Metabolomics Reveals Metabolic Targets and Biphasic Responses in Breast Cancer Cells Treated by Curcumin Alone and in Association with Docetaxel

Abstract

BackgroundCurcumin (CUR) has deserved extensive research due to its anti-inflammatory properties, of interest in human diseases including cancer. However, pleiotropic even paradoxical responses of tumor cells have been reported, and the mechanisms of action of CUR remain uncompletely elucidated.Methodology/Principal Findings 1H-NMR spectroscopy-based metabolomics was applied to get novel insight into responses of MCF7 and MDA-MB-231 breast cancer cells to CUR alone, and MCF7 cells to CUR in cotreatment with docetaxel (DTX). In both cell types, a major target of CUR was glutathione metabolism. Total glutathione (GSx) increased at low dose CUR (≤ 10 mg.l−1–28 µM-) (up to +121% in MCF7 cells, P<0.01, and +138% in MDA-MB-231 cells, P<0.01), but decreased at high dose (≥ 25 mg.l−1 −70 µM-) (−49%, in MCF7 cells, P<0.02, and −56% in MDA-MB-231 cells, P<0.025). At high dose, in both cell types, GSx-related metabolites decreased, including homocystein, creatine and taurine (−60 to −80%, all, P<0.05). Together with glutathione-S-transferase actvity, data established that GSx biosynthesis was upregulated at low dose, and GSx consumption activated at high dose. Another major target, in both cell types, was lipid metabolism involving, at high doses, accumulation of polyunsaturated and total free fatty acids (between ×4.5 and ×11, P<0.025), and decrease of glycerophospho-ethanolamine and -choline (about −60%, P<0.025). Multivariate statistical analyses showed a metabolic transition, even a biphasic behavior of some metabolites including GSx, between low and high doses. In addition, CUR at 10 mg.l−1 in cotreatment with DTX induced modifications in glutathione metabolism, lipid metabolism, and glucose utilization. Some of these changes were biphasic depending on the duration of exposure to CUR.Conclusions/SignificanceMetabolomics reveals major metabolic targets of CUR in breast cancer cells, and biphasic responses that challenge the widely accepted beneficial effects of the phytochemical.

Recent advances of curcumin and its analogues in breast cancer prevention and treatment

“…88 Curcumin, alone or in combination with docetaxel modifies metabolic properties such as glutathione and lipid/phospholipid metabolism and glucose utilization in MCF7 and MDA-MB-231 breast cancer cells. 116 Catania et al 117 conducted a comparison of the effectiveness of free curcumin, liposome loaded with curcumin, and immunoliposome loaded with curcumin bearing herceptin, a HER2 antibody, on JIMT1 and MCF-7 breast cancer cell lines. Greater cytotoxic activities were observed in JIMT1 cells.…”

Optimized Method for Untargeted Metabolomics Analysis of MDA-MB-231 Breast Cancer Cells

“…Despite the widespread use of this cell line, a reliable and sensitive protocol for an untargeted extraction of metabolites has not been reported for this cell line. Current adherent cell extraction methods may not be ideally suited to our aims for several reasons: Methods that had been optimized for alternative analytical platforms were not suitable for untargeted LC-MS analysis [17,18,19,20,21,22,23]. Additionally, extraction methods for different mammalian cell lines may not be ideal for MDA-MB-231 cells due to the different metabolic profile and physical properties of each cell type [24].…”

Potential Therapeutic Efficacy of Curcumin in Liver Cancer

“…It is formerly considered as a drug possessing anti-angiogenic, anti-inflammation and antioxidation effect (Kwon et al, 2005;Suckow et al, 2006;EI-Azab et al, 2011;. Previous researches in 2013 have demonstrated the antitumor effect of Cum in a series of cancers (Bayet-Robert et al, 2013;Du et al, 2013;Kumaravel et al, 2013;Masuelli et al, 2013;Ono et al, 2013;Wei et al, 2013;Yallapu et al, 2013;Zhang et al, 2013). …”