去甲二氢愈创木酸靶向MyD88抗肿瘤研究  

Research on the anti-tumor effect of nordihydroguaiaretic acid targeting MyD88

作　　者：王月 屈祎 柯细松 张雪 WANG Yue;QU Yi;KE Xi-song;ZHANG Xue(Institute of Interdisciplinary Integrative Medicine Research,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China;Shanghai Frontiers Science Center of TCM Chemical Biology,Shanghai 201203,China)

机构地区：[1]上海中医药大学交叉科学研究院,上海201203 [2]上海市中药化学生物学前沿基地,上海201203

出　　处：《药学学报》2023年第4期946-953,共8页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(81803754)。

摘　　要：本研究主要探究髓系分化初级反应蛋白88(myeloid differentiation primary response protein 88,MyD88)在肿瘤发生发展中的作用,发现靶向MyD88的抗肿瘤活性小分子。本研究利用CRISPR/Cas9技术和裸鼠移植瘤模型检测MyD88缺失对肿瘤生长的作用,实验动物伦理审查编号为PZSHUTCM200828006;利用微量热泳动技术(microscale thermophoresis technology,MST)筛选直接结合MyD88的天然产物小分子,并进一步检测候选小分子对细胞增殖的影响。结果表明,MyD88缺失后显著抑制结肠癌、胰腺癌和皮肤癌的肿瘤生长并且抑制肿瘤细胞的NF-κB信号通路活性;MST结果发现,去甲二氢愈创木酸(nordihydroguaiaretic acid,NDGA)与MyD88直接结合,其结合解离常数K_(d)=14.61μmol·L^(-1);去甲二氢愈创木酸阻断NF-κB报告系统的激活,并抑制NF-κB通路关键因子p65磷酸化;此外,克隆形成实验结果发现去甲二氢愈创木酸抑制肿瘤细胞增殖。以上结果表明,MyD88是结肠癌、胰腺癌、皮肤癌潜在治疗靶标,去甲二氢愈创木酸与MyD88直接结合并且抑制其下游NF-κB信号通路的活性,从而抑制胰腺癌、皮肤癌及结肠癌细胞增殖。This study mainly explores the role of myeloid differentiation primary response protein 88(MyD88)in tumorigenesis and development,to identify active compounds targeting MyD88.CRISPR/Cas9 system and xenograft tumor model were used to detect the effect of MyD88 deletion on tumor growth,and the experimental animal ethics review number was PZSHUTCM200828006.Microscale thermophoresis technology(MST)was used to identify compounds directly bind to MyD88 and further detect the impact of candidate small molecules on cell proliferation.Results showed that depletion of MyD88 significantly inhibited xenograft tumor growth of colon cancer,pancreatic cancer and skin cancer and the activity of NF-κB signaling pathway.MST showed that nordihydroguaiaretic acid(NDGA)bound to MyD88,with the binding dissociation constant K_(d) of 14.61μmol·L^(-1).NDGA inhibited NF-κB reporting system activation and phosphorylation of p65,the key factor in NF-κB signal pathway.In addition,the results of colony formation assay showed that NDGA suppressed the proliferation of tumor cells.The above results show that,MyD88 is a potential therapeutic target for colon cancer,pancreatic cancer and skin cancer,NDGA directly binds to MyD88 and inhibits the activity of NF-κB signaling pathway,as well as inhibits the proliferation of pancreatic cancer,skin cancer and colon cancer cells.

关 键 词：髓系分化初级反应蛋白88 结肠癌 皮肤癌 胰腺癌 NF-ΚB信号通路 去甲二氢愈创木酸 

分 类 号：R966[医药卫生—药理学]