Investigations on the cell metabolomics basis of multidrug resistance from tumor cells by ultra-performance liquid chromatography-mass spectrometry.

Abstract

Although anticancer drug resistance has been linked to high expression of P-glycoprotein and the enhanced DNA repair ability, the biochemical process and the underlying mechanisms of drug resistance are not clear. In order to clarify the biochemical mechanisms of drug resistance during anticancer drug treatment, we studied the metabolomics of MCF-7/S and MCF-7/Adr cell lines, the COC1 and COC1/DDP cell lines, including the metabolic pathways of multidrug-resistant tumor cells and the changes of endogenous substances in cells. The intracellular metabolites were profiled using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). In this study, 24 biomarkers in MCF-7/Adr cells and 15 biomarkers in COC1/DDP cells that are involved in some important metabolic pathways were putatively identified. Several metabolic pathways are changed in tumor cells showing drug resistance, such as protein synthesis pathways, cysteine synthesis, the glutamine metabolic pathway, and the ammonia cycle; the first of these are involved in the synthesis of some important proteins including membrane proteins, multidrugresistance-associatedproteins, and P-glycoprotein (P-gp). Proteins related to drug resistance were overexpressed in multidrug-resistant tumor cells. These proteins depended on energy and play important roles in the emergence of drug resistance. The changes in glutathione and cysteine metabolic pathways showed that the cells can activate related metabolic pathways and reduce the cellapoptosis when they encounter oxidative damage. These findings indicate that drug resistance is likely associated with increased P-gp synthesis and reducedapoptosis of tumor cells. Graphical Abstract Drug resistance was charactered in the changing of genomics and proteomics. Like enhancing DNA repair, reducing uptake, high P-g protein expression. Here, we studied the changes of metabolite pathway which could be also play an imported role in drug resistance.