Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341

• Published in: Blood Vol. 101; no. 4; pp. 1530 - 1534
• Main Authors: Hideshima, Teru, Mitsiades, Constantine, Akiyama, Masaharu, Hayashi, Toshiaki, Chauhan, Dharminder, Richardson, Paul, Schlossman, Robert, Podar, Klaus, Munshi, Nikhil C., Mitsiades, Nicholas, Anderson, Kenneth C.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.02.2003; The Americain Society of Hematology
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacology; Ataxia Telangiectasia Mutated Proteins; Biological and medical sciences; Boronic Acids - pharmacology; Boronic Acids - therapeutic use; Bortezomib; Caspase 3; Caspase 8; Caspase 9; Caspases - metabolism; Cell Cycle Proteins; Cell Death - drug effects; DNA-Activated Protein Kinase; DNA-Binding Proteins; Enzyme Activation - drug effects; Gene Expression - drug effects; General aspects; Hematologic and hematopoietic diseases; Humans; JNK Mitogen-Activated Protein Kinases; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; MAP Kinase Kinase 4; Medical sciences; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - metabolism; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Nuclear Proteins; Pharmacology. Drug treatments; Phosphorylation; Phosphoserine - metabolism; Protease Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-mdm2; Pyrazines - pharmacology; Pyrazines - therapeutic use; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins; Antineoplastic agent; Human; Immunopathology; Multicatalytic endopeptidase complex; Multiple; Enzyme; Malignant hemopathy; Myeloma; In vitro; Biological activity; Peptidases; Chemotherapy; Immunoglobulinopathy; Enzymatic activity; Lymphoproliferative syndrome; Established cell line; Hydrolases; Inhibitor
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2002-08-2543

We have recently shown that proteasome inhibitor PS-341 induces apoptosis in drug-resistant multiple myeloma (MM) cells, inhibits binding of MM cells in the bone marrow microenvironment, and inhibits cytokines mediating MM cell growth, survival, drug resistance, and migration in vitro. PS-341 also inhibits human MM cell growth and prolongs survival in a SCID mouse model. Importantly, PS-341 has achieved remarkable clinical responses in patients with refractory relapsed MM. We here demonstrate molecular mechanisms whereby PS-341 mediates anti-MM activity by inducing p53 and MDM2 protein expression; inducing the phosphorylation (Ser15) of p53 protein; activating c-Jun NH2-terminal kinase (JNK), caspase-8, and caspase-3; and cleaving the DNA protein kinase catalytic subunit, ATM, and MDM2. Inhibition of JNK activity abrogates PS-341–induced MM cell death. These studies identify molecular targets of PS-341 and provide the rationale for the development of second-generation, more targeted therapies.