title: Dual targeting of the thioredoxin and glutathione antioxidant systems in malignant B cells: a novel synergistic therapeutic approach.
abstract: B-cell malignancies are a common type of cancer. One approach to cancer therapy is to either increase oxidative stress or inhibit the stress response systems on which cancer cells rely. In this study, we combined nontoxic concentrations of Auranofin (AUR), an inhibitor of the thioredoxin system, with nontoxic concentrations of buthionine-sulfoximine (BSO), a compound that reduces intracellular glutathione levels, and investigated the effect of this drug combination on multiple pathways critical for malignant B-cell survival. Auranofin interacted synergistically with BSO at low concentrations to trigger death in multiple malignant B-cell lines and primary mantle-cell lymphoma cells. Additionally, there was less toxicity toward normal B cells. Low AUR concentrations inhibited thioredoxin reductase (TrxR) activity, an effect significantly increased by BSO cotreatment. Overexpression of TrxR partially reversed AUR+BSO toxicity. Interestingly, the combination of AUR+BSO inhibited nuclear factor κB (NF-κB) signaling. Moreover, synergistic cell death induced by this regimen was attenuated in cells overexpressing NF-κB proteins, arguing for a functional role for NF-κB inhibition in AUR+BSO-mediated cell death. Together, these findings suggest that AUR+BSO synergistically induces malignant B-cell death, a process mediated by dual inhibition of TrxR and NF-κB, and such an approach warrants further investigation in B-cell malignancies.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA. Electronic address: michelle_kiebala@urmc.rochester.edu.
authors.forename: Michelle
authors.initials: M
authors.lastname: Kiebala
authors.affiliation: Division of Biology, Alfred University, Alfred, NY, USA.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Skalska
authors.affiliation: James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: Casulo
authors.affiliation: Department of Anesthesiology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Brookes
authors.affiliation: Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Derick R
authors.initials: DR
authors.lastname: Peterson
authors.affiliation: Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Shannon P
authors.initials: SP
authors.lastname: Hilchey
authors.affiliation: Division of Hematology and Oncology and Palliative Care, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Division of Hematology and Oncology and Palliative Care, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Sanjay B
authors.initials: SB
authors.lastname: Maggirwar
authors.affiliation: James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Bernstein
mesh_terms: D000963:Antimetabolites / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001310:Auranofin / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D061251:Primary Cell Culture; D015398:Signal Transduction; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013879:Thioredoxins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000963:Antimetabolites; D000970:Antineoplastic Agents; D016328:NF-kappa B; C491203:TXN protein, human; D001310:Auranofin; D019328:Buthionine Sulfoximine; D013879:Thioredoxins; D013880:Thioredoxin-Disulfide Reductase; D005978:Glutathione