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

Warren Fiskus, Nakhle Saba, Min Shen, Mondana Ghias, Jinyun Liu, Soumyasri Das Gupta, Lata Chauhan, Rekha Rao, Sumedha Gunewardena, Kevin Schorno, Christopher P. Austin, Kami Maddocks, John Byrd, Ari Melnick, Peng Huang, Adrian Wiestner, Kapil N. Bhalla

Research output: Contribution to journalArticle

139 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2520-2532
Number of pages13
JournalCancer research
Volume74
Issue number9
DOIs
StatePublished - Jan 5 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Auranofin induces lethal oxidative and endoplasmic reticulum stress and exerts potent preclinical activity against chronic lymphocytic leukemia'. Together they form a unique fingerprint.

Cite this