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 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.

• Publication year

  2014

• Venue

  Redox Biology

• Publication date

  2014-11-18

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1016/j.redox.2014.11.002PMID 25485927PMCID 4309843
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• DioxolaneA3-phosphatidylethanolamines are generated by human platelets and stimulate neutrophil integrin expression

  2017cited by this paper
• Superoxide dismutase 1 acts as a nuclear transcription factor to regulate oxidative stress resistance

  2014cited by this paper
• SOD2 to SOD1 Switch in Breast Cancer*

  2014cited by this paper
• SOD1, an unexpected novel target for cancer therapy

  2014cited by this paper
• Oxidizing to death

  2014cited by this paper
• Proteasome inhibitors in acute leukemia

  2014cited by this paper
• Targeting SOD1 reduces experimental non–small-cell lung cancer.

  2014cited by this paper
• Interferon-γ-induced upregulation of immunoproteasome subunit assembly overcomes bortezomib resistance in human hematological cell lines

  2014cited by this paper
• Proteasome inhibitors in acute leukemia

  2014cited by this paper
• Where we were, where we are, where we are going: progress in multiple myeloma.

  2014cited by this paper
• Cancer statistics, 2014

  2014cited by this paper
• Who We Were

  2013cited by this paper
• Role of Glutathione in Cancer Progression and Chemoresistance

  2013cited by this paper
• Combination chemotherapy increases cytotoxicity of multiple myeloma cells by modification of nuclear factor (NF)-κB activity.

  2013cited by this paper
• The resistance mechanisms of proteasome inhibitor bortezomib

  2013cited by this paper
• Manganese superoxide dismutase regulation and cancer.

  2012cited by this paper
• Lymphoma cells with increased anti-oxidant defenses acquire chemoresistance.

  2012cited by this paper
• Management strategies for relapsed/refractory multiple myeloma: current clinical perspectives.

  2012cited by this paper
• Impaired bortezomib binding to mutant β5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells

  2012cited by this paper
• Sequence analysis of β-subunit genes of the 20S proteasome in patients with relapsed multiple myeloma treated with bortezomib or dexamethasone.

  2012cited by this paper
• Alterations in Glutathione Levels and Apoptotic Regulators Are Associated with Acquisition of Arsenic Trioxide Resistance in Multiple Myeloma

  2012cited by this paper
• Disulfiram, an old drug with new potential therapeutic uses for human hematological malignancies

  2012cited by this paper
• Interleukin-6 counteracts therapy-induced cellular oxidative stress in multiple myeloma by up-regulating manganese superoxide dismutase

  2012cited by this paper
• Pivotal Advance: Protein synthesis modulates responsiveness of differentiating and malignant plasma cells to proteasome inhibitors

  2012cited by this paper
• Nonprofit drugs as the salvation of the world's healthcare systems: the case of Antabuse (disulfiram).

  2012cited by this paper
• Increase of novel biomarkers for oxidative stress in patients with plasma cell disorders and in multiple myeloma patients with bone lesions

  2012cited by this paper
• Manipulation of cellular redox parameters for improving therapeutic responses in B‐cell lymphoma and multiple myeloma

  2012cited by this paper
• Targeting the insulin-like growth factor-1 receptor to overcome bortezomib resistance in preclinical models of multiple myeloma.

  2012cited by this paper
• Targeting malignancies with disulfiram (Antabuse): multidrug resistance, angiogenesis, and proteasome.

  2011cited by this paper
• SOD1 Transcriptional and Posttranscriptional Regulation and Its Potential Implications in ALS

  2011cited by this paper
• Two endoplasmic reticulum PDI peroxidases increase the efficiency of the use of peroxide during disulfide bond formation.

  2011cited by this paper
• Dexamethasone-induced oxidative stress enhances myeloma cell radiosensitization while sparing normal bone marrow hematopoiesis.

  2010cited by this paper
• Post-translational modifications of superoxide dismutase.

