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Auranofin induces lethal oxidative and endoplasmic reticulum stress and exerts potent preclinical activity against chronic lymphocytic leukemia.
Cancer Res. 2014 May 01; 74(9):2520-32.CR

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+Show Affiliations

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.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

24599128

Citation

Fiskus, Warren, et al. "Auranofin Induces Lethal Oxidative and Endoplasmic Reticulum Stress and Exerts Potent Preclinical Activity Against Chronic Lymphocytic Leukemia." Cancer Research, vol. 74, no. 9, 2014, pp. 2520-32.
Fiskus W, Saba N, Shen M, et al. Auranofin induces lethal oxidative and endoplasmic reticulum stress and exerts potent preclinical activity against chronic lymphocytic leukemia. Cancer Res. 2014;74(9):2520-32.
Fiskus, W., Saba, N., Shen, M., Ghias, M., Liu, J., Gupta, S. D., Chauhan, L., Rao, R., Gunewardena, S., Schorno, K., Austin, C. P., Maddocks, K., Byrd, J., Melnick, A., Huang, P., Wiestner, A., & Bhalla, K. N. (2014). Auranofin induces lethal oxidative and endoplasmic reticulum stress and exerts potent preclinical activity against chronic lymphocytic leukemia. Cancer Research, 74(9), 2520-32. https://doi.org/10.1158/0008-5472.CAN-13-2033
Fiskus W, et al. 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. PubMed PMID: 24599128.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Auranofin induces lethal oxidative and endoplasmic reticulum stress and exerts potent preclinical activity against chronic lymphocytic leukemia. AU - Fiskus,Warren, AU - Saba,Nakhle, AU - Shen,Min, AU - Ghias,Mondana, AU - Liu,Jinyun, AU - Gupta,Soumyasri Das, AU - Chauhan,Lata, AU - Rao,Rekha, AU - Gunewardena,Sumedha, AU - Schorno,Kevin, AU - Austin,Christopher P, AU - Maddocks,Kami, AU - Byrd,John, AU - Melnick,Ari, AU - Huang,Peng, AU - Wiestner,Adrian, AU - Bhalla,Kapil N, Y1 - 2014/03/05/ PY - 2014/3/7/entrez PY - 2014/3/7/pubmed PY - 2014/7/7/medline SP - 2520 EP - 32 JF - Cancer research JO - Cancer Res. VL - 74 IS - 9 N2 - 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. SN - 1538-7445 UR - https://www.unboundmedicine.com/medline/citation/24599128/Auranofin_induces_lethal_oxidative_and_endoplasmic_reticulum_stress_and_exerts_potent_preclinical_activity_against_chronic_lymphocytic_leukemia_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=24599128 DB - PRIME DP - Unbound Medicine ER -