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Copper–zinc superoxide dismutase-mediated redox regulation of bortezomib resistance in multiple myeloma
Multiple myeloma (MM) is an incurable B-cell malignancy. The proteasome inhibitor bortezomib (BTZ) is a frontline MM drug; however, intrinsic or acquired resistance to BTZ remains a clinical hurdle. As BTZ induces oxidative stress in MM cells, we queried if altered redox homeostasis promotes BTZ res...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309843/ https://www.ncbi.nlm.nih.gov/pubmed/25485927 http://dx.doi.org/10.1016/j.redox.2014.11.002 |
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author | Salem, Kelley McCormick, Michael L. Wendlandt, Erik Zhan, Fenghuang Goel, Apollina |
author_facet | Salem, Kelley McCormick, Michael L. Wendlandt, Erik Zhan, Fenghuang Goel, Apollina |
author_sort | Salem, Kelley |
collection | PubMed |
description | Multiple myeloma (MM) is an incurable B-cell malignancy. The proteasome inhibitor bortezomib (BTZ) is a frontline MM drug; however, intrinsic or acquired resistance to BTZ remains a clinical hurdle. As BTZ induces oxidative stress in MM cells, we queried if altered redox homeostasis promotes BTZ resistance. In primary human MM samples, increased gene expression of copper–zinc superoxide dismutase (CuZnSOD or SOD1) correlated with cancer progression, high-risk disease, and adverse overall and event-free survival outcomes. As an in vitro model, human MM cell lines (MM.1S, 8226, U266) and the BTZ-resistant (BR) lines (MM.1SBR, 8226BR) were utilized to determine the role of antioxidants in intrinsic or acquired BTZ-resistance. An up-regulation of CuZnSOD, glutathione peroxidase-1 (GPx-1), and glutathione (GSH) were associated with BTZ resistance and attenuated prooxidant production by BTZ. Enforced overexpression of SOD1 induced BTZ resistance and pharmacological inhibition of CuZnSOD with disulfiram (DSF) augmented BTZ cytotoxicity in both BTZ-sensitive and BTZ-resistant cell lines. Our data validates CuZnSOD as a novel therapeutic target in MM. We propose DSF as an adjuvant to BTZ in MM that is expected to overcome intrinsic and acquired BTZ resistance as well as augment BTZ cytotoxicity. |
format | Online Article Text |
id | pubmed-4309843 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-43098432015-02-14 Copper–zinc superoxide dismutase-mediated redox regulation of bortezomib resistance in multiple myeloma Salem, Kelley McCormick, Michael L. Wendlandt, Erik Zhan, Fenghuang Goel, Apollina Redox Biol Research Paper Multiple myeloma (MM) is an incurable B-cell malignancy. The proteasome inhibitor bortezomib (BTZ) is a frontline MM drug; however, intrinsic or acquired resistance to BTZ remains a clinical hurdle. As BTZ induces oxidative stress in MM cells, we queried if altered redox homeostasis promotes BTZ resistance. In primary human MM samples, increased gene expression of copper–zinc superoxide dismutase (CuZnSOD or SOD1) correlated with cancer progression, high-risk disease, and adverse overall and event-free survival outcomes. As an in vitro model, human MM cell lines (MM.1S, 8226, U266) and the BTZ-resistant (BR) lines (MM.1SBR, 8226BR) were utilized to determine the role of antioxidants in intrinsic or acquired BTZ-resistance. An up-regulation of CuZnSOD, glutathione peroxidase-1 (GPx-1), and glutathione (GSH) were associated with BTZ resistance and attenuated prooxidant production by BTZ. Enforced overexpression of SOD1 induced BTZ resistance and pharmacological inhibition of CuZnSOD with disulfiram (DSF) augmented BTZ cytotoxicity in both BTZ-sensitive and BTZ-resistant cell lines. Our data validates CuZnSOD as a novel therapeutic target in MM. We propose DSF as an adjuvant to BTZ in MM that is expected to overcome intrinsic and acquired BTZ resistance as well as augment BTZ cytotoxicity. Elsevier 2014-11-18 /pmc/articles/PMC4309843/ /pubmed/25485927 http://dx.doi.org/10.1016/j.redox.2014.11.002 Text en https://creativecommons.org/licenses/by-nc-nd/3.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License (https://creativecommons.org/licenses/by-nc-nd/3.0/) . |
spellingShingle | Research Paper Salem, Kelley McCormick, Michael L. Wendlandt, Erik Zhan, Fenghuang Goel, Apollina Copper–zinc superoxide dismutase-mediated redox regulation of bortezomib resistance in multiple myeloma |
title | Copper–zinc superoxide dismutase-mediated redox regulation of bortezomib resistance in multiple myeloma |
title_full | Copper–zinc superoxide dismutase-mediated redox regulation of bortezomib resistance in multiple myeloma |
title_fullStr | Copper–zinc superoxide dismutase-mediated redox regulation of bortezomib resistance in multiple myeloma |
title_full_unstemmed | Copper–zinc superoxide dismutase-mediated redox regulation of bortezomib resistance in multiple myeloma |
title_short | Copper–zinc superoxide dismutase-mediated redox regulation of bortezomib resistance in multiple myeloma |
title_sort | copper–zinc superoxide dismutase-mediated redox regulation of bortezomib resistance in multiple myeloma |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309843/ https://www.ncbi.nlm.nih.gov/pubmed/25485927 http://dx.doi.org/10.1016/j.redox.2014.11.002 |
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