Redox homeostasis modulates the sensitivity of myeloma cells to bortezomib

• Published in: British journal of haematology Vol. 141; no. 4; pp. 494 - 503
• Main Authors: Nerini‐Molteni, Silvia, Ferrarini, Marina, Cozza, Sara, Caligaris‐Cappio, Federico, Sitia, Roberto
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.05.2008; Blackwell
• Subjects: Acetylcysteine - pharmacology; Activating Transcription Factor 4 - metabolism; Antineoplastic Agents - pharmacology; Antioxidants - pharmacology; Biological and medical sciences; Boronic Acids - antagonists & inhibitors; Boronic Acids - pharmacology; Bortezomib; Cell Death - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; glutathione; Glutathione - metabolism; Hematologic and hematopoietic diseases; Homeostasis - drug effects; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; multiple myeloma; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Neoplasm Proteins - metabolism; Nrf2; Oxidation-Reduction - drug effects; Protease Inhibitors - pharmacology; proteasome inhibitors; Pyrazines - antagonists & inhibitors; Pyrazines - pharmacology; redox homeostasis; Transcription Factor CHOP - metabolism; Tumor Cells, Cultured; Antineoplastic agent; Immunopathology; multiple myeloma; Bortezomib; Hematology; Homeostasis; B cell neoplasm; proteasome inhibitors; Malignant hemopathy; redox homeostasis; Lymphoid neoplasm; Myeloma; Sensitivity; Immunoglobulinopathy; Nrf2; Analog; Lymphoproliferative syndrome; Proteasome inhibitor; Dipeptides; Cancer; Glutathione
• ISSN: 0007-1048; 1365-2141; 1365-2141
• DOI: 10.1111/j.1365-2141.2008.07066.x

Summary 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 eIF2α‐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.