Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications.
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.
Mitsiades
Nicholas
N
Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Mitsiades
Constantine S
CS
Poulaki
Vassiliki
V
Chauhan
Dharminder
D
Richardson
Paul G
PG
Hideshima
Teru
T
Munshi
Nikhil C
NC
Treon
Steven P
SP
Anderson
Kenneth C
KC
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
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