Saikosaponin D from Radix Bupleuri Suppresses Triple-negative Breast Cancer Cell Growth by Targeting β-catenin Signaling

Background: Triple-negative breast cancer (TNBC) is one of the most aggressive and poor prognosis breast cancers. Currently, chemotherapy with conventional cytotoxic agents is the only available option to treat TNBC. Hence, we identified new therapeutic agents against TNBC from traditional Chinese medicine Radix Bupleuri and unveiled the molecule mechanism of anti-TNBC effects.

Methods: Multi-component bioactivity and structure-guided methods were used to identify the most effective anti-TNBC compound Saikosaponin D (SSD) from Radix Bupleuri. Cell viability and apoptosis assays were employed to demonstrate the effect of SSD on the proliferation and apoptosis of TNBC cells. Dynamic mass redistribution assay, TopFlash assay, western blotting, and special agonist were applied to dissect the potential molecular mechanisms of SSD.

Results: We screened twenty fractions in Radix Bupleuri and identified SSD as the most effective component to inhibit the proliferation of TNBC cells. Investigating the interaction of SSD with the frequently overexpressed targets in TNBC led to the identification that it markedly suppressed Wnt/β-catenin signaling, but did not act on epidermal growth factor receptor and neurotensin receptor-1. Moreover, we demonstrated that SSD significantly repressed β-catenin and its downstream target genes, resulting in TNBC cell apoptosis. Specifically, docking of SSD to the crystal structure of β-catenin suggested that SSD interacted with β-catenin via hydrogen bonds and hydrophobic interaction.

Conclusion: We identified the most effective component SSD from Radix Bupleuri in inhibiting the proliferation of TNBC cells by targeting β-catenin signaling. Given the important role of Wnt/β-catenin signaling in breast cancer, SSD may present an opportunity to discover new therapeutics for the treatment of TNBC.