title: Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications.
abstract: Thalidomide (Thal) achieves responses even in the setting of refractory multiple myeloma (MM). Although increased angiogenesis in MM bone marrow and the antiangiogenic effect of Thal formed the empiric basis for its use in MM, we have shown that Thal and its immunomodulatory analogs (IMiDs) directly induce apoptosis or growth arrest of MM cells, alter adhesion of MM cells to bone marrow stromal cells, inhibit the production of cytokines (interleukin-6 and vascular endothelial growth factor) in bone marrow, and stimulate natural killer cell anti-MM immunity. In the present study, we demonstrate that the IMiDs trigger activation of caspase-8, enhance MM cell sensitivity to Fas-induced apoptosis, and down-regulate nuclear factor (NF)-kappa B activity as well as expression of cellular inhibitor of apoptosis protein-2 and FLICE inhibitory protein. IMiDs also block the stimulatory effect of insulinlike growth factor-1 on NF-kappa B activity and potentiate the activity of TNF-related apoptosis-inducing ligand (TRAIL/Apo2L), dexamethasone, and proteasome inhibitor (PS-341) therapy. These studies both delineate the mechanism of action of IMiDs against MM cells in vitro and form the basis for clinical trials of these agents, alone and coupled with conventional and other novel therapies, to improve outcome in MM.
authors.affiliation: Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitsiades
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Poulaki
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.forename: Steven P
authors.initials: SP
authors.lastname: Treon
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D008024:Ligands; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000276:Adjuvants, Immunologic; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D008024:Ligands; D016328:NF-kappa B; D013792:Thalidomide; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases