TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition

Abstract

Multiple myeloma (MM) is a B-cell malignancy characterized by an accumulation of abnormal clonal plasma cells in the bone marrow. Introduction of the proteasome-inhibitor bortezomib has improved MM prognosis and survival; however hypoxia-induced or acquired bortezomib resistance remains a clinical problem. This study highlighted the role of thioredoxin reductase 1 (TrxR1) in the hypoxia-induced and acquired bortezomib resistance in MM. Higher TrxR1 gene expression correlated with high-risk disease, adverse overall survival, and poor prognosis in myeloma patients. We demonstrated that hypoxia induced bortezomib resistance in myeloma cells and increased TrxR1 protein levels. Inhibition of TrxR1 using auranofin overcame hypoxia-induced bortezomib resistance and restored the sensitivity of hypoxicmyeloma cells to bortezomib. Hypoxia increased NF-kb subunit p65 nuclear protein levels and TrxR1 inhibition decreased hypoxia-induced NF-kb p65 protein levels in the nucleus and reduced the expression of NF-kb-regulated genes. In addition, higher TrxR1 protein levels were observed in bortezomib-resistant myeloma cells compared to the na€ ıve cells, and its inhibition using either auranofin or TrxR1-specific siRNAs reversed bortezomib resistance. TrxR1 inhibition reduced p65 mRNA and protein expression in bortezomib-resistant myeloma cells, and also decreased the expression of NF-kb-regulated anti-apoptotic and proliferative genes. Thus, TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance by inhibiting the NF-kb signaling pathway. Our findings demonstrate that elevated TrxR1 levels correlate with the acquisition of bortezomib resistance in MM. We propose considering TrxR1-inhibiting drugs, such as auranofin, either for single agent or combination therapy to circumvent bortezomibresistance and improve survival outcomes of MM patients.

Multiple myeloma cells’ capacity to decompose H2O2 determines lenalidomide sensitivity

“…TrxR inhibitors and Trx inhibitors have previously been reported by others to have activity in MM cells. [37][38][39] The direct TrxR inhibitor auranofin, an organic gold compound used in clinic as treatment of rheumatoid arthritis, 40 was very effective in inducing cell death in MM cell lines, in a CRBN-independent fashion. Using MM.1R isogeneic cells with and without CRBN, and the CRBN-overexpressing OCIMY-5 cell line (transfected with wild-type CRBN), we showed that auranofin treatment caused cytotoxicity irrespective of CRBN expression, while lenalidomide was only effective in CRBN-expressing cells ( Figure 7A-C).…”

Pirh2 mediates the sensitivity of myeloma cells to bortezomib via canonical NF-κB signaling pathway

“…The present study highlighted a molecular mechanism by which Pirh2 overcame bortezomib resistance in myeloma cells. NF-κB is activated in patients with bortezomib-refractory primary MM and bortezomib-resistant MM, which is associated with the increased basal nuclear localization of NF-κB p65 (Raninga et al, 2016 ). Increased NF-κB p65, pp65, pIKBa, and IKKa levels were observed in bortezomib-resistant cells.…”

Thioredoxin Confers Intrinsic Resistance to Cytostatic Drugs in Human Glioma Cells

“…This further drove us to investigate the role of Trx in chemoresistance. To this end, we applied PX-12, a small-molecule inhibitor which has already been demonstrated to overcome drug resistance in multiple myeloma [ 44 , 45 ], alone and in combination with cisplatin or TMZ. PX-12 chemically belongs to the group of alkylated 2-imidazolyl disulfide Trx inhibitors.…”