Astragalus polysaccharide enhances the therapeutic efficacy of cisplatin in triple-negative breast cancer through multiple mechanisms.

BACKGROUND: Cisplatin (DDP) has been used in the treatment of various human cancers. However, DDP alone lacks efficacy in treating triple-negative breast cancer (TNBC), and its clinical application is often hampered by side effects. Astragalus polysaccharide (APS) is one of the active components extracted from Astragalus membranaceus and has gained attention for its various biological properties. This research is aimed to evaluate the effectiveness of a combination of APS and DDP on TNBC and explore the potential mechanisms. METHODS: The efficacy and mechanisms of single or combined treatment were evaluated using Cell Counting Kit-8 (CCK8) assay, Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining, wound healing assay, trans-well invasion/migration assay, hematoxylin-eosin (HE) staining, immunohistochemical (IHC) staining, Western Blot (WB) analysis, and fluorescence-activated cell sorting (FACS). An orthotopic model of TNBC was used to assess the in vivo treatment efficacy of single or combination treatment. RESULTS: APS significantly enhanced the anti-proliferative, anti-migratory, and anti-invasive effects of DDP on TNBC cells. The combination of APS and DDP downregulated anti-apoptotic genes (Bcl2 and Bcl-xL) while upregulating pro-apoptotic genes (Puma, Cle-Caspase3, Cle-PARP), leading to enhanced apoptosis. This combination treatment increased E-cadherin levels, decreased Vimentin, Snail, Slug, and Twist levels, and effectively suppressed epithelial-mesenchymal transition (EMT)-associated cell invasion. In the orthotopic model of TNBC, a synergistic reduction in tumor growth was observed in mice treated with APS and DDP. Additionally, the combination of APS and DDP induced the infiltration of CD8(+) T lymphocytes into the tumor immune microenvironment. CONCLUSION: The combination of APS and DDP exhibits more potent tumor inhibition and anti-tumor immunity than either agent alone, representing a novel approach to enhance therapeutic efficacy without increasing the side effects of DDP.