title: Redox homeostasis modulates the sensitivity of myeloma cells to bortezomib.
abstract: The use of proteasome inhibitors have been a major advance in the treatment of multiple myeloma (MM), but their mechanisms of action remain largely unclear. A better understanding of the cellular events downstream of proteasome inhibition is essential to improve the response and identify new combination therapies for MM and other malignancies. This study analysed the relationships between redox homeostasis and bortezomib treatment in MM cells. Our data showed that decreasing intracellular glutathione through buthionine sulfoximine treatment strongly enhances bortezomib toxicity, whilst antioxidants protect MM cells from bortezomib-mediated cell death. Bortezomib treatment decreases intracellular glutathione both in MM cell lines and in malignant plasma cells obtained from MM patients. Glutamate-cysteine ligase (GCLM) and haem-oxygenase-1 (HMOX1), two genes involved in the Nrf-2-mediated antioxidant response, as well as two eIF2alpha-downstream transcription factors, activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), are upregulated, indicating that redox-related adaptive responses are initiated in bortezomib-treated MM cells. These findings demonstrate tight links between sensitivity to proteasome inhibition and redox homeostasis in MM cells and have potential implications for treatment.
authors.affiliation: Department of Functional Genomics-Molecular Biology, San Rafaelle Scientific Institute, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Nerini-Molteni
authors.forename: Marina
authors.initials: M
authors.lastname: Ferrarini
authors.forename: Sara
authors.initials: S
authors.lastname: Cozza
authors.forename: Federico
authors.initials: F
authors.lastname: Caligaris-Cappio
authors.forename: Roberto
authors.initials: R
authors.lastname: Sitia
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D001897:Boronic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000069286:Bortezomib; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005978:Glutathione / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D009363:Neoplasm Proteins / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C497109:ATF4 protein, human; D000970:Antineoplastic Agents; D000975:Antioxidants; D001897:Boronic Acids; C497249:DDIT3 protein, human; D009363:Neoplasm Proteins; D011480:Protease Inhibitors; D011719:Pyrazines; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D000069286:Bortezomib; D005978:Glutathione; D000111:Acetylcysteine