Targeting P-glycoprotein function, p53 and energy metabolism: Combination of metformin and 2-deoxyglucose reverses the multidrug resistance of MCF-7/Dox cells to doxorubicin.

Chaojun Xue,Jinyong Peng,Kexin Liu,Xiaokui Huo,Changyuan Wang,Xiaodong Ma,Yaoting Sun,Huijun Sun,Pengyuan Sun,Zhihao Liu,Xiaochi Ma,Qiang Meng

doi:10.18632/oncotarget.14373

Chaojun Xue, Jinyong Peng + Show 10 more

Open Access

PDF Available

https://doi.org/10.18632/oncotarget.14373

Copy DOI

Export

Save

Cite

Journal: Oncotarget	Publication Date: Dec 30, 2016
Citations: 33	License type: cc-by

Affiliation: Hebei General Hospital, Dalian Medical University

Abstract
Highlights/Summary
Full-Text PDF
Similar Papers

Abstract

Listen

Multidrug resistance(MDR) is a major obstacle to efficiency of breast cancer chemotherapy. We investigated whether combination of metformin and 2-deoxyglucose reverses MDR of MCF-7/Dox cells and tried to elucidate the possible mechanisms. The combination of metformin and 2-deoxyglucose selectively enhanced cytotoxicity of doxorubicin against MCF-7/Dox cells. Combination of the two drugs resumed p53 function via inhibiting overexpression of murine doubleminute 2(MDM2) and murine doubleminute 4(MDM4) leading to G2/M arrest and apoptosis in MCF-7/Dox cells. Combination of the two drugs had no effect on P-glycoprotein mRNA expression and P-glycoprotein ATPase activity but increased doxorubicin accumulation in MCF-7/Dox cells. The increased doxorubicin accumulation maybe associate with metabolic stress. Combination of metformin and 2-deoxyglucose initiated a strong metabolic stress in MCF-7/Dox cells via inhibiting glucose uptake, lactate, fatty acid, ATP production and protein kinase B(AKT)/ mammalian target of rapamycin(mTOR) pathway. Taken together, combination of metformin and 2-deoxyglucose reverses MDR of MCF-7/Dox cells by recovering p53 function and increasing doxorubicin accumulation. Furthermore, doxorubicin selectively increases MCF-7/Dox apoptosis via aggravating metabolic stress induced by metformin plus 2-deoxyglucose. The mutually reinforcing effect made the combination of metformin and 2DG had a better effect on reversing MDR.

Highlights

Breast cancer, the most common malignancy, injures the health of women seriously
We investigated whether combination of metformin and 2-deoxyglucose reverses multidrug resistance (MDR) of MCF-7/Dox cells and tried to elucidate the possible mechanisms
The cytotoxicity of metformin and 2-deoxyglucose(2DG) against MCF-7 (Figure 1A) and MCF7/Dox (Figure 1B) cells treated for 24h was determined by MTT assay. 0.5 mM metformin and 0.5 mM 2DG, which had cytotoxicity in both cell lines, were selected in the MDR reversal study

Summary

Introduction

The most common malignancy, injures the health of women seriously. Therapies include surgery, radiotherapy and systemic treatment [1]. The goodnews is that the 5-year overall survival rate of breast cancer patients is extremely high with the development of treatment. 30% of breast cancer will develop recurrent or metastatic disease and chemotherapy agents are limited by multidrug resistance (MDR), these problems still plague the clinical treatment of breast cancer [2]. Paclitaxel, docetaxel and doxorubicin are the most commonly used cytotoxic drugs for breast cancer [3]. The resistance of cancer cells to structurally and mechanistically unrelated classes of anticancer drugs is known as MDR [4]. The development of MDR is possibly the result of several changes in breast cancer include efflux transporter, uptake transporter, drug metabolizing enzymes, apoptotic, DNA damage repair pathway and other candidate mechanisms [5]

Methods

Results

Conclusion