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  • Lycopene br In conclusion wogonoside inhibits angiogenesis i

    2020-03-17


    In conclusion, wogonoside inhibits angiogenesis in TNBC by reducing VEGF Lycopene and inhibiting the Hedgehog signaling pathway in vitro and in vivo. Specifically, wogonoside inhibits the nuclear translocation and transcription activity of Gli1 by binding to SMO directly and specifically promoting ubiq-uitination-dependent degradation of SMO in TNBC cells. These findings offer compelling preclinical evidence in support of wo-gonoside development as a potential angiogenesis inhibitor for the treatment of TNBC.
    SIGNIFICANCE
    In this study, we applied a systems pharmacology approach that integrates known drug-target network and large-scale
    genomic profiles of TNBC for identification of effective ther-apeutic agents in treating TNBC. We found that wogonoside, one of the major active flavonoids derived from Scutellaria baicalensis Georgi, exhibited an effective angiogenesis inhibitor of TNBC in vitro and in vivo. In summary, we demon-strated that wogonoside inhibited the Gli1 nuclear translo-cation and transcription activities of Hedgehog signaling by promoting SMO degradation in a proteasome-dependent manner. This study offers a powerful, integrated computa-tional and experimental pharmacology approach for oncological drug discovery and identifies wogonoside as a potential angiogenesis inhibitor to treat TNBC in preclinical studies. Our approach can minimize the translational gap between preclinical testing results in animal models and clinical outcomes, which is a significant problem in the development of efficient therapeutic strategies for TNBC. From a translational perspective, if broadly applied, the computational and experimental pharmacology tools devel-oped here could help develop effective treatment strategies for other types of cancer and complex diseases in clinic.
    STAR+METHODS
    Detailed methods are provided in the online version of this paper and include the following:
    d KEY RESOURCES TABLE
    d CONTACT FOR REAGENT AND RESOURCE SHARING d EXPERIMENTAL MODEL AND SUBJECT DETAILS
    B Cell Lines
    B Animal Studies d METHOD DETAILS
    B Manual Curation of Functional Genes for Triple-Nega-tive Breast Cancer (TNBC)
    B Reconstruction of Drug-Target Network for Natural Products
    B In Silico Prediction of Anti-TNBC Indications for Natural Products
    B Chemical Structure Clustering Analysis
    B Tissue-specific Human Protein-Protein Interactome Network Analysis
    B Compound Preparation B Immunohistochemistry B Cell Viability Assay
    B Enzyme-Linked ImmunoSorbent Assay (ELISA) B VEGF-Luciferase Reporter Assay
    B Western Blot Analysis B Real-Time PCR Analysis B Gene Knockdown
    B Molecular Docking Studies
    (B) The whole mount of CD31 staining was viewed by laser scanning confocal microscope.
    (C) The hemoglobin content in Matrigel plugs was determined.
    (D) The expression of CD31 in MDA-MB-231 cells xenograft in nude mice was tested by immunochemistry.
    (E) Effect of VEGF-neutralizing antibody (10 mg/mL) on the tube formation of HUVECs induced by CM from MDA-MB-231 or MDA-MB-468 cells was tested by endothelial cell tube formation assay.
    (F) Effect of VEGF-neutralizing antibody (10 mg/mL) on the enhanced angiogenesis induced by MDA-MB-231 cells or MDA-MB-468 cells (1 3 106 cells/CAM) was tested by chicken CAM assay.
    The comparisons were made relative to MDA-MB-231 or MDA-MB-468 cell groups and the significance of the difference is indicated as **p < 0.01.
    Please cite this article in press as: Huang et al., A Systems Pharmacology Approach Uncovers Wogonoside as an Angiogenesis Inhibitor of Triple-Negative Breast Cancer by Targeting Hedgehog Signaling, Cell Chemical Biology (2019), https://doi.org/10.1016/j.chembiol.2019.05.004
    B BODIPY-cyclopamine Based Fluorescence Bind-ing Assay
    B Cellular Thermal Shift Assay (CETSA) B Gli-luciferase Reporter Assay