Tetrandrine and adriamycin reverse multidrug resistance by regulating NLRP3/Caspase-1/GSDMD signaling in human breast cancer cells

Purpose This study examined the effects and underlying mechanisms of tetrandrine (TET) combined with adriamycin (ADR) in reversing multidrug resistance (MDR) in breast cancer cells. Methods Cell viability, proliferation, and drug resistance were assessed via the MTT assay. Small interfering RNA (siRNA) transfection was used to knock down GSDMD expression in MCF-7/ADR cells. Pyroptosis induction by the combined TET and ADR treatment was evaluated through morphological observations, cytotoxicity assays, and flow cytometry. The expression levels of mRNA and proteins were analyzed using qRT-PCR and western blotting, respectively. Results At non-cytotoxic concentrations, the combined treatment of TET and ADR significantly inhibited the growth of MCF-7/ADR cells, demonstrating a synergistic effect in reversing MDR. This combination effectively reduced MDR protein expression in MCF-7/ADR cells via GSDMD modulation, which diminished efflux activity and promoted ADR accumulation. The increased accumulation of ADR subsequently activated the NLRP3/Caspase-1/GSDMD signaling pathway, leading to elevated LDH release and enhanced pyroptosis rates. Conclusion The combined use of TET and ADR not only suppresses MCF-7/ADR cell growth but also reverses MDR by targeting the NLRP3/Caspase-1/GSDMD pyroptosis pathway. These findings propose a promising therapeutic strategy for combatting MDR in breast cancer and highlight the potential for further clinical application of this combination therapy.