  2010cited by this paper
• Bortezomib-resistant myeloma cell lines: a role for mutated PSMB5 in preventing the accumulation of unfolded proteins and fatal ER stress

  2010cited by this paper
• Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma

  2010cited by this paper
• Targeted inhibition of the immunoproteasome is a potent strategy against models of multiple myeloma that overcomes resistance to conventional drugs and nonspecific proteasome inhibitors.

  2009cited by this paper
• Increased levels of superoxide and H2O2 mediate the differential susceptibility of cancer cells versus normal cells to glucose deprivation.

  2009cited by this paper
• The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition.

  2009cited by this paper
• Adaptation to Oxidative Stress, Chemoresistance, and Cell Survival

  2009cited by this paper
• Study of antioxidant levels in patients with multiple myeloma

  2009cited by this paper
• Acquisition of a Multidrug Resistant Phenotype with a Proteasome Inhibitor in Multiple Myeloma

  2009cited by this paper
• Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?

  2009cited by this paper
• High-risk myeloma: a gene expression based risk-stratification model for newly diagnosed multiple myeloma treated with high-dose therapy is predictive of outcome in relapsed disease treated with single-agent bortezomib or high-dose dexamethasone.

  2008cited by this paper
• Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein.

  2008cited by this paper
• Mechanisms of proteasome inhibitor action and resistance in cancer.

  2008influential reference
• Redox homeostasis modulates the sensitivity of myeloma cells to bortezomib

  2008cited by this paper
• Point Mutation of the Proteasome β5 Subunit Gene Is an Important Mechanism of Bortezomib Resistance in Bortezomib-Selected Variants of Jurkat T Cell Lymphoblastic Lymphoma/Leukemia Line

  2008cited by this paper
• Proteasome β Subunit Pharmacogenomics: Gene Resequencing and Functional Genomics

  2008cited by this paper
• High-risk myeloma: a gene expression–based risk-stratification model for newly diagnosed multiple myeloma treated with high-dose therapy is predictive of outcome in relapsed disease treated with single-agent bortezomib or high-dose dexamethasone

  2008cited by this paper
• Redox Regulation of Cell Survival

  2008cited by this paper
• The proteasome and its role in the degradation of oxidized proteins

  2008cited by this paper
• Image-Based Screening for the Identification of Novel Proteasome Inhibitors

  2007cited by this paper
• The histone deacetylase inhibitor, PXD101, potentiates bortezomib‐induced anti‐multiple myeloma effect by induction of oxidative stress and DNA damage

  2007cited by this paper
• Clinical impact of bortezomib in frontline regimens for patients with multiple myeloma.

  2007cited by this paper
• Synergistic activity of the proteasome inhibitor PS-341 with non-myeloablative 153-Sm-EDTMP skeletally targeted radiotherapy in an orthotopic model of multiple myeloma.

  2006cited by this paper
• Correlates of imexon sensitivity in human multiple myeloma cell lines

  2006influential reference
• Mitochondrial mutations in cancer

  2006cited by this paper
• No evidence of mutations of the PSMB5 (beta-5 subunit of proteasome) in a case of myeloma with clinical resistance to Bortezomib.

  2006cited by this paper
• Degradation of Amyotrophic Lateral Sclerosis-linked Mutant Cu,Zn-Superoxide Dismutase Proteins by Macroautophagy and the Proteasome*

  2006cited by this paper
• A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1.

  2006cited by this paper
• PS-341-mediated selective targeting of multiple myeloma cells by synergistic increase in ionizing radiation-induced apoptosis.

  2005cited by this paper
• High-sensitivity cytotoxicity assays for nonadherent cells.

  2005cited by this paper
• Oxidant/antioxidant parameters and their relationship with medical treatment in multiple myeloma

  2005cited by this paper
• Alpha-synuclein up-regulation and aggregation during MPP+-induced apoptosis in neuroblastoma cells: intermediacy of transferrin receptor iron and hydrogen peroxide.

  2004cited by this paper
• Synergistic Induction of Oxidative Injury and Apoptosis in Human Multiple Myeloma Cells by the Proteasome Inhibitor Bortezomib and Histone Deacetylase Inhibitors

  2004cited by this paper
• α-Synuclein Up-regulation and Aggregation during MPP+-induced Apoptosis in Neuroblastoma Cells

  2004cited by this paper
• Chromosomal DNA fragmentation in apoptosis and necrosis induced by oxidative stress.

