ROS Overproduction Sensitises Myeloma Cells to Bortezomib-Induced Apoptosis and Alleviates Tumour Microenvironment-Mediated Cell Resistance

Abstract

Multiple myeloma (MM) is a plasma cell neoplasm that remains incurable due to innate or acquired resistance. Although MM cells produce high intracellular levels of reactive oxygen species (ROS), we hypothesised that they could remain sensitive to ROS unbalance. We tested if the inhibition of ROS, on one hand, or the overproduction of ROS, on the other, could (re)sensitise cells to bortezomib (BTZ). Two drugs were used in a panel of MM cell lines with various responses to BTZ: VAS3947 (VAS), an inhibitor of NADPH oxidase and auranofin (AUR), an inhibitor of thioredoxin reductase (TXNRD1), an antioxidant enzyme overexpressed in MM cells. We used several culture models: in suspension, on a fibronectin layer, in coculture with HS-5 mesenchymal cells, and/or in 3-D culture (or spheroids) to study the response of MM primary cells and cell lines. Several MM cell lines were sensitive to VAS but the combination with BTZ showed antagonistic or additive effects at best. By contrast, in all culture systems studied, the combined AUR/BTZ treatment showed synergistic effects on cell lines, including those less sensitive to BTZ and primary cells. MM cell death is due to the activation of apoptosis and autophagy. Modulating the redox balance of MM cells could be an effective therapy for refractory or relapse post-BTZ patients.

Keywords

• reactive oxygen species
• resistance
• bortezomib
• auranofin
• antioxidant enzymes
• survival