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This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mitsiades, N. Articles by Anderson, K. C. Search for Related Content PubMed PubMed Citation Articles by Mitsiades, N. Articles by Anderson, K. C. Related Collections Neoplasia Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 June 2002, Vol. 99, No. 11, pp. 4079-4086 NEOPLASIA Biologic sequelae of nuclear factor-B blockade in multiple myeloma: therapeutic applications Nicholas Mitsiades, Constantine S. Mitsiades, Vassiliki Poulaki, Dharminder Chauhan, Paul G. Richardson, Teru Hideshima, Nikhil Munshi, Steven P. Treon, and Kenneth C. Anderson From the Department of Adult Oncology, Dana Farber Cancer Institute, Harvard Medical School; the Department of Medicine, Harvard Medical School; and the Retina Research Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA. The transcription factor nuclear factor-B (NF-B) 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-B activity as part of their diverse actions. However, studies to date have not delineated the effects of specific inhibition of NF-B activity in MM. We therefore investigated the effect of SN50, a cell-permeable specific inhibitor of NF-B 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- (TNF-) is present locally in the bone marrow microenvironment and induces NF-B-dependent up-regulation of adhesion molecules on both MM cells and bone marrow stromal cells, with resultant increased adhesion. In this study, TNF- alone induced NF-B nuclear translocation, cIAP-1 and cIAP-2 up-regulation, and MM cell proliferation; in contrast, SN50 pretreatment sensitized MM cells to TNF--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- family member TNF-related apoptosis-inducing ligand (TRAIL)/Apo2L. Moreover, SN50 inhibited TNF--induced expression of another NF-B 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-B pathways. Our results therefore demonstrate that NF-B activity in MM cells promotes tumor-cell survival and protects against apoptotic stimuli. 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