Reversal Of Adriamycin Resistance In Breast Cancer By Quercetin And Its Mechanism

Background: In a recent study by Global Cancer Statistics 2020,it was found that the incidence of breast cancer has surpassed that of lung cancer as the most commonly diagnosed cancer,and breast cancer is the fifth leading cause of cancer mortality worldwide.With the advancement of molecular diagnosis and sequencing technology,different treatment strategies are given to different types and stages of breast cancer to improve the overall survival,reduce recurrence and even cure breast cancer patients.However,drug resistance remains a major challenge in the process of drug therapy.It has been found that adenosine triphosphate-binding cassette transporter B1（ABCB1）is overexpressed in tumors and stem cells and regulates drug metabolism,resulting in drug resistance in tumor cells.It has also been found that some polyphenolic compounds can interact with ABCB1 in multiple ways.Natural products are a major source of drug development,especially in the long history of the fight against cancer.And quercetin,as a polyphenolic natural product,has the potential to modulate ABCB1,but the specific effects and mechanisms of action still need to be further investigated.OBJECTIVE: To investigate whether quercetin reverses adriamycin resistance through GAS5-mediated inhibition of ABCB1 expression by GSK-3β-β-catenin.Methods: The cytotoxicity of quercetin（Q）on adriamycin-resistant cells and its reversal effect on adriamycin resistance were detected by CCK-8;cell proliferation,cell apoptosis and intracellular rhodamine 123（Rh123）accumulation were examined by colony formation,Hoechst 332582 staining and flow cytometry respectively;q RTPCR revealed that the expression level of GAS5 and ABCB1 RNA in cells;Western blot demonstrated that GSK-3β,β-catenin,c-MYC,cyclin D1 and ABCB1 protein expression levels.The expression levels of GSK-3β,β-catenin,c-MYC,cyclin D1 and ABCB1 were measured by q RT-PCR.RESULTS: Quercetin（10,20,40 μM）enhanced the sensitivity of MCF-7/ADR to adriamycin,inhibited cell proliferation,increased intracellular Rh123 accumulation,promoted the expression of GAS5 and GSK-3β,and inhibited the expression of β-catenin,c-MYC,cyclin D1,and ABCB1;cells transfected with pc DNA-GAS5 When quercetin（40 μM）was added and co-treated with si-GAS5,compared with the snc RNA plus quercetin co-treatment control,lnc RNA GAS5 and GSK-3β were significantly down-regulated,and β-catenin,c-MYC,cyclin D1 and ABCB1 were significantly down-regulated.D1 and ABCB1 were significantly up-regulated.Conclusion: Quercetin can inhibit ABCB1 expression through GAS5-mediated GSK-3β/β-catenin pathway to reverse adriamycin resistance in breast cancer cells.