Biologic sequelae of nuclear factor-kappaB blockade in multiple myeloma: therapeutic applications.
The transcription factor nuclear factor-kappaB (NF-kappaB) confers significant survival potential in a variety of tumors. Several established or novel anti-multiple myeloma (anti-MM) agents, such as dexamethasone, thalidomide, and proteasome inhibitors (PS-341), inhibit NF-kappaB activity as part of their diverse actions. However, studies to date have not delineated the effects of specific inhibition of NF-kappaB activity in MM. We therefore investigated the effect of SN50, a cell-permeable specific inhibitor of NF-kappaB nuclear translocation and activity, on MM cells. SN50 induced apoptosis in MM cell lines and patient cells; down-regulated expression of Bcl-2, A1, X-chromosome-linked inhibitor-of-apoptosis protein (XIAP), cellular inhibitor-of-apoptosis protein 1 (cIAP-1), cIAP-2, and survivin; up-regulated Bax; increased mitochondrial cytochrome c release into the cytoplasm; and activated caspase-9 and caspase-3, but not caspase-8. We have previously demonstrated that tumor necrosis factor-alpha (TNF-alpha) is present locally in the bone marrow microenvironment and induces NF-kappaB-dependent up-regulation of adhesion molecules on both MM cells and bone marrow stromal cells, with resultant increased adhesion. In this study, TNF-alpha alone induced NF-kappaB nuclear translocation, cIAP-1 and cIAP-2 up-regulation, and MM cell proliferation; in contrast, SN50 pretreatment sensitized MM cells to TNF-alpha-induced apoptosis and cleavage of caspase-8 and caspase-3, similar to our previous finding of SN50-induced sensitization to apoptosis induced by the TNF-alpha family member TNF-related apoptosis-inducing ligand (TRAIL)/Apo2L. Moreover, SN50 inhibited TNF-alpha-induced expression of another NF-kappaB target gene, intercellular adhesion molecule-1. Although the p38 inhibitor PD169316 did not directly kill MM cells, it potentiated the apoptotic effect of SN50, suggesting an interaction between the p38 and NF-kappaB pathways. Our results therefore demonstrate that NF-kappaB activity in MM cells promotes tumor-cell survival and protects against apoptotic stimuli. These studies provide the framework for targeting NF-kappaB activity in novel biologically based therapies for 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
N
Treon
Steven P
SP
Anderson
Kenneth C
KC
D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D003574:Cytochrome c Group / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010455:Peptides / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014407:Tumor Cells, Cultured
D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D007093:Imidazoles; D016328:NF-kappa B; D010455:Peptides; C118258:SN50 peptide; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; C408604:2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole