title: Targeting the microtubular network as a new antimyeloma strategy.
abstract: We identified nocodazole as a potent antimyeloma drug from a drug screening library provided by the Multiple Myeloma Research Foundation. Nocodazole is a benzimidazole that was originally categorized as a broad-spectrum anthelmintic drug with antineoplastic properties. We found that nocodazole inhibited growth and induced apoptosis of primary and multiresistant multiple myeloma cells cultured alone and in the presence of bone marrow stromal cells. Nocodazole caused cell-cycle prophase and prometaphase arrest accompanied by microtubular network disarray. Signaling studies indicated that increased expression of Bim protein and reduced X-linked inhibitor of apoptosis protein and Mcl-1(L) levels were involved in nocodazole-induced apoptosis. Further investigation showed Bcl-2 phosphorylation as a critical mediator of cell death, triggered by the activation of c-jun-NH(2) kinase (JNK) instead of p38 kinase or extracellular signal-regulated kinases. Treatment with JNK inhibitor decreased Bcl-2 phosphorylation and subsequently reduced nocodazole-induced cell death. Nocodazole combined with dexamethasone significantly inhibited myeloma tumor growth and prolonged survival in a human xenograft mouse model. Our studies show that nocodazole has potent antimyeloma activity and that targeting the microtubular network might be a promising new treatment approach for multiple myeloma.
authors.affiliation: Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA.
authors.forename: Rentian
authors.initials: R
authors.lastname: Feng
authors.forename: Shirong
authors.initials: S
authors.lastname: Li
authors.forename: Caisheng
authors.initials: C
authors.lastname: Lu
authors.forename: Carrie
authors.initials: C
authors.lastname: Andreas
authors.forename: Donna B
authors.initials: DB
authors.lastname: Stolz
authors.forename: Markus Y
authors.initials: MY
authors.lastname: Mapara
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lentzsch
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008870:Microtubules / Q000187:drug effects*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D015739:Nocodazole / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011897:Random Allocation; D050257:Tubulin Modulators / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D050257:Tubulin Modulators; D003907:Dexamethasone; D048670:MAP Kinase Kinase 4; D015739:Nocodazole