Auranofin induces lethal oxidative and endoplasmic reticulum stress and exerts potent preclinical activity against chronic lymphocytic leukemia

Cancer Res. 2014 May 1;74(9):2520-32. doi: 10.1158/0008-5472.CAN-13-2033. Epub 2014 Mar 5.


Chronic lymphocytic leukemia (CLL) exhibits high remission rates after initial chemoimmunotherapy, but with relapses with treatment, refractory disease is the most common outcome, especially in CLL with the deletion of chromosome 11q or 17p. In addressing the need of treatments for relapsed disease, we report the identification of an existing U.S. Food and Drug Administration-approved small-molecule drug to repurpose for CLL treatment. Auranofin (Ridaura) is approved for use in treating rheumatoid arthritis, but it exhibited preclinical efficacy in CLL cells. By inhibiting thioredoxin reductase activity and increasing intracellular reactive oxygen species levels, auranofin induced a lethal endoplasmic reticulum stress response in cultured and primary CLL cells. In addition, auranofin displayed synergistic lethality with heme oxygenase-1 and glutamate-cysteine ligase inhibitors against CLL cells. Auranofin overcame apoptosis resistance mediated by protective stromal cells, and it also killed primary CLL cells with deletion of chromosome 11q or 17p. In TCL-1 transgenic mice, an in vivo model of CLL, auranofin treatment markedly reduced tumor cell burden and improved mouse survival. Our results provide a rationale to reposition the approved drug auranofin for clinical evaluation in the therapy of CLL.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Auranofin / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Screening Assays, Antitumor
  • Endoplasmic Reticulum Stress / drug effects*
  • HSP90 Heat-Shock Proteins / metabolism
  • Histone Deacetylase 6
  • Histone Deacetylases / metabolism
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
  • Mice
  • Mice, Transgenic
  • Oxidative Stress / drug effects*
  • Reactive Oxygen Species / metabolism
  • Thioredoxin Reductase 1 / antagonists & inhibitors
  • Thioredoxin Reductase 1 / metabolism
  • Transcriptome / drug effects
  • ZAP-70 Protein-Tyrosine Kinase / metabolism


  • Antineoplastic Agents
  • HSP90 Heat-Shock Proteins
  • Reactive Oxygen Species
  • Auranofin
  • TXNRD1 protein, human
  • Thioredoxin Reductase 1
  • ZAP-70 Protein-Tyrosine Kinase
  • ZAP70 protein, human
  • HDAC6 protein, human
  • Histone Deacetylase 6
  • Histone Deacetylases