Reversal effect and mechanism of multidrug resistance of imperatorin in breast cancer tamoxifen
Objective Investigate the role of imperatorin in reversing multidrug resistance in breast cancer MCF-7/tamoxifen (TAM) cells and its related mechanism. Methods Breast cancer MCF-7 cells and MCF-7/TAM cells were treated with imperatorin,TAM,and imperatorin combined with TAM in vitro,respectively. The drug resistance,cell viability and reversal ratio of MCF-7/TAM cells were detected by MTT assay. MCF-7/TAM cell migration,invasion and colony formation were evaluated by wound healing test,Transwell test and colony formation test,Western blotting was used to detect the changes in the protein expression of multidrug resistance-associated protein 1 (MRP1),multidrug resistance 1 (MDR1) and glutathione S-transferase π (GST-π). The MCF-7/TAM cell line was inoculated subcutaneously in nude mice to construct a TAM resistant xenograft model of breast cancer in nude mice,and the nude mice who successfully constructed xenografts were randomly divided into control group,TAM (4.6 mg/kg) group,imperatorin (20 mg/kg) group,TAM (4.6 mg/kg) combined with imperatorin low-dose (10 mg/kg) group,and TAM (4.6 mg/kg) combined with imperatorin high-dose (20 mg/kg) group,ig administration was performed for 21 days,during which tumor volume was measured and body weight was weighed. After the end of administration,nude mice were sacrificed to dissect tumor tissues to weigh the tumor mass,and the apoptosis of tumor cells was detected by TUNEL method. Immunohistochemistry was used to detect the expression and pathology of marker of proliferation Ki-67. Reverse transcription quantitative polymerase chain reaction,RT-qPCR and Western blotting were used to detect the protein expressions of multidrug resistance proteins MRP1,MDR1 and GST-π. Results In vitro,imperatorin inhibited the proliferation of MCF-7/TAM cells in a dose-dependent manner,and the combination of imperatorin and TAM significantly inhibited the migration,invasion and colony formation ability of fine MCF-7/TAM cells ( P<0.05,0.01),and significantly down-regulate the expression of multidrug resistant proteins MRP1,MDR1 and GST-π (P<0.05,0.01). In vivo,imperatorin combined with TAM could reverse the multidrug resistance of TAM-resistant human breast cancer,inhibit tumor proliferation (P<0.05),increase tumor cell apoptosis (P<0.05,0.01),and significantly down-regulate the expression of multidrug resistant proteins MRP1,MDR1 and GST-π (P<0.05,0.01). Conclusion Imperatorin can enhance the TAM sensitivity of MCF-7/TAM cells,reduce the expression of MRP1,MDR1 and GST-π,and inhibit TAM resistance in breast cancer.
imperatorinbreast cancertamoxifendrug resistancemultidrug resistance protein
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