Journal
EXPERIMENTAL HEMATOLOGY
Volume 43, Issue 2, Pages 89-99Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.exphem.2014.10.004
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Funding
- National Institutes of Health [R01 NS054578, R01 NS066801, R03 DA035086, R01 HL071158, R01 CA167708]
- Specialized Program of Research Excellence (SPORE) in Myeloma Grant [1P50CA142509]
- Leukemia and Lymphoma Society of America [6472-15]
- Leukemia and Lymphoma Society Translational Grant [6344-11]
- United States Public Health Service Grant [RO1-CA122645]
- SPORE in Lymphoma Grant [P50-CA130805]
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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 kappa B (NF-kappa B) signaling. Moreover, synergistic cell death induced by this regimen was attenuated in cells overexpressing NF-kappa B proteins, arguing for a functional role for NF-kappa B 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-kappa B, and such an approach warrants further investigation in B-cell malignancies. Copyright (C) 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc.
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