Arctigenin inhibits STAT3 and exhibits anticancer potential in human triple-negative breast cancer therapy

Oncotarget. 2017 Jan 3;8(1):329-344. doi: 10.18632/oncotarget.13393.

Abstract

Triple-negative breast cancers (TNBCs) are the most aggressive and hard-to-treat breast tumors with poor prognosis, and exploration for novel therapeutic drugs is impending. Arctigenin (Atn), a bioactive lignan isolated from seeds of Arctium lappa L, has been reported to inhibit many cancer types; however, the effect of Atn on TNBC remains unclear. In this study, we demonstrated that Atn decreased proliferation, and induced apoptosis in TNBC cells. Furthermore, we explored the underlying mechanism of Atn inhibition on TNBC cells. Computational docking and affinity assay showed that Atn bound to the SH2 domain of STAT3. Atn inhibited STAT3 binding to genomic DNA by disrupting hydrogen bond linking between DNA and STAT3. In addition, Atn augmented Taxotere®-induced TNBC cell cytotoxicity. TNBC xenograft tests also confirmed the antitumor effect of Atn in vivo. These characteristics render Atn as a promising candidate drug for further development and for designing new effective STAT3 inhibitors.

Keywords: STAT3; arctigenin; computational docking; taxotere; triple-negative breast cancers.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Arctium / chemistry*
  • Asia, Eastern
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA / metabolism
  • Docetaxel
  • Drug Evaluation, Preclinical
  • Drug Synergism
  • Female
  • Fluorescent Antibody Technique
  • Furans / pharmacology*
  • Furans / therapeutic use
  • Humans
  • Hydrogen Bonding / drug effects
  • Lignans / pharmacology*
  • Lignans / therapeutic use
  • Mice, Nude
  • Molecular Docking Simulation
  • Plants, Medicinal / chemistry
  • Protein Domains
  • STAT3 Transcription Factor / antagonists & inhibitors*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Taxoids / pharmacology*
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / pathology
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Furans
  • Lignans
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Taxoids
  • Docetaxel
  • DNA
  • arctigenin