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.

Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib

“…Data sets of genes with the altered expression profile derived from the gene expression microarray analyses were imported into the Ingenuity Pathway Analysis (IPA) Tool (Ingenuity Systems, Redwood City, CA). 39 Within this gene list, IPA identified the top 5 most perturbed gene networks in the MO2058 cells following treatment with JQ1 and assigned a score for these associated network functions (supplemental Table 2). The score (eg, a score of 57) assigned by the IPA indicates the probability (1 in 10 57 ) that the focus-genes in the data set are grouped together in a perturbed network due to random chance alone.…”

Drug repurposing screens and synergistic drug‐combinations for infectious diseases

“…It showed good activities against multidrug‐resistant bacteria, including methicillin‐resistant Staphylococcus aureus (MRSA) and K. pneumoniae (Harbut et al , 2015; Sun et al , 2016b). Auranofin also exhibited activities against other diseases including HIV/AIDS (Chirullo et al , 2013), and some parasitic diseases (Debnath et al , 2012), as well as Alzheimer's disease, Parkinson's disease (Madeira et al , 2013; Madeira et al , 2014) and cancer (Fiskus et al , 2014). Notably, auranofin was evaluated in human clinical studies for gastrointestinal protozoa, HIV, and cancer.…”

Dual targeting of the thioredoxin and glutathione systems in cancer and HIV

“…A recent study showed that mitochondrial TrxR contributes to tumor growth through the HIF-1 pathway (64), supporting the idea that mitochondrial redox signaling is important for tumorigenesis. Conversely, the TrxR inhibitor auranofin partially inhibits the growth of leukemia and relapsed Hodgkin lymphoma cells in vitro (65,66). TrxR inhibitors may generally promote apoptosis or differentiation.…”