Biologic sequelae of nuclear factor-kappaB blockade in multiple myeloma: therapeutic applications.

Abstract

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.

• Authors: Nicholas Mitsiades, Constantine S Mitsiades, Vassiliki Poulaki, Dharminder Chauhan, Paul G Richardson, Teru Hideshima, Nikhil Munshi, Steven P Treon, Kenneth C Anderson
• Journal: Blood (Blood) Vol. 99 Issue 11 Pg. 4079-86 (Jun 01 2002) ISSN: 0006-4971 [Print] United States
• PMID: 12010810 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cytochrome c Group
• Enzyme Inhibitors
• Imidazoles
• NF-kappa B
• Peptides
• SN50 peptide
• Poly(ADP-ribose) Polymerases
• Caspases
• 2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole

Topics

• Apoptosis (drug effects)
• Caspases (metabolism)
• Cell Nucleus (physiology)
• Cell Survival (drug effects)
• Cytochrome c Group (metabolism)
• Enzyme Inhibitors (pharmacology)
• Humans
• Imidazoles (pharmacology)
• Multiple Myeloma (drug therapy, pathology, physiopathology)
• NF-kappa B (antagonists & inhibitors)
• Peptides (pharmacology)
• Poly(ADP-ribose) Polymerases (metabolism)
• Tumor Cells, Cultured