  2003cited by this paper
• Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341.

  2003cited by this paper
• Phase II trial of tetrathiomolybdate in patients with advanced kidney cancer.

  2003cited by this paper
• The proteasome inhibitor bortezomib promotes mitochondrial injury and apoptosis induced by the small molecule Bcl-2 inhibitor HA14-1 in multiple myeloma cells

  2003cited by this paper
• Effect of geranylgeranylaceton on cellular damage induced by proteasome inhibition in cultured spinal neurons

  2002cited by this paper
• Overexpression of copper zinc superoxide dismutase suppresses human glioma cell growth.

  2002influential reference
• Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple.

  2001influential reference
• A fraction of yeast Cu,Zn-superoxide dismutase and its metallochaperone, CCS, localize to the intermembrane space of mitochondria. A physiological role for SOD1 in guarding against mitochondrial oxidative damage.

  2001cited by this paper
• Oxidative Stress-Associated Impairment of Proteasome Activity during Ischemia–Reperfusion Injury

  2000cited by this paper
• The role of cellular glutathione peroxidase redox regulation in the suppression of tumor cell growth by manganese superoxide dismutase.

  2000cited by this paper
• Treatment of metastatic cancer with tetrathiomolybdate, an anticopper, antiangiogenic agent: Phase I study.

  2000cited by this paper
• Tissue-specific functions of individual glutathione peroxidases.

  1999cited by this paper
• [Lipid peroxidation and activity of antioxidative enzymes in patients with multiple myeloma].

  1996cited by this paper
• Importance of Se-glutathione peroxidase, catalase, and Cu/Zn-SOD for cell survival against oxidative stress.

  1994cited by this paper
• Glutathione peroxidase compensates for the hypersensitivity of Cu,Zn-superoxide dismutase overproducers to oxidant stress.

  1994cited by this paper
• DNA strand scission and free radical production in menadione-treated cells. Correlation with cytotoxicity and role of NADPH quinone acceptor oxidoreductase.

  1992cited by this paper
• The balance between copper-zinc superoxide dismutase and catalase affects the sensitivity of mouse epidermal cells to oxidative stress

  1991cited by this paper
• The balance between Cu,Zn-superoxide dismutase and catalase affects the sensitivity of mouse epidermal cells to oxidative stress.

  1991cited by this paper
• Alteration of endogenous glutathione peroxidase, manganese superoxide dismutase, and glutathione transferase activity in cells transfected with a copper-zinc superoxide dismutase expression vector. Explanation for variations in paraquat resistance.

  1990cited by this paper
• A Randomized Phase II Study of Cisplatin Alone Versus Cisplatin Plus Disulfiram

  1990cited by this paper
• Cancer statistics

  1989cited by this paper
• Potentiation of nitrogen mustard cytotoxicity by disulfiram, diethyldithiocarbamic acid, and diethylamine in mice.

  1989cited by this paper
• An assay for superoxide dismutase activity in mammalian tissue homogenates.

  1989cited by this paper
• Expression of transfected human CuZn superoxide dismutase gene in mouse L cells and NS20Y neuroblastoma cells induces enhancement of glutathione peroxidase activity.

  1988cited by this paper
• Bypasses of the antimycin a block of mitochondrial electron transport in relation to ubisemiquinone function.

  1984cited by this paper
• Catalase in vitro.

  1984cited by this paper
• Structure and mechanism of copper, zinc superoxide dismutase

  1983cited by this paper
• Determination of glutathione and glutathione disulfide using glutathione reductase and 2-vinylpyridine.

  1980cited by this paper
• Role of superoxide dismutase in cancer: a review.

  1979cited by this paper
• Glutathione peroxidase activity in selenium-deficient rat liver.

  1976cited by this paper
• Superoxide dismutases.

  1975cited by this paper
• Structure and Mechanism of Copper Oxidases

  1974cited by this paper

• The role of antioxidants in multiple myeloma: diagnostic, prognostic, and therapeutic applications: a narrative review.

