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Breast Cancer Res Treat (2010) 120:613626 DOI 10.1007/s10549-009-0430-1
PRECLINICAL STUDY
Pharmacometabolomics of docetaxel-treated human MCF7 breast cancer cells provides evidence of varying cellular responsesat high and low doses
Mathilde Bayet-Robert Daniel Morvan Philippe Chollet Chantal Barthomeuf
Received: 19 January 2009 / Accepted: 23 May 2009 / Published online: 10 June 2009 Springer Science+Business Media, LLC. 2009
Abstract There is growing evidence that docetaxel, a microtubule-targeting agent like the other taxane paclitaxel, induces dual cytotoxicity mechanism according to dose level. Postgenomics screening technologies are now more and more applied to the elucidation of drug response mechanisms. Proton nuclear magnetic resonance spectroscopy-based pharmacometabolomics was here applied to get further insight into the response of human MCF7 breast carcinoma cells to docetaxel at high (clinical, 5 lM) and low (1 nM) doses. The global response to both doses was evaluated by nuclear morphology and DNA content, the latter as an index of cell proliferation and DNA ploidy. High dose provoked long-lasting cell cycle arrest in mitosis during the rst 48 h of exposure to treatment and severe decrease in DNA content followed by signicant amount of cell death. In contrast, at low dose, no long-lasting cell cycle arrest was observed on micrographies, and DNA content was decreased but less than at high dose (P \ 0.05), without signicant cell death. This response was compared to biochemical alteration assessed by pharmacometabolomics. Thirty metabolites were identied and quantied. Metabolite proling at clinical dose revealed time-dependent disorders in derivatives of glycolysis, lipid metabolism and glutathione metabolism.
Comparison between high and low doses was performed at 72 h and showed common traits including the accumulation of cytidinediphosphocholine (95.0 and 96.9, respectively, P \ 0.03), the decrease in phosphatidylcholine (90.3 and 90.2, respectively, P \ 0.03), and gluthathione (90.6 and 90.6, respectively, P \ 0.03). Despite that, signicant dose-dependent differences were found in 12 of 30 measured metabolites. Among them, the most discriminant metabolites were polyunsaturated fatty acids (ratio of high-to-low dose of 14.8, P \ 0.05), glutamate, myoinositol, and homo-cysteine (ratio \ 0.4, P \ 0.05). In addition, the mechanism for glutathione decrease was different. At high dose, it resulted from extensive consumption with precursor starvation (glutamate: -89%, P \ 0.05) and increased glutathione S-transferase activity (95, P \ 0.01), whereas at...