具核梭杆菌小分子抑制剂的筛选及其抗结直肠癌活性研究  

Screening and anti-colorectal activity of small molecule inhibitors of Fusobacterium nucleatum

作　　者：白学鑫 陈玉平 盛春泉 武善超 BAI Xuexin;CHEN Yuping;SHENG Chunquan;WU Shanchao(Department of Medicinal Chemistry,School of Pharmacy,Naval Medical University,Shanghai 200433,China)

机构地区：[1]海军军医大学药学系药物化学教研室,上海200433

出　　处：《药学实践与服务》2024年第12期503-507,共5页Journal of Pharmaceutical Practice and Service

基　　金：国家自然科学基金(22377145,22077138);国家重点研发计划(2020YFA0509204);上海市青年科技启明星项目(22QA1411300)。

摘　　要：目的基于市售化合物库的表型筛选获得抗具核梭杆菌(Fn)活性化合物,评价其在Fn干预下的抗结直肠癌活性,为新型抗结直肠癌药物研发提供先导化合物。方法首先验证Fn促结直肠癌类器官增殖效应;其次,比较考察抗Fn化合物在Fn与结肠癌HCT116细胞共孵育下对其体外抗癌活性的影响;最后,评价高活性化合物对Fn灌胃干预下裸鼠结肠癌HCT116移植瘤的体内抗癌药效。结果Fn可显著促进直肠癌类器官增殖;9个抗Fn化合物均能显著提升Fn与HTC116细胞共孵育下的体外抗癌活性,其中甲氨蝶呤抗癌活性最强,IC50达0.03μmol/L;甲氨蝶呤(0.5 mg/kg)与PD-1(5.0mg/kg)联用能显著抑制Fn灌胃干预下裸鼠人结肠癌HCT116移植瘤的生长,抑瘤率达67.46%,抑瘤效果优于单药。结论Fn小分子抑制剂甲氨蝶呤对有Fn干预的结直肠癌细胞和裸鼠移植瘤具有良好的体内外抗癌活性,为后续结构优化打下基础,并有望拓展甲氨蝶呤的新适应证。Objective To screen small molecule inhibitors of Fusobacterium nucleatum(Fn)based on commercially available compound libraries,and investigate their anti-colorectal cancer activities under Fn intervention in order to obtain novel anti-colorectal cancer lead compounds.Methods The promotion of colorectal cancer proliferation on organoid was validated by Fn.Secondly,the effects of anti-Fn compounds on their in vitro anticancer activity under Fn’s co-incubation with colorectal cancer HCT116 cell were comparative investigated.Finally,in vivo anticancer efficacy of highly active compounds on nude mouse colon cancer HCT116 transplanted tumor under the intervention of Fn was evaluated by gavage.Results Fn could significantly promote the proliferation of rectal cancer organoids.9 anti-Fn active compounds could significantly enhance their in vitro anticancer activity under Fn’s co-incubation with HCT116 cells.Methotrexate had the strongest anti-cancer activity with IC50 as 0.03μmol/L.The combined use of methotrexate(0.5 mg/kg)and PD-1(5.0 mg/kg)had a stronger anti-tumor effect than their standalone use.Conclusion As new small molecule inhibitor of Fn,methotrexate exhibited good in vitro and in vivo anti-colorectal cancer activity against HCT116 cells and nude mouse xenografts under Fn intervention,which showed the foundation for subsequent structural optimization,and could be expected to expand the new indications of methotrexate.

关 键 词：具核梭杆菌 表型筛选 抗结肠癌 类器官 甲氨蝶呤 

分 类 号：R96[医药卫生—药理学]