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

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Triple-negative breast cancer (TNBC) is an aggressive cancer subtype lacking targeted therapy options.
• Angiogenesis, the formation of new blood vessels, is crucial for tumor growth and metastasis in TNBC.
• Current therapeutic strategies for TNBC are limited due to its heterogeneity and lack of actionable targets.

Purpose of the Study:

• To identify novel therapeutic agents for triple-negative breast cancer (TNBC) using a systems pharmacology approach.
• To investigate the anti-angiogenic potential of wogonoside, a major active flavonoid, in TNBC.
• To elucidate the molecular mechanisms underlying wogonoside's anti-angiogenic effects in TNBC.

Main Methods:

• Integrated drug-target networks with large-scale genomic profiles of TNBC.
• In vitro assays to assess wogonoside's effects on endothelial cell functions (migration, tube formation, microvessel outgrowth).
• In vivo studies using chicken chorioallantoic membrane and TNBC xenograft models to evaluate anti-angiogenic and anti-tumor effects.
• Mechanistic studies involving Western blotting and nuclear translocation assays to investigate wogonoside's impact on Hedgehog signaling pathway.

Main Results:

• Wogonoside was identified as a potent inhibitor of angiogenesis in TNBC.
• Wogonoside significantly attenuated endothelial cell migration, tube formation, and microvessel outgrowth in vitro.
• In vivo studies demonstrated that wogonoside reduces blood vessel formation in the chicken chorioallantoic membrane and inhibits tumor growth and angiogenesis in TNBC xenograft models.
• Wogonoside's anti-angiogenic effects were linked to the inhibition of vascular endothelial growth factor (VEGF) secretion.
• Mechanistically, wogonoside inhibits Gli1 nuclear translocation and transcriptional activity by promoting Smoothened degradation via a proteasome-dependent pathway.

Conclusions:

• Wogonoside exhibits significant anti-angiogenic and anti-tumor activities against triple-negative breast cancer.
• The study highlights a systems pharmacology approach as a powerful strategy for identifying novel cancer therapeutics.
• Wogonoside represents a potential therapeutic candidate for targeting angiogenesis in TNBC, offering a new avenue for treatment.