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

Yujie Huang; Jiansong Fang; Weiqiang Lu; Zihao Wang; Qi Wang; Yuan Hou; Xingwu Jiang; Ofer Reizes; Justin Lathia; Ruth Nussinov; Charis Eng; Feixiong Cheng

doi:10.1016/j.chembiol.2019.05.004

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

Cell Chem Biol. 2019 Aug 15;26(8):1143-1158.e6. doi: 10.1016/j.chembiol.2019.05.004. Epub 2019 Jun 6.

Authors

Yujie Huang¹, Jiansong Fang², Weiqiang Lu³, Zihao Wang⁴, Qi Wang¹, Yuan Hou⁵, Xingwu Jiang⁶, Ofer Reizes⁷, Justin Lathia⁷, Ruth Nussinov⁸, Charis Eng⁹, Feixiong Cheng¹⁰

Affiliations

¹ Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China.
² 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: [email protected].
³ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China. Electronic address: [email protected].
⁴ Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
⁵ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
⁶ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
⁷ 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.
⁸ 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.
⁹ 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.
¹⁰ 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: [email protected].

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.

Keywords: Smoothened; angiogenesis; hedgehog signaling; systems pharmacology; triple-negative breast cancer; wogonoside.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / isolation & purification
Angiogenesis Inhibitors / pharmacology*
Animals
Antineoplastic Agents, Phytogenic / chemistry
Antineoplastic Agents, Phytogenic / isolation & purification
Antineoplastic Agents, Phytogenic / pharmacology*
Biological Products / chemistry
Biological Products / isolation & purification
Biological Products / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Screening Assays, Antitumor
Female
Flavanones / chemistry
Flavanones / isolation & purification
Flavanones / pharmacology*
Glucosides / chemistry
Glucosides / isolation & purification
Glucosides / pharmacology*
Hedgehog Proteins / antagonists & inhibitors*
Hedgehog Proteins / metabolism
Humans
Mammary Neoplasms, Experimental / drug therapy
Mammary Neoplasms, Experimental / metabolism
Mammary Neoplasms, Experimental / pathology
Mice
Mice, Inbred BALB C
Mice, Nude
Neovascularization, Pathologic / drug therapy*
Neovascularization, Pathologic / metabolism
Neovascularization, Pathologic / pathology
Scutellaria baicalensis / chemistry
Signal Transduction / drug effects
Triple Negative Breast Neoplasms / drug therapy*
Triple Negative Breast Neoplasms / metabolism
Triple Negative Breast Neoplasms / pathology

Substances

Angiogenesis Inhibitors
Antineoplastic Agents, Phytogenic
Biological Products
Flavanones
Glucosides
Hedgehog Proteins
wogonoside

Abstract

Publication types

MeSH terms

Substances

Grants and funding