title: Copper-zinc superoxide dismutase-mediated redox regulation of bortezomib resistance in multiple myeloma.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, Free Radical and Radiation Biology Program, Iowa City, IA, USA.
authors.forename: Kelley
authors.initials: K
authors.lastname: Salem
authors.affiliation: Department of Radiation Oncology, Free Radical and Radiation Biology Program, Iowa City, IA, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: McCormick
authors.affiliation: Department of Internal Medicine, The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Wendlandt
authors.affiliation: Department of Internal Medicine, The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Fenghuang
authors.initials: F
authors.lastname: Zhan
authors.affiliation: Department of Radiation Oncology, Free Radical and Radiation Biology Program, Iowa City, IA, USA. Electronic address: apollina-goel@uiowa.edu.
authors.forename: Apollina
authors.initials: A
authors.lastname: Goel
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D000069286:Bortezomib / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D004221:Disulfiram / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005978:Glutathione / Q000096:biosynthesis; D005979:Glutathione Peroxidase / Q000096:biosynthesis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D000094765:Glutathione Peroxidase GPX1
chemical_list: D017382:Reactive Oxygen Species; D000069286:Bortezomib; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005978:Glutathione; D004221:Disulfiram; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human
keywords: Bortezomib; Copper–zinc superoxide dismutase; Disulfiram; Multiple myeloma; SOD1