  2026cites this paper
• Targeting metalloptosis in tumor therapy: from molecular mechanisms to application of metal nanoparticles

  2025cites this paper
• Peroxiredoxins as novel indicators in multiple myeloma associated with ferroptosis and immune infiltration

  2025cites this paper
• Molecular Characterization of Superoxide Dismutase and Its Putative Relationship With Drug Resistance in Eimeria Tenella

  2025cites this paper
• Effects of bortezomib on intracellular antioxidant and apoptosis in HepG2cells

  2025cites this paper
• pH-responsive ZIF-8 nanoplatform co-loaded with DSF and ICG for multiple synergistic antitumor therapy.

  2025cites this paper
• Targeting oxidative stress-mediated regulated cell death as a vulnerability in cancer

  2025cites this paper
• Imperative connotation of SODs in cancer: Emerging targets and multifactorial role of action

  2024cites this paper
• Novel Pathogenic Variants Leading to Sporadic Amyotrophic Lateral Sclerosis in Greek Patients

  2024cites this paper
• In Vitro Low-Bortezomib Doses Induce Apoptosis and Independently Decrease the Activities of Glutathione S-Transferase and Glutathione Peroxidase in Multiple Myeloma, Taking into Account the GSTT1 and GSTM1 Gene Variants

  2024cites this paper
• FDA-approved disulfiram induces ferroptosis via alteration of redox balance and lipid peroxidation and overcomes carfilzomib resistance in multiple myeloma

  2024influential citation
• Acquired Bortezomib Resistance in Multiple Myeloma: From Mechanisms to Strategy.

  2024cites this paper
• Superoxide Dismutase from Marine as a Cytotoxic Agent

  2024cites this paper
• Different Strategies to Overcome Resistance to Proteasome Inhibitors—A Summary 20 Years after Their Introduction

  2024cites this paper
• Identification of a novel lactylation-related gene signature predicts the prognosis of multiple myeloma and experiment verification

  2024cites this paper
• Tigecycline Opposes Bortezomib Effect on Myeloma Cells Decreasing Mitochondrial Reactive Oxygen Species Production

  2024cites this paper
• Hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanocrystals for cancer therapy.

  2023cites this paper
• Liquid extramedullary disease in multiple myeloma strongly predicts a poor prognosis and is associated with bortezomib resistance gene upregulation.

  2023cites this paper
• A novel glycolysis-related gene signature for predicting the prognosis of multiple myeloma

  2023cites this paper
• Identification and validation of a novel cuproptosis-related gene signature in multiple myeloma

  2023cites this paper
• Encapsulation of SOD in chitosan-coated gel particles of alginate or mixture of alginate and shellac for targeted intestinal delivery

  2023cites this paper
• Dual inhibition of HSF1 and DYRK2 impedes cancer progression

  2023cites this paper
• Evaluation of the effects of disulfiram, an alcohol-aversive agent with anti-cancer activity, on mouse bone marrow cells

  2022cites this paper
• Effects of Antioxidant Gene Overexpression on Stress Resistance and Malignization In Vitro and In Vivo: A Review

  2022cites this paper
• Natural Antioxidant Evaluation: A Review of Detection Methods

  2022cites this paper
• Nuclear SOD1 in Growth Control, Oxidative Stress Response, Amyotrophic Lateral Sclerosis, and Cancer

  2022cites this paper
• Inhibition of the ʟ-glutamine transporter ASCT2 sensitizes plasma cell myeloma cells to proteasome inhibitors.

  2021cites this paper
• In vitro measurement of superoxide dismutase-like nanozyme activity: a comparative study.

  2021cites this paper
• Crosstalk between endoplasmic reticulum stress and oxidative stress: a dynamic duo in multiple myeloma

  2021cites this paper
• Suppression of multiple myeloma by mitochondrial targeting

  2021cites this paper
• Superoxide dismutase: an updated review on its health benefits and industrial applications

  2021cites this paper
• Targeting Reactive Oxygen Species Metabolism to Induce Myeloma Cell Death

  2021cites this paper
• Copper-lowering agents as an adjuvant in chemotherapy

  2021cites this paper
• Anticancer effects of disulfiram: a systematic review of in vitro, animal, and human studies

  2021cites this paper
• Leveraging disulfiram to treat cancer: Mechanisms of action, delivery strategies, and treatment regimens.

