Ginsenoside Rd reverses cisplatin resistance in non-small-cell lung cancer A549 cells by downregulating the nuclear factor erythroid 2-related factor 2 pathway

Anticancer Drugs. 2019 Sep;30(8):838-845. doi: 10.1097/CAD.0000000000000781.

Abstract

Clinical drug resistance to platinum-based chemotherapy is considered a major impediment in the successful treatment of non-small-cell lung cancer (NSCLC). The nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway regulates the oxidative stress response, and in many cancer types, the high constitutive expression of NRF2 leads to proliferation and chemoresistance. Ginsenoside Rd (GS-Rd) is the main active component of ginsenosides. Here, GS-Rd was found to inhibit the proliferation of A549 lung cancer cells and induce G0/G1 phase arrest. We established cisplatin (DDP)-resistant A549 cell lines (A549/DDP). The half maximal inhibitory concentrations of DDP, gemcitabine, and adriamycin were much higher in A549/DDP cells than in A549 cells. The A549/DDP cell lines developed multidrug resistance, accompanied by activation of multidrug resistance protein 1 and multidrug resistance-associated protein 1, as well as NRF2 and its target genes. Treatment with GS-Rd inhibited the NRF2 pathway and significantly sensitized A549/DDP cells to therapeutic drugs. In addition, NRF2 knockdown attenuated the synergistic effects of GS-Rd in both A549 and A54/DDP cells. Taken together, these data show that NRF2 plays an important role in acquired drug resistance in NSCLC, and GS-Rd may ameliorate this chemoresistance by downregulating the NRF2 pathway. This study demonstrates that the NRF2 pathway may serve as a therapeutic target in NSCLC, and ginseng compounds may be effective for the treatment of this disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Cycle
  • Cell Proliferation
  • Cisplatin / pharmacology*
  • Drug Resistance, Neoplasm / drug effects*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Ginsenosides / pharmacology*
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • NF-E2-Related Factor 2 / antagonists & inhibitors*
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Ginsenosides
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Cisplatin
  • ginsenoside Rd