Tumor Biology

, Volume 37, Issue 7, pp 8587–8597 | Cite as

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

  • Chaojun Xue
  • Changyuan Wang
  • Qi Liu
  • Qiang Meng
  • Huijun Sun
  • Xiaokui Huo
  • Xiaodong Ma
  • Zhihao Liu
  • Xiaochi Ma
  • Jinyong Peng
  • Kexin Liu
Original Article

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.

Keywords

Metformin 2-Deoxyglucose Multidrug resistance P-glycoprotein Energy metabolism 

Notes

Acknowledgments

We wish to express our heartfelt gratitude to Professor Zeng Su (College of Pharmacy, Zhejiang University, China) for providing MDR1-MDCK cells.

Compliance with ethical standards

Funding

This study was funded by the National Natural Science Foundation of China (nos. 81273580 and 81473280).

Conflicts of interest

None

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Chaojun Xue
    • 1
  • Changyuan Wang
    • 1
  • Qi Liu
    • 1
  • Qiang Meng
    • 1
  • Huijun Sun
    • 1
  • Xiaokui Huo
    • 1
  • Xiaodong Ma
    • 1
  • Zhihao Liu
    • 1
  • Xiaochi Ma
    • 1
  • Jinyong Peng
    • 1
  • Kexin Liu
    • 1
  1. 1.Department of Clinical Pharmacology, College of PharmacyDalian Medical UniversityDalianChina

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