  2021cites this paper
• Anticancer Effects of Disul ram: A Systematic Review of in Vitro, Animal, and Human Studies

  2021influential citation
• Actionable Strategies to Target Multiple Myeloma Plasma Cell Resistance/Resilience to Stress: Insights From “Omics” Research

  2020cites this paper
• ROS Overproduction Sensitises Myeloma Cells to Bortezomib-Induced Apoptosis and Alleviates Tumour Microenvironment-Mediated Cell Resistance

  2020cites this paper
• Plasma lipid peroxidation and antioxidant status in patients with oral precancerous lesions and oral cancer

  2020cites this paper
• FGF Trapping Inhibits Multiple Myeloma Growth through c-Myc Degradation–Induced Mitochondrial Oxidative Stress

  2020cites this paper
• Racial disparities, cancer and response to oxidative stress.

  2019influential citation
• The role of proteasome activity for activating and inhibitory signalling in human platelets.

  2019cites this paper
• Proteomic analysis identifies mechanism(s) of overcoming bortezomib resistance via targeting ubiquitin receptor Rpn13

  2019cites this paper
• Inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 2 perturbs 26S proteasome-addicted neoplastic progression

  2019cites this paper
• Aproximación genética en la esclerosis lateral amiotrófica.

  2019cites this paper
• Therapeutic potentials of superoxide dismutase

  2018cites this paper
• Tocotrienol‐rich fraction supplementation prevents foetal loss in females mated with corticosterone‐treated male Sprague–Dawley rats

  2018cites this paper
• Ancient drug curcumin impedes 26S proteasome activity by direct inhibition of dual-specificity tyrosine-regulated kinase 2

  2018cites this paper
• Curcumin ameliorates the in vitro efficacy of carfilzomib in human multiple myeloma U266 cells targeting p53 and NF-κB pathways.

  2018cites this paper
• Effect of Coenzyme Q10 Supplementation on Testosterone

  2018cites this paper
• Glutaminase inhibitor CB-839 synergizes with carfilzomib in resistant multiple myeloma cells

  2017cites this paper
• Protective effects of agomelatine on testicular damage caused by bortezomib

  2017cites this paper
• Sclareol inhibits cell proliferation and sensitizes cells to the antiproliferative effect of bortezomib via upregulating the tumor suppressor caveolin-1 in cervical cancer cells

  2017cites this paper
• Docosahexaenoic acid and disulfiram act in concert to kill cancer cells: a mutual enhancement of their anticancer actions

  2017cites this paper
• Targeting unique oxidative metabolism of clonogenic multiple myeloma cells for therapy

  2016influential citation
• Mitochondrial-Targeted Decyl-Triphenylphosphonium Enhances 2-Deoxy-D-Glucose Mediated Oxidative Stress and Clonogenic Killing of Multiple Myeloma Cells

  2016cites this paper
• Disulfiram's Anticancer Activity: Evidence and Mechanisms.

  2016cites this paper
• Oxidative stress and proteasome inhibitors in multiple myeloma.

  2016cites this paper
• Targeted knockdown of DJ-1 induces multiple myeloma cell death via KLF6 upregulation

  2016cites this paper
• Effect of Fe3O4 nanoparticles and iron chelate on the antioxidant capacity and nutritional value of soil-cultivated maize (Zea mays) plants

  2016cites this paper
• TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition

  2016cites this paper
• Chapter 3 – Enzymatic Biosensors

  2015cites this paper
• Mitochondria-targeted therapy for metastatic melanoma

  2015cites this paper
• Emerging Therapeutic Strategies for Overcoming Proteasome Inhibitor Resistance.

  2015cites this paper
• The effect of metallothionein 2A core promoter region single-nucleotide polymorphism on accumulation of toxic metals in sinonasal inverted papilloma tissues.

  2015cites this paper