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Shikonin is a novel and selective IMPDH2 inhibitor that target triple‐negative breast cancer
Author(s) -
Wang Wanyan,
Wu Yu,
Chen Si,
Liu Xi,
He Jiacheng,
Wang Shuyi,
Lu Weiqiang,
Tang Yong,
Huang Jin
Publication year - 2021
Publication title -
phytotherapy research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.019
H-Index - 129
eISSN - 1099-1573
pISSN - 0951-418X
DOI - 10.1002/ptr.6825
Subject(s) - triple negative breast cancer , cancer research , chemistry , cell growth , cell culture , breast cancer , pharmacology , cancer , biology , biochemistry , medicine , genetics
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 of Lithospermum 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.