文献类型：期刊文献

英文题名：Shikonin is a novel and selectiveIMPDH2inhibitor that target triple-negative breast cancer

作者：Wang, Wanyan[1];Wu, Yu[1];Chen, Si[2,3];Liu, Xi[1];He, Jiacheng[2,3];Wang, Shuyi[2,3];Lu, Weiqiang[2,3];Tang, Yong[4];Huang, Jin[1]

机构：[1]East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[2]East China Normal Univ, Shanghai Key Lab Regulatory Biol, Inst Biomed Sci, Shanghai 200241, Peoples R China;[3]East China Normal Univ, Sch Life Sci, Shanghai 200241, Peoples R China;[4]Guangxi Med Univ, Dept Urol, Wuming Hosp, Nanning 530199, Guangxi, Peoples R China

年份：2021

卷号：35

期号：1

起止页码：463

外文期刊名：PHYTOTHERAPY RESEARCH

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000557790000001)】；

基金：National Natural Science Foundation of China 81773775 81972828 81973362; Shanghai Committee of Science and Technology 19ZR1473500 18431900500; The Open Fund of Key laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education; Open Project of Guangxi Key Laboratory of Biomolecular Medicine Research, China (GXBMR201605); Open Project of Guangxi Key Laboratory of Biological Targeting Diagnosis and Treatment Research, China (GXSWBX201501)

语种：英文

外文关键词：guanine nucleotides; IMPDH2; natural product; shikonin; triple-negative breast cancer

摘要：Triple-negative breast cancer (TNBC) is heterogeneous disease with a poor prognosis. It is therefore important to explore novel therapeutic agents to improve the clinical efficacy for TNBC. The inosine 5 '-monophosphate dehydrogenase 2 (IMPDH2) is a rate-limiting enzyme in the de novo synthesis of guanine nucleotides. It is always overexpressed in many types of tumors, including TNBC and regarded as a potential target for cancer therapy. Through screening a library of natural products, we identified shikonin, a natural bioactive component ofLithospermum erythrorhizon, is a novel and selective IMPDH2 inhibitor. Enzymatic analysis using Lineweaver-Burk plot indicates that shikonin is a competitive inhibitor of IMPDH2. The interaction between shikonin and IMDPH2 was further investigated by thermal shift assay, fluorescence quenching, and molecular docking simulation. Shikonin treatment effectively inhibits the growth of human TNBC cell line MDA-MB-231, and murine TNBC cell line, 4T1 in a dose-dependent manner, which is impaired by exogenous supplementation of guanosine, a salvage pathway of purine nucleotides. Most importantly, IMPDH2 knockdown significantly reduced cell proliferation and conferred resistance to shikonin in TNBC. Collectively, our findings showed the natural product shikonin as a selective inhibitor of IMPDH2 with anti-TNBC activity, impelling its further study in clinical trials.