Although there are a lot of chemical drugs to treat breast cancer, increasing drug resistance of cancer cells has strongly hindered the effectiveness of chemotherapy. ATP-binding cassette transporters represented by P-glycoprotein (P-gp), multidrug resistance associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) play an important role in drug resistance. This study aims to investigate the effect of 7-O-geranylquercetin (GQ) combining microRNA-451(miR-451) on reversing drug resistance of breast cancer and reveal the mechanism related to P-gp. Real-time RT-PCR and western blot assays showed that miR-326, miR-328, miR-451 and miR-155 inhibitor down-regulated the expression of genes MRP1, BCRP, MDR1 and the corresponding proteins MRP1, BCRP, P-gp, respectively. Cell counting kit-8 (CCK-8) assay indicated that these miRNAs reversed the resistance of MCF-7/ADR cells to Adriamycin (ADR), and miR-451 showed the greatest reversal effect. Combination of GQ and miR-451 enhanced the inhibitory effects of ADR on the proliferation and migration of MCF-7/ADR cells, and attenuated the expression of MDR1 and P-gp in MCF-7/ADR cells. A xenograft tumor model was used to show that GQ and miR-451 amplified the antitumor effect of ADR in nude mice, while western blot and immunohistochemical assays revealed the decreased expression of P-gp in tumor tissues. These results suggest that GQ and miR-451 have synergistic effect on reversing drug resistance through reducing the expression of MDR1 and P-gp in breast cancer MCF-7/ADR cells.

中文翻译：

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7-O-香叶基槲皮素和 microRNA-451 的组合通过保留 P-gp 介导的乳腺癌耐药性增强阿霉素的抗肿瘤作用

虽然治疗乳腺癌的化学药物有很多，但癌细胞耐药性的增加强烈阻碍了化疗的效果。以P-糖蛋白（P-gp）、多药耐药相关蛋白1（MRP1）和乳腺癌耐药蛋白（BCRP）为代表的ATP结合盒转运蛋白在耐药性中发挥着重要作用。本研究旨在探讨7- O-香叶基槲皮素（GQ）联合微小RNA-451（miR-451）逆转乳腺癌耐药的作用，并揭示与P-gp相关的机制。实时RT-PCR和蛋白质印迹分析表明，miR-326、miR-328、miR-451和miR-155抑制剂下调MRP1、BCRP、MDR1基因以及相应蛋白MRP1、BCRP、P-的表达。分别是GP。细胞计数试剂盒8（CCK-8）检测表明这些miRNA逆转了MCF-7/ADR细胞对阿霉素（ADR）的耐药性，其中miR-451表现出最大的逆转效果。GQ和miR-451联用增强了ADR对MCF-7/ADR细胞增殖和迁移的抑制作用，并减弱了MCF-7/ADR细胞中MDR1和P-gp的表达。异种移植肿瘤模型显示GQ和miR-451在裸鼠中放大了ADR的抗肿瘤作用，而蛋白质印迹和免疫组化检测显示肿瘤组织中P-gp的表达降低。这些结果表明，GQ和miR-451通过降低乳腺癌MCF-7/ADR细胞中MDR1和P-gp的表达，对逆转耐药性具有协同作用。