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Metabolomics analysis of multidrug resistance in colorectal cancer cell and multidrug resistance reversal effect of verapamil.

Authors
  • Wang, Xinying1
  • Wang, Zihan1
  • Wang, Kaili1
  • Gao, Ming1
  • Zhang, Hang1
  • Xu, Xia1
  • 1 Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China. , (China)
Type
Published Article
Journal
Biomedical Chromatography
Publisher
Wiley (John Wiley & Sons)
Publication Date
Feb 01, 2021
Volume
35
Issue
2
Identifiers
DOI: 10.1002/bmc.4976
PMID: 32852057
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Multidrug resistance remains a huge challenge in the chemotherapy of cancer and numerous studies have reported that P-glycoprotein is the most common mechanism of multidrug resistance. Verapamil has been shown to be able to reverse development of multidrug resistance mediated by P-glycoprotein. However, the mechanism of action for verapamil in reversing multidrug resistance at the metabolic level has been rarely reported. In this research, we report the reversal effect of verapamil on multidrug resistance and its mechanisms of action using metabolomics. The results show that the P-glycoprotein-mediated chemotherapy drug resistance was significantly reversed by verapamil in resistant SW620/Ad300 cells. In-depth studies demonstrated that verapamil at reversal concentration had no effect on the P-glycoprotein expression level, but increased intramolecular accumulation of paclitaxel in SW620/Ad300 cells. Metabolomics revealed that the multidrug resistance of SW620/Ad300 cells was related to changes in glycerophospholipid metabolism, sphingolipid metabolism and citric acid cycle, and verapamil could antagonize the multidrug resistance by reversing the above-mentioned glycerophospholipid metabolism and sphingolipid metabolism. This research shows the multidrug resistance reversal mechanism of verapamil at the metabolic level, which helps in understanding the exact multidrug resistance mechanism of verapamil and might be potentially useful to find new multidrug resistance reversal agents. The combination of verapamil (VRP) and paclitaxel (PTX) yielded synergistic effects. VRP had no effect on the expression of P-gp, but increased intramolecular accumulation of PTX. VRP antagonized the MDR by regulating glycerophospholipid metabolism and sphingolipid metabolism. © 2020 John Wiley & Sons, Ltd.

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