title: 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.
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.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.|Department of Pharmacy, Hebei General Hospital, Shijiazhuang, China.
authors.forename: Chaojun
authors.initials: C
authors.lastname: Xue
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
authors.forename: Changyuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
authors.forename: Yaoting
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Huo
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
authors.forename: Pengyuan
authors.initials: P
authors.lastname: Sun
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
authors.forename: Xiaochi
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
authors.forename: Jinyong
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
authors.forename: Kexin
authors.initials: K
authors.lastname: Liu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D003847:Deoxyglucose / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D008687:Metformin / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D008687:Metformin; D003847:Deoxyglucose; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: P-glycoprotein; energy metabolism; multidrug resistance; p53