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

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...

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Autores principales: Caillot, Mélody, Zylbersztejn, Florence, Maitre, Elsa, Bourgeais, Jérôme, Hérault, Olivier, Sola, Brigitte
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693395/
https://www.ncbi.nlm.nih.gov/pubmed/33114738
http://dx.doi.org/10.3390/cells9112357
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author Caillot, Mélody
Zylbersztejn, Florence
Maitre, Elsa
Bourgeais, Jérôme
Hérault, Olivier
Sola, Brigitte
author_facet Caillot, Mélody
Zylbersztejn, Florence
Maitre, Elsa
Bourgeais, Jérôme
Hérault, Olivier
Sola, Brigitte
author_sort Caillot, Mélody
collection PubMed
description 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.
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spelling pubmed-76933952020-11-28 ROS Overproduction Sensitises Myeloma Cells to Bortezomib-Induced Apoptosis and Alleviates Tumour Microenvironment-Mediated Cell Resistance Caillot, Mélody Zylbersztejn, Florence Maitre, Elsa Bourgeais, Jérôme Hérault, Olivier Sola, Brigitte Cells Article 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. MDPI 2020-10-26 /pmc/articles/PMC7693395/ /pubmed/33114738 http://dx.doi.org/10.3390/cells9112357 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Caillot, Mélody
Zylbersztejn, Florence
Maitre, Elsa
Bourgeais, Jérôme
Hérault, Olivier
Sola, Brigitte
ROS Overproduction Sensitises Myeloma Cells to Bortezomib-Induced Apoptosis and Alleviates Tumour Microenvironment-Mediated Cell Resistance
title ROS Overproduction Sensitises Myeloma Cells to Bortezomib-Induced Apoptosis and Alleviates Tumour Microenvironment-Mediated Cell Resistance
title_full ROS Overproduction Sensitises Myeloma Cells to Bortezomib-Induced Apoptosis and Alleviates Tumour Microenvironment-Mediated Cell Resistance
title_fullStr ROS Overproduction Sensitises Myeloma Cells to Bortezomib-Induced Apoptosis and Alleviates Tumour Microenvironment-Mediated Cell Resistance
title_full_unstemmed ROS Overproduction Sensitises Myeloma Cells to Bortezomib-Induced Apoptosis and Alleviates Tumour Microenvironment-Mediated Cell Resistance
title_short ROS Overproduction Sensitises Myeloma Cells to Bortezomib-Induced Apoptosis and Alleviates Tumour Microenvironment-Mediated Cell Resistance
title_sort ros overproduction sensitises myeloma cells to bortezomib-induced apoptosis and alleviates tumour microenvironment-mediated cell resistance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693395/
https://www.ncbi.nlm.nih.gov/pubmed/33114738
http://dx.doi.org/10.3390/cells9112357
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