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Using LC–MS/MS-based targeted proteomics to monitor the pattern of ABC transporters expression in the development of drug resistance

Authors Meng F, Zou L, Zhang T, Jiang L, Ding Y, Yu P, Peng J

Received 6 February 2018

Accepted for publication 23 April 2018

Published 23 August 2018 Volume 2018:10 Pages 2859—2870

DOI https://doi.org/10.2147/CMAR.S164766

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 2

Editor who approved publication: Professor Lu-Zhe Sun


Fanqi Meng,1 Le Zou,2 Tengyu Zhang,3 Lei Jiang,1 Yao Ding,4 Peng Yu,1 Jie Peng5

1Department of Drug Analysis, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan Province, China; 2Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China; 3Department of Pharmacy, University of Copenhagen, København Ø, Denmark; 4Department of Analyses and Testing, Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha 410013, Hunan Province, China; 5Department of Pharmacy, Jiangxi Provincial People’s Hospital, Nanchang 330006, Jiangxi Province, China

Purpose: The overexpression of ATP-binding cassette transporters (ABC transporters), mainly including permeability glycoproteins (P-gp), multidrug resistance (MDR)-related protein 1 (MRP1), and breast cancer resistance proteins (BCRP), is one of the main reasons for the development of MDR which directly leads to chemotherapy failure. However, most of the currently used detection methods in MDR-related studies are qualitative or semiquantitative, but not quantitative. As a result, the measurement criteria of different experiments are not unified. Moreover, there are many contradictory results of the studies of the induction effect of drugs on ABC transporters. So, it is necessary to establish a quantitative assay for the quantification of P-gp, MRP1, and BCRP to study the mechanism of drug resistance.
Methods: In this paper, a novel and advanced liquid chromatography/mass spectrometry (MS)/MS-based targeted proteomics method for the quantification of P-gp, MRP1, and BCRP was developed and validated. Then, the cell lines MCF-7, HepG-2, and SMMC-7721 were, respectively, induced by different concentrations of doxorubicin (adriamycin [ADM]), mitoxantrone (MX), and methotrexate (MTX), to establish resistance cell lines. The method established was used to quantify the expression of P-gp, MRP1, and BCRP.
Results: The result showed that the induction effects of drugs on protein were relatively stable and selective. ADM, MX, and MTX could induce overexpression of P-gp, MRP1, and BCRP. And, the induction effect of different drugs on proteins was selective. The pattern of overexpression of ABC transporters in the three types of resistance cell lines was different.
Conclusion: During the development of drug resistance, the cell type and patch, but not drug type, were the most important determinant factors of the overexpression level of ABC transporters in resistance cell lines. This study provides a good foundation for understanding the development of drug resistance in cell lines and can be used to explain the contradictory results in other published studies as described above.

Keywords: P-gp, MRP1, BCRP, multidrug resistance, quantification

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