Chelidonine overcomes P-gp-mediated adriamycin resistance in MCF-7/ADR cells by inhibiting PDGFR/PI3K/Akt pathway.

[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- (PDGFR) 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, PDGFR expression in MCF-7/ADR cells was markedly higher than that in MCF-7 cells ( < 0.01), and PDGFR 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-B (p-IKB), and nuclear factor-B (NF-B) and phosphatase and tensin homolog (PTEN) hyperexpression by chelidonine treatment ( < 0.01). Notably, PDGFR silencing enhanced the inhibitory effect of chelidonine on the activation of the PI3K/Akt pathway. Moreover, chelidonine suppressed PDGF-BB stimulation of the PDGFR/PI3K/Akt axis.

[CONCLUSION] These findings underscore the potential role of PDGFR in regulating chemotherapy resistance in BC. Chelidonine could effectively overcome the resistance of MCF-7/ADR cells to ADR by targeting the PDGFR/PI3K/Akt axis. Meanwhile, these findings highlight the potential of chelidonine as a promising natural chemoresistant agent for BC treatment.