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A Systems Pharmacology Approach Uncovers Wogonoside as an Angiogenesis Inhibitor of Triple-Negative Breast Cancer by Targeting Hedgehog Signaling

  1. Author:
    Huang, Yujie
    Fang, Jiansong
    Lu, Weiqiang
    Wang, Zihao
    Wang, Qi
    Hou, Yuan
    Jiang, Xingwu
    Reizes, Ofer
    Lathia, Justin
    Nussinov,Ruth
    Eng, Charis
    Cheng, Feixiong

  2. Author Address

    Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China., Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: fangjs@gzucm.edu.cn., Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China. Electronic address: wqlu@bio.ecnu.edu.cn., Southern University of Science and Technology, Shenzhen, Guangdong 518055, China., Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA., Computational Structural Biology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel., Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA., Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Electronic address: chengf@ccf.org.,
    1. Year: 2019
    2. Date: Aug 15
    3. Epub Date: 2019 05 30
  2. Journal: Cell chemical biology
    1. 26
    2. 8
    3. Pages: 1143-1158.e
  4. Type of Article: Article
  5. ISSN: 2451-9448
  1. Abstract:

    Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous disease that lacks clinically actionable genetic alterations that limit targeted therapies. Here we explore a systems pharmacology approach that integrates drug-target networks and large-scale genomic profiles of TNBC and identify wogonoside, one of the major active flavonoids, as a potent angiogenesis inhibitor. We validate that wogonoside attenuates cell migration, tube formation, and rat aorta microvessel outgrowth, and reduces formation of blood vessels in chicken chorioallantoic membrane and TNBC cell-induced Matrigel plugs. In addition, wogonoside inhibits growth and angiogenesis in TNBC cell xenograft models. This network-based approach predicts, and we empirically validate, wogonoside's antiangiogenic effects resulting from vascular endothelial growth factor secretion. Mechanistically, wogonoside inhibits Gli1 nuclear translocation and transcriptional activities associated with Hedgehog signaling, by promoting Smoothened degradation in a proteasome-dependent mechanism. This study offers a powerful, integrated, systems pharmacology-based strategy for oncological drug discovery and identifies wogonoside as a potential TNBC angiogenesis inhibitor. Copyright © 2019 Elsevier Ltd. All rights reserved.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.chembiol.2019.05.004
  3. PMID: 31178408
  4. View record in Web of Science®
  5. WOS: 000481604100011
  6. PII : S2451-9456(19)30173-4

Library Notes

  1. Fiscal Year: FY2018-2019
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