The Study On The Combination Of Chalcone Derivatives With Doxorubicin On The Multidrug Resistance Of Breast Cancer

Doxorubicin(DOX)is one of the commonly used breast cancer treatment drugs.However,DOX not only has serious toxic side effects,but also always induces tumor cells resistant.To solve the problem of DOX resistance in breast cancer treatment,we combined D OX with a series of chalcone derivatives,and in order to find some compounds which can improve DOX treatment.We found out a new chalcone derivative,C49,which can combined with DOX effectively.MTT results showed that C49 combined with DOX significantly decreased the DOX-IC50 in MCF-7/DOX cells by comparison to DOX single treatment.According to the results of colony-forming assay,Hoechst 33258 staining assay and flow cytometry,we observed the combination of C49 and DOX obviously inhibited cancer cell MCF-7/DOX proliferation and promoted their apoptosis.Western blotting assay showed that C49 acted as a competitive inhibitor of P-gp drug-efflux transporter.Flow cytometry and fluorescence microscopy assay have been further demonstrated that C49 is a competitive inhibitor of P-gp drug delivery,which increases the accumulation of DOX in MCF-7/DOX cells,thereby increasing the cytotoxicity of DOX to cells.Western blotting assay also proved that the combination of C49 and DOX further promoted DOX-induced activation of apoptotic pathway and PI3K/AKT signal pathway,increasing therapeutic effect of DOX.Moreover,compared with single drug treatment,the combination of C49 and DOX could significantly inhibit tumor growth in a tumor resistant mouse model.Therefore,the above findings clearly showed that DOX combined with C49 can inhibit the proliferation of drug-resistant breast cancer.Further studies have shown that C49,as a P-gp protein drug export transporter,can competitively inhibit the drug resistance of drug-resistant cells in breast cancer,and has high application value in clinic.