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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.
Oncotarget. 2017 Jan 31; 8(5):8622-8632.O

Abstract

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.

Authors+Show Affiliations

Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China. Department of Pharmacy, Hebei General Hospital, Shijiazhuang, China.Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28052008

Citation

Xue, Chaojun, et al. "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." Oncotarget, vol. 8, no. 5, 2017, pp. 8622-8632.
Xue C, Wang C, Sun Y, et al. 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. Oncotarget. 2017;8(5):8622-8632.
Xue, C., Wang, C., Sun, Y., Meng, Q., Liu, Z., Huo, X., Sun, P., Sun, H., Ma, X., Ma, X., Peng, J., & Liu, K. (2017). 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. Oncotarget, 8(5), 8622-8632. https://doi.org/10.18632/oncotarget.14373
Xue C, et al. 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. Oncotarget. 2017 Jan 31;8(5):8622-8632. PubMed PMID: 28052008.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Xue,Chaojun, AU - Wang,Changyuan, AU - Sun,Yaoting, AU - Meng,Qiang, AU - Liu,Zhihao, AU - Huo,Xiaokui, AU - Sun,Pengyuan, AU - Sun,Huijun, AU - Ma,Xiaodong, AU - Ma,Xiaochi, AU - Peng,Jinyong, AU - Liu,Kexin, PY - 2016/08/01/received PY - 2016/12/07/accepted PY - 2017/1/5/pubmed PY - 2018/2/27/medline PY - 2017/1/5/entrez KW - P-glycoprotein KW - energy metabolism KW - multidrug resistance KW - p53 SP - 8622 EP - 8632 JF - Oncotarget JO - Oncotarget VL - 8 IS - 5 N2 - 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. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/28052008/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_ L2 - http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=14373 DB - PRIME DP - Unbound Medicine ER -