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Drug resistance of cancer cells is involved in multi-factors and complex biochemical processes.Continuous exposure of breast cancer cells to adriamycin can induce high expression of P-gp and chemoresistance.To explore the underlying mechanism of the chemoresistance, metabolites in breast cancer cell line, MCF-7, were profiled using GC-TOF/MS and the metabolic effects of adriamycin on both sensitive MCF-7S and resistant MCF-7Adr were evaluated.Chronic exposure of MCF-7S to adriamycin produced a stable, resistant cell line of MCF-7Adr of different metabolic pattern from that of MCF-7S.The reprogrammed metabolic events in MCF-7Adr showed significant inhibition in glyenlysis, purine, pyrimidine biosynthesis, simultaneously depressed glutathione biosynthesis and increased glycerol metabolism, both of which aggravated oxidative stress.Based on metabolomic data, the mathematic model showed that metabolic pattern of MCF-7/Adr cells was less affected by exposure to adriamycin than that of MCF-7S.In addition to the elevated ROS, the down-regulated xCT was indicated to contribute to the higher expression of P-gp rendered by adriamycin.Over-express ofxCT in MCF-7/Adr remitted oxidative stress and down-regulated level of P-gp.It is indicated that the effect of adriamycin on xCT plays a key role in promoting P-gp, and the blocking ofadriamycin on xCT is an alternative way to eliminate chemoresistance in breast cancer.