TitleAuranofin induces lethal oxidative and endoplasmic reticulum stress and exerts potent preclinical activity against chronic lymphocytic leukemia.
Publication TypeJournal Article
Year of Publication2014
AuthorsFiskus, Warren, Saba Nakhle, Shen Min, Ghias Mondana, Liu Jinyun, Gupta Soumyasri Das, Chauhan Lata, Rao Rekha, Gunewardena Sumedha, Schorno Kevin, Austin Christopher P., Maddocks Kami, Byrd John, Melnick Ari, Huang Peng, Wiestner Adrian, and Bhalla Kapil N.
JournalCancer Res
Date Published2014 May 01
KeywordsAnimals, Antineoplastic Agents, Apoptosis, Auranofin, Cell Line, Tumor, Cell Survival, Drug Screening Assays, Antitumor, Endoplasmic Reticulum Stress, Histone Deacetylase 6, Histone Deacetylases, HSP90 Heat-Shock Proteins, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Mice, Mice, Transgenic, Oxidative Stress, Reactive Oxygen Species, Thioredoxin Reductase 1, Transcriptome, ZAP-70 Protein-Tyrosine Kinase

<p>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.</p>

Alternate JournalCancer Res
PubMed ID24599128
PubMed Central IDPMC4172421
Grant ListP01 CA081534 / CA / NCI NIH HHS / United States
R01 CA085563 / CA / NCI NIH HHS / United States
R01 CA100428 / CA / NCI NIH HHS / United States