Abstract
Objective: Chemoresistance represents a major obstacle in breast cancer (BC) treatment. Chelidonine could prevent various tumor cell types. However, the effect and mechanism of chelidonine against BC chemotherapy resistance have not been elucidated. This paper aimed to explore the effect and mechanism of chelidonine on BC chemoresistance. Methods: A CCK-8 assay, flow cytometry and fluorescence microscopy were applied to evaluate the resistance reversal effect of chelidonine on MCF-7/ADR cells. The signaling pathways by which chelidonine suppresses BC were predicted by network pharmacology and validated by Western blotting. The chemoresistant reversal mechanism of chelidonine was clarified using platelet-derived growth factor receptor-β (PDGFRβ) silencing with small interfering RNA (siRNA), platelet-derived growth factor-BB (PDGF-BB) stimulation, Western blotting and real-time quantitative polymerase chain reaction (RT-qPCR). Results: Chelidonine remarkably reversed adriamycin (ADR) resistance by decreasing P-glycoprotein (P-gp) expression and the efflux of ADR in MCF-7/ADR cells. Additionally, PDGFRβ expression in MCF-7/ADR cells was markedly higher than that in MCF-7 cells (P < 0.01), and PDGFRβ knockdown prevented P-gp expression and intracellular ADR accumulation. Network pharmacology identified phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) as a primary pathway of chelidonine-inhibiting BC, which was verified by the marked underexpression of phosphorylated kappa B inhibitor protein kinase (p-IKK), phosphorylated inhibitor of nuclear factor-κB (p-IKB), and nuclear factor-κB (NF-κB) and phosphatase and tensin homolog (PTEN) hyperexpression by chelidonine treatment (P < 0.01). Notably, PDGFRβ silencing enhanced the inhibitory effect of chelidonine on the activation of the PI3K/Akt pathway. Moreover, chelidonine suppressed PDGF-BB stimulation of the PDGFRβ/PI3K/Akt axis. Conclusion: These findings underscore the potential role of PDGFRβ in regulating chemotherapy resistance in BC. Chelidonine could effectively overcome the resistance of MCF-7/ADR cells to ADR by targeting the PDGFRβ/PI3K/Akt axis. Meanwhile, these findings highlight the potential of chelidonine as a promising natural chemoresistant agent for BC treatment.