title: Auranofin induces lethal oxidative and endoplasmic reticulum stress and exerts potent preclinical activity against chronic lymphocytic leukemia.
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.
authors.affiliation: Authors' Affiliations: Houston Methodist Research Institute; The University of Texas M.D. Anderson Cancer Center, Houston, Texas; Hematology Branch, National Heart Lung and Blood Institute (NHLBI); National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland; The University of Kansas Medical Center; Institute for Advancing Medical Innovation, Kansas University, Kansas City, Kansas; Division of Hematology, Department of Internal Medicine, The Comprehensive Cancer Center at the Ohio State University, Columbus, Ohio; and Weill Cornell Medical College, New York, New York.
authors.forename: Warren
authors.initials: W
authors.lastname: Fiskus
authors.forename: Nakhle
authors.initials: N
authors.lastname: Saba
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.forename: Mondana
authors.initials: M
authors.lastname: Ghias
authors.forename: Jinyun
authors.initials: J
authors.lastname: Liu
authors.forename: Soumyasri Das
authors.initials: SD
authors.lastname: Gupta
authors.forename: Lata
authors.initials: L
authors.lastname: Chauhan
authors.forename: Rekha
authors.initials: R
authors.lastname: Rao
authors.forename: Sumedha
authors.initials: S
authors.lastname: Gunewardena
authors.forename: Kevin
authors.initials: K
authors.lastname: Schorno
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
authors.forename: Kami
authors.initials: K
authors.lastname: Maddocks
authors.forename: John
authors.initials: J
authors.lastname: Byrd
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
authors.forename: Adrian
authors.initials: A
authors.lastname: Wiestner
authors.forename: Kapil N
authors.initials: KN
authors.lastname: Bhalla
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001310:Auranofin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D054481:Thioredoxin Reductase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D017382:Reactive Oxygen Species; D001310:Auranofin; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases