title: Sustained activation of c-jun-N-terminal kinase plays a critical role in arsenic trioxide-induced cell apoptosis in multiple myeloma cell lines.
abstract: Multiple myeloma (MM) is a presently incurable B-cell malignancy, and newer biologically based therapies are needed. Arsenic trioxide (ATO) has been established as a therapeutic agent for relapsed acute promyelocytic leukemia patients, and has been used for MM patients in clinical trials. In this study, we investigated the role of c-jun-N-terminal kinase (JNK) in ATO-induced apoptosis in MM lines. The exogenous interleukin (IL)-6 dependent MM line, ILKM-3, and independent MM lines, U266 and XG-7, were treated with a therapeutic concentration of ATO with or without JNK inhibitor 1 (a JNK-specific inhibitor) and anisomycin (a JNK activator). Their cell growth, cell cycle, JNK activation and NF-kappaB activation were investigated. ATO induced apoptosis in U266 and ILKM-3 regardless of their exogenous IL-6 dependency. This apoptosis, accompanied with decreased mitochondrial transmembrane potential, sustained activation of JNK but not cell cycle arrest. Pretreatment of JNK inhibitor prevented ATO-induced apoptosis in ATO-sensitive lines. Combined treatment with ATO and anisomycin induced sustained activation of JNK and apoptosis in the ATO-insensitive MM line, XG-7. Results of various time period treatments of ATO showed that sustained activation of JNK was needed in ATO-induced apoptosis in MM. IkBalpha phosphorylation was not associated with ATO-sensitivity of MM lines. These findings suggest that sustained activation of JNK plays a critical role in ATO-induced apoptosis in MM cell lines. Cotreatment with ATO and the agent, which can induce sustained activation of JNK, might improve the outcome in MM therapy.
authors.affiliation: Department of Hematology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan. kajiguct@mail.nih.gov
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kajiguchi
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Iida
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Ueda
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Emi
authors.forename: Tomoki
authors.initials: T
authors.lastname: Naoe
mesh_terms: D000841:Anisomycin / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D010087:Oxides / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D004791:Enzyme Inhibitors; D010087:Oxides; D011500:Protein Synthesis Inhibitors; D000841:Anisomycin; D048031:JNK Mitogen-Activated Protein Kinases; D000077237:Arsenic Trioxide