A New Chalcone Derivative C49 Reverses Doxorubicin Resistance in MCF-7/DOX Cells by Inhibiting P-Glycoprotein Expression.

Ting Wang,Wanli Deng,Hua Sui,Jingjing Dong,Haotian Wen,Xu Yuan,Jianwen Liu,Linguangjin Wu

doi:10.3389/fphar.2021.653306

Abstract

Objective: C49 is a chalcone derivative. The aim of the current study is to illuminate the efficacy of C49 in reversing multidrug resistance (MDR) in MCF-7/DOX cells and its underlying molecular mechanism. Methods: The cytotoxic effects of C49 on MCF-7/DOX cells were evaluated by MTT assay using different concentration (0–250 μmol/L) of C49. Cell proliferation was evaluated by colony formation assay. Cell death was examined by morphological analysis using Hoechst 33,258 staining. Flow cytometry and immunofluorescence were utilized to evaluate the intracellular accumulation of doxorubicin (DOX) and cell apoptosis. The differentially expressed genns between MCF-7 and MCF-7/DOX cells were analyzed by GEO database. The expression of PI3K/Akt pathway proteins were assessed by Western blot The activities of C49 combined with DOX was evaluated via xenograft tumor model in female BALB/c nude mice. Results: C49 inhibited the growth of MCF-7 cells (IC50 = 59.82 ± 2.10 μmol/L) and MCF-7/DOX cells (IC50 = 65.69 ± 8.11 μmol/L) with dosage-dependent and enhanced the cellular accumulation of DOX in MCF-7/DOX cells. The combination of C49 and DOX inhibited cell proliferation and promoted cell apoptosis. MCF-7/DOX cells regained drug sensibility with the combination treatment through inhibiting the expression of P-gp, p-PI3K and p-Akt proteins. Meanwhile, C49 significantly increased the anticancer efficacy of DOX in vivo. Conclusion: C49 combined with DOX restored DOX sensitivity in MCF-7/DOX cells through inhibiting P-gp protein.

Highlights

Breast cancer has the highest mortality of female cancers and is the second cause of death in females (Siegel et al, 2020)
C49 combined with DOX restored DOX sensitivity in MCF-7/DOX cells through inhibiting P-gp protein
Before we investigated the anticancer efficiency of C49 with different dose of DOX, we first examined the doxorubicinresistance of MCF-7 and MCF-7/DOX cells by MTT assay at 24 h

Summary

Introduction

Breast cancer has the highest mortality of female cancers and is the second cause of death in females (Siegel et al, 2020). The first-line chemotherapeutic drug for breast cancer is doxorubicin (DOX), which is an anthracycline (Li et al, 2019b; Pondé et al, 2019; Tun et al, 2019; Zeinoddini et al, 2019). Breast cancer cells generate DOX resistance and cause serious cardiotoxicity with increasing length of chemotherapy. These two factors are major causes for treatment failure and metastasis of breast cancer (Cappetta et al, 2017; Li et al, 2017; Ponnusamy et al, 2018; Wenningmann et al, 2019; Zheng et al, 2019; Al-Malky et al, 2020)

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Conclusion