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2 results on '"XUE Chaojun"'

1. 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.

Author

Xue C, Wang C, Sun Y, Meng Q, Liu Z, Huo X, Sun P, Sun H, Ma X, Ma X, Peng J, and Liu K

Subjects
ATP Binding Cassette Transporter, Subfamily B genetics, ATP Binding Cassette Transporter, Subfamily B metabolism, Antibiotics, Antineoplastic metabolism, Apoptosis drug effects, Breast Neoplasms genetics, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Cycle Proteins, Dose-Response Relationship, Drug, Doxorubicin metabolism, Female, G2 Phase Cell Cycle Checkpoints drug effects, Humans, MCF-7 Cells, Nuclear Proteins antagonists & inhibitors, Nuclear Proteins metabolism, Proto-Oncogene Proteins antagonists & inhibitors, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-mdm2 antagonists & inhibitors, Proto-Oncogene Proteins c-mdm2 metabolism, Signal Transduction drug effects, Tumor Suppressor Protein p53 genetics, Antibiotics, Antineoplastic pharmacology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Breast Neoplasms drug therapy, Deoxyglucose pharmacology, Doxorubicin pharmacology, Drug Resistance, Multiple drug effects, Drug Resistance, Neoplasm drug effects, Energy Metabolism drug effects, Metformin pharmacology, Tumor Suppressor Protein p53 metabolism
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.

Published
2017
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2. 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.

Author

Xue C, Wang C, Liu Q, Meng Q, Sun H, Huo X, Ma X, Liu Z, Ma X, Peng J, and Liu K

Subjects
ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Antibiotics, Antineoplastic pharmacology, Antimetabolites pharmacology, Apoptosis drug effects, Blotting, Western, Cell Proliferation drug effects, Drug Resistance, Neoplasm drug effects, Drug Therapy, Combination, Humans, Hypoglycemic Agents pharmacology, K562 Cells, Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured, ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors, Deoxyglucose pharmacology, Doxorubicin pharmacology, Drug Resistance, Multiple drug effects, Energy Metabolism drug effects, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Metformin pharmacology
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.

Published
2016
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