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Cystine supplementation rebalances the redox homeostasis of microenvironment in non-small cell lung cancer cells and reverses their resistance to docetaxel

Abstract

Continuous docetaxel (DTX) treatment of non-small cell lung cancer induces development of drug resistance, but the mechanism is poorly understood. In this study we performed metabolomics analysis to characterize the metabolic patterns of sensitive and resistant A549 non-small cell lung cancer cells (A549/DTX cells). We showed that the sensitive and resistant A549 cells exhibited distinct metabolic phenotypes: the resistant cells were characterized by an altered microenvironment of redox homeostasis with reduced glutathione and elevated reactive oxygen species (ROS). DTX induction reprogrammed the metabolic phenotype of the sensitive cells, which acquired a phenotype similar to that of the resistant cells: it reduced cystine influx, inhibited glutathione biosynthesis, increased ROS and decreased glutathione/glutathione disulfide (GSH/GSSG); the genes involved in glutathione biosynthesis were dramatically depressed. Addition of the ROS-inducing agent Rosup (25, 50 μg/mL) significantly increased P-glycoprotein expression and reduced intracellular DTX in the sensitive A549 cells, which ultimately acquired a phenotype similar to that of the resistant cells. Supplementation of cystine (1.0 mM) significantly increased GSH synthesis, rebalanced the redox homeostasis of A549/DTX cells, and reversed DTX-induced upregulation of P-glycoprotein, and it markedly improved the effects of DTX and inhibited the growth of A549/DTX in vitro and in vivo. These results suggest that microenvironmental redox homeostasis plays a key role in the acquired resistance of A549 cancer cells to DTX. The enhancement of GSH synthesis by supplementary cystine is a promising strategy to reverse the resistance of tumor cells and has potential for translation in the clinic.

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Fig. 1: Differential responses of sensitive and resistant A549 cells to DTX.
Fig. 2: Metabolic phenotypes of sensitive and resistant cells.
Fig. 3: The metabolic phenotype of resistant A549/DTX cells is characterized by increased oxidative stress and inhibited antioxidative potency.
Fig. 4: Imbalance in the oxidative stress microenvironment promoted the occurrence and development of drug resistance.
Fig. 5: Supplementation with cystine enhanced the efficacy of DTX in vitro.
Fig. 6: Differential responses to DTX and differential metabolic phenotypes in sensitive and resistant cells.
Fig. 7: Supplementation with cystine enhanced the efficacy of DTX in vivo.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China, grant number 81773814, “Double First-Class” University project (CPU2018GF01), Leading Technology Foundation Research Project of Jiangsu province (BK20192005) and Sanming Project of Medicine in Shenzhen (SZSM201801060).

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JYA, SJL, BC, YX, and GJW designed the manuscript. SJL, ZYL, and SHG carried out the experiments. RBS, SJL, and ZYL analyzed the data. SJL and BC prepared the manuscript. JYA and GJW critically revised the manuscript.

Corresponding author

Correspondence to Ji-ye Aa.

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The authors declare no competing interests.

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Li, Sj., Cao, B., Lu, Zy. et al. Cystine supplementation rebalances the redox homeostasis of microenvironment in non-small cell lung cancer cells and reverses their resistance to docetaxel. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-020-00610-3

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Keywords

  • non-small cell lung cancer cells
  • docetaxel
  • drug resistance
  • metabolomics
  • microenvironment
  • redox homeostasis
  • P-glycoprotein
  • cystine
  • Rosup
  • NAC

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