title: Cross-talk between two antioxidants, thioredoxin reductase and heme oxygenase-1, and therapeutic implications for multiple myeloma.
abstract: Multiple myeloma (MM) is characterized by an accumulation of abnormal clonal plasma cells in the bone marrow. Despite recent advancements in anti-myeloma therapies, MM remains an incurable disease. Antioxidant molecules are upregulated in many cancers, correlating with tumor proliferation, survival, and chemoresistance and therefore, have been suggested as potential therapeutic targets. This study investigated the cross-talk between two antioxidant molecules, thioredoxin reductase (TrxR) and heme oxygenase-1 (HO-1), and their therapeutic implications in MM. We found that although auranofin, a TrxR inhibitor, significantly inhibited TrxR activity by more than 50% at lower concentrations, myeloma cell proliferation was only inhibited at higher concentrations of auranofin. Inhibition of TrxR using lower auranofin concentrations induced HO-1 protein expression in myeloma cells. Using a sub-lethal concentration of auranofin to inhibit TrxR activity in conjunction with HO-1 inhibition significantly decreased myeloma cell growth and induced apoptosis. TrxR was shown to regulate HO-1 via the Nrf2 signaling pathway in a ROS-dependent manner. Increased HO-1 mRNA levels were observed in bortezomib-resistant myeloma cells compared to parent cells and HO-1 inhibition restored the sensitivity to bortezomib in bortezomib-resistant myeloma cells. These findings indicate that concurrent inhibition of HO-1 with either a TrxR inhibitor or with bortezomib would improve therapeutic outcomes in MM patients. Hence, our findings further support the need to target multiple antioxidant systems alone or in combination with other therapeutics to improve therapeutic outcomes in MM patients.
authors.affiliation: School of Natural Sciences, Griffith University, QLD 4111, Australia; Eskitis Institute for Drug Discovery, Griffith University, QLD 4111, Australia.
authors.forename: Prahlad V
authors.initials: PV
authors.lastname: Raninga
authors.affiliation: School of Natural Sciences, Griffith University, QLD 4111, Australia.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Di Trapani
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; The University of Queensland, QLD 4072, Australia.
authors.forename: Slavica
authors.initials: S
authors.lastname: Vuckovic
authors.affiliation: School of Natural Sciences, Griffith University, QLD 4111, Australia; Eskitis Institute for Drug Discovery, Griffith University, QLD 4111, Australia. Electronic address: K.Tonissen@griffith.edu.au.
authors.forename: Kathryn F
authors.initials: KF
authors.lastname: Tonissen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001310:Auranofin / Q000494:pharmacology; D000069286:Bortezomib / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D004791:Enzyme Inhibitors; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D001310:Auranofin; D000069286:Bortezomib; D051547:Heme Oxygenase-1; D013880:Thioredoxin-Disulfide Reductase
keywords: Apoptosis; Chemoresistance; Heme oxygenase-1; Multiple myeloma; Thioredoxin reductase