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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.
Tumour Biol. 2016 Jul; 37(7):8587-97.TB

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.

Authors+Show Affiliations

Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, 116044, China.Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, 116044, China.Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, 116044, China.Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, 116044, China.Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, 116044, China.Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, 116044, China.Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, 116044, China.Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, 116044, China.Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, 116044, China.Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, 116044, China.Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, 116044, China. kexinliu@dlmedu.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

26733176

Citation

Xue, Chaojun, et al. "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." Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine, vol. 37, no. 7, 2016, pp. 8587-97.
Xue C, Wang C, Liu Q, et al. 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. Tumour Biol. 2016;37(7):8587-97.
Xue, C., Wang, C., Liu, Q., Meng, Q., Sun, H., Huo, X., Ma, X., Liu, Z., Ma, X., Peng, J., & Liu, K. (2016). 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. Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine, 37(7), 8587-97. https://doi.org/10.1007/s13277-015-4478-8
Xue C, et al. 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. Tumour Biol. 2016;37(7):8587-97. PubMed PMID: 26733176.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Xue,Chaojun, AU - Wang,Changyuan, AU - Liu,Qi, AU - Meng,Qiang, AU - Sun,Huijun, AU - Huo,Xiaokui, AU - Ma,Xiaodong, AU - Liu,Zhihao, AU - Ma,Xiaochi, AU - Peng,Jinyong, AU - Liu,Kexin, Y1 - 2016/01/06/ PY - 2015/09/02/received PY - 2015/11/19/accepted PY - 2016/1/7/entrez PY - 2016/1/7/pubmed PY - 2017/2/10/medline KW - 2-Deoxyglucose KW - Energy metabolism KW - Metformin KW - Multidrug resistance KW - P-glycoprotein SP - 8587 EP - 97 JF - Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine JO - Tumour Biol VL - 37 IS - 7 N2 - 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. SN - 1423-0380 UR - https://www.unboundmedicine.com/medline/citation/26733176/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_ L2 - https://link.springer.com/article/10.1007/s13277-015-4478-8 DB - PRIME DP - Unbound Medicine ER -