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01-07-2016 | Original Article

Targeting P-glycoprotein expression and cancer cell energy metabolism: combination of metformin and 2-deoxyglucose reverses the multidrug resistance of K562/Dox cells to doxorubicin

Authors: Chaojun Xue, Changyuan Wang, Qi Liu, Qiang Meng, Huijun Sun, Xiaokui Huo, Xiaodong Ma, Zhihao Liu, Xiaochi Ma, Jinyong Peng, Kexin Liu

Published in: Tumor Biology | Issue 7/2016

Abstract

P-glycoprotein (P-gp) is one of the major obstacles to efficiency of cancer chemotherapy. Here, we investigated whether combination of metformin and 2-deoxyglucose reverses the multidrug resistance (MDR) of K562/Dox cells and tried to elucidate the possible mechanisms. The combination of metformin and 2-deoxyglucose selectively enhanced the cytotoxicity of doxorubicin against K562/Dox cells. Metformin was not a substrate of P-gp but suppressed the elevated level of P-gp in K562/Dox cells. The downregulation of P-gp may be partly attributed to the inhibition of extracellular signal-regulated kinase pathway. The addition of 2-deoxyglucose to metformin initiated a strong metabolic stress in both K562 and K562/Dox cells. Combination of metformin and 2-deoxyglucose inhibited glucose uptake and lactate production in K562 and K562/Dox cells leading to a severe depletion in ATP and a enhanced autophagy. Above all, P-gp substrate selectively aggravated this ATP depletion effect and increased cell apoptosis in K562/Dox cells. In conclusion, metformin decreases P-gp expression in K562/Dox cells via blocking phosphorylation of extracellular signal-regulated kinase. P-gp substrate increases K562/Dox cell apoptosis via aggravating ATP depletion induced by combination of metformin and 2-deoxyglucose. Our observations highlight the importance of combination of metformin and 2-deoxyglucose in reversing multidrug resistance.

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Title: Targeting P-glycoprotein expression and cancer cell energy metabolism: combination of metformin and 2-deoxyglucose reverses the multidrug resistance of K562/Dox cells to doxorubicin
Authors: Chaojun Xue
Changyuan Wang
Qi Liu
Qiang Meng
Huijun Sun
Xiaokui Huo
Xiaodong Ma
Zhihao Liu
Xiaochi Ma
Jinyong Peng
Kexin Liu
Publication date: 01-07-2016
Publisher: Springer Netherlands
Published in: Tumor Biology / Issue 7/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI: https://doi.org/10.1007/s13277-015-4478-8

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