title: Metabolomic approach to evaluating adriamycin pharmacodynamics and resistance in breast cancer cells.
abstract: Continuous exposure of breast cancer cells to adriamycin induces high expression of P-gp and multiple drug resistance. However, the biochemical process and the underlying mechanisms for the gradually induced resistance are not clear. To explore the underlying mechanism and evaluate the anti-tumor effect and resistance of adriamycin, the drug-sensitive MCF-7S and the drug-resistant MCF-7Adr breast cancer cells were used and treated with adriamycin, and the intracellular metabolites were profiled using gas chromatography mass spectrometry. Principal components analysis of the data revealed that the two cell lines showed distinctly different metabolic responses to adriamycin. Adriamycin exposure significantly altered metabolic pattern of MCF-7S cells, which gradually became similar to the pattern of MCF-7Adr, indicating that metabolic shifts were involved in adriamycin resistance. Many intracellular metabolites involved in various metabolic pathways were significantly modulated by adriamycin treatment in the drug-sensitive MCF-7S cells, but were much less affected in the drug-resistant MCF-7Adr cells. Adriamycin treatment markedly depressed the biosynthesis of proteins, purines, pyrimidines and glutathione, and glycolysis, while it enhanced glycerol metabolism of MCF-7S cells. The elevated glycerol metabolism and down-regulated glutathione biosynthesis suggested an increased reactive oxygen species (ROS) generation and a weakened ability to balance ROS, respectively. Further studies revealed that adriamycin increased ROS and up-regulated P-gp in MCF-7S cells, which could be reversed byN-acetylcysteine treatment. It is suggested that adriamycin resistance is involved in slowed metabolism and aggravated oxidative stress. Assessment of cellular metabolomics and metabolic markers may be used to evaluate anti-tumor effects and to screen for candidate anti-tumor agents.
authors.affiliation: Lab of Metabolomics, Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 21009 China.
authors.forename: Bei
authors.initials: B
authors.lastname: Cao
authors.affiliation: Lab of Metabolomics, Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 21009 China.
authors.forename: Mengjie
authors.initials: M
authors.lastname: Li
authors.affiliation: Lab of Metabolomics, Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 21009 China.
authors.forename: Weibin
authors.initials: W
authors.lastname: Zha
authors.affiliation: Lab of Metabolomics, Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 21009 China.
authors.forename: Qijin
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Lab of Metabolomics, Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 21009 China.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Gu
authors.affiliation: Lab of Metabolomics, Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 21009 China.
authors.forename: Linsheng
authors.initials: L
authors.lastname: Liu
authors.affiliation: Lab of Metabolomics, Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 21009 China.
authors.forename: Jian
authors.initials: J
authors.lastname: Shi
authors.affiliation: Lab of Metabolomics, Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 21009 China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Lab of Metabolomics, Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 21009 China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Lab of Metabolomics, Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 21009 China.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Wu
authors.affiliation: School of Pharmacy, The University of Auckland, Auckland, 1142 New Zealand.
authors.forename: Zimei
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Lab of Metabolomics, Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 21009 China.
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
authors.affiliation: Lab of Metabolomics, Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 21009 China.
authors.forename: Jiye
authors.initials: J
authors.lastname: Aa
keywords: Adriamycin; Biomarkers; Breast cancer MCF-7 cell line; Cellular metabolomics; Drug resistance; Reactive oxygen species
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