制  

Cell Apcptosis Induced by Conjugation of 1-Deoxynojirimycin and 7-Hydroxycoumarin

作　　者：许奕兴 张然 汤丽青 姜雪萍 李煜麒 李豪 桂仲争 Xu Yixing;Zhang Ran;Tang Liqing;Jiang Xueping;Li Yuqi;Li Hao;Gui Zhongzheng(School of Biotechnology,Jiangsu University of Science and Technology,Key Laboratory of Silkworm and Mulberry Ge-netic Improvement,Ministry of Agriculture and Rural Affairs,Zhenjiang Jiangsu 212100)

机构地区：[1]江苏科技大学生物技术学院,农业农村部蚕桑遗传改良重点实验室,江苏镇江212100

出　　处：《蚕业科学》2024年第4期339-349,共11页ACTA SERICOLOGICA SINICA

基　　金：科技部国家高端外国专家引进计划项目(G2023014068);江苏省研究生创新计划项目(SJCX23_3849)。

摘　　要：1-脱氧野尻霉素(1-deoxynojirimycin,DNJ)是蚕桑资源特有的天然活性物质,具有良好的抗肿瘤活性。但由于DNJ脂溶性差、生物利用度低等缺陷,极大地限制了其开发与应用。7-羟基香豆素(7-hydroxycoumarin,UMB)因其独特的苯并芘结构而具有显著的抗肿瘤效果。将DNJ与UMB通过烷烃链耦合成新的DNJ衍生物4、5和6,以改善其抗肿瘤活性。结果显示,化合物6的log P值为1.09±0.24,具有良好的脂溶性;其对HCC-1937细胞的IC 50值为(45.54±3.26)μmol/L,抑制活性较DNJ提高了115倍,显著改善了DNJ抗肿瘤效果。此外,化合物6显著抑制HCC-1937细胞的增殖和迁移,诱导DNA损伤,阻滞细胞周期于S期,并破坏线粒体膜电位,增加细胞内活性氧和Ca 2+含量,引起未折叠蛋白反应导致细胞凋亡,表明化合物6通过线粒体紊乱、氧化应激和内质网应激多途径诱导HCC-1937细胞凋亡。本研究为治疗乳腺癌提供了新的治疗策略。1-Deoxynojirimycin(DNJ),a unique natural active ingredient in sericultural resources,exhibits excellent anti-tumor activity.However,the utilization and development of DNJ is restricted due to its poor lipophilicity and low bioavailability.7-Hydroxycoumarin(UMB)has significant anti-tumor effects due to its unique benzopyrene structure.In this study,a series of compound 4,5 and 6 were synthesized,in which DNJ was linked to UMB via an alkyl chain linker,aiming to alleviate the cytotoxicity of DNJ.Compound 6 exhibited an excellent lipophilicity with the experimental log P of 1.09±0.24,and a superior antiproliferative effects with IC 50 of(45.54±3.26)μmol/L to HCC-1937 cell,the inhibitory ability was increased by 115 fold of DNJ.Furthermore,compound 6 significantly inhibited the proliferation and migration of HCC-1937 cell,induced DNA damage,arrested cell cycle at S phase,and induced cell apoptosis by mediating mitochondrial membrane potential disruption,increasing the content of ROS and Ca 2+,and causing unfolded protein response.These findings indicated that compound 6 intervened in several cellular processes including mitochondrial damage,oxidative stress and endoplasmic reticulum stress to induce apoptosis of HCC-1937 cell,providing a new useful strategy for treating breast cancer.

关 键 词：1-脱氧野尻霉素 香豆素类化合物 衍生物 抗肿瘤活性 分子机制 

分 类 号：S888.2[农业科学—特种经济动物饲养] R915[农业科学—畜牧兽医]