Frontiers in Pharmacology (Jan 2020)

Berberine Maintains the Neutrophil N1 Phenotype to Reverse Cancer Cell Resistance to Doxorubicin

  • Shuhui Zhang,
  • Lin Zhou,
  • Mengdi Zhang,
  • Yuehua Wang,
  • Mengqi Wang,
  • Jincheng Du,
  • Jincheng Du,
  • Wenwen Gu,
  • Fuguang Kui,
  • Jiahuan Li,
  • Shengnan Geng,
  • Gangjun Du,
  • Gangjun Du

DOI
https://doi.org/10.3389/fphar.2019.01658
Journal volume & issue
Vol. 10

Abstract

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This study explores the contributions of neutrophils to chemotherapeutic resistance and berberine-regulated cancer cell sensitivity to doxorubicin (DOX). In vitro experiments, continuous DOX treatment led to the shift of HL-60 cells to N2 neutrophils and thus induced chemotherapeutic resistance. The combination treatment with DOX and 2 µM berberine resulted in the differentiation of HL-60 cells toward N1 and therefore stimulated HL-60 cell immune clearance. Berberine increased reactive oxygen species (ROS) and decreased autophagy and therefore induced apoptosis in HL-60-N2 cells with morphological changes, but had no effect on cell viability in HL-60-N1 cells. The neutrophil-regulating efficacy of berberine was confirmed in the urethane-induced lung carcinogenic model and H22 liver cancer allograft model. Furthermore, we found that DOX-derived neutrophils had high levels of CD133 and CD309 surface expression, which prevented both chemotherapeutic sensitivity and immune rejection by self-expression of PD-L1 and surface expression of PD-1 receptor on T cells, whereas berberine could downregulate CD133 and CD309 surface expression. Finally, berberine-relevant targets and pathways were evaluated. This study first suggests an important role of berberine in regulating neutrophil phenotypes to maintain cancer cell sensitivity to DOX.

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