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 by N-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.Electronic supplementary materialThe online version of this article (doi:10.1007/s11306-013-0517-x) contains supplementary material, which is available to authorized users.
Highlights
Adriamycin, a DNA intercalating agent, is an active and popular agent conventionally used for breast cancer management (Gewirtz 1999; Jassem et al 2009)
Measurement of intracellular adriamycin showed that there was not significant difference between MCF-7S (1.84 ± 0.11 nmol/mg protein) and MCF7A (1.75 ± 0.12 nmol/mg protein, n = 4) when MCF-7S and MCF-7A were exposed to adriamycin at 1 lM and 5 lM respectively for 12 h
A principal component analysis (PCA) based on cellular metabolites demonstrated that the two cell lines clustered closely within each group and separately from each other, indicating different metabolic patterns between the sensitive MCF-7S and the resistant MCF-7Adr cells (Fig. 1a)
Summary
Adriamycin, a DNA intercalating agent, is an active and popular agent conventionally used for breast cancer management (Gewirtz 1999; Jassem et al 2009). To explore the underlying mechanism of adriamycin-induced chemoresistance, genomics and proteomics were recently applied, and the results revealed some candidate genes and proteins that are involved in breast cancer drug resistance. Relative to the sensitive MCF-7S cells, increased epithelial-mesenchymal transition and extracellular matrix composition contributed to adriamycin-resistant MCF-7Adr cell chemoresistance (Iseri et al 2010, 2011). A proteomic analysis of the chemoresistant and sensitive MCF7 cells identified proteins that are involved in apoptosis, the cell cycle, glucose metabolism and fatty acid oxidation as contributing to drug resistance (Chuthapisith et al 2007; Strong et al 2006)
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