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Blood, 1 June 2002, Vol. 99, No. 11, pp. 4079-4086

NEOPLASIA

Biologic sequelae of nuclear factor-kappa 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-kappa B (NF-kappa 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-kappa B activity as part of their diverse actions. However, studies to date have not delineated the effects of specific inhibition of NF-kappa B activity in MM. We therefore investigated the effect of SN50, a cell-permeable specific inhibitor of NF-kappa 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-alpha (TNF-alpha ) is present locally in the bone marrow microenvironment and induces NF-kappa B-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-kappa B 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-kappa 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-kappa B pathways. Our results therefore demonstrate that NF-kappa B activity in MM cells promotes tumor-cell survival and protects against apoptotic stimuli. These studies provide the framework for targeting NF-kappa B activity in novel biologically based therapies for MM.

© 2002 by The American Society of Hematology.
 

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T. Hideshima, D. Chauhan, T. Hayashi, K. Podar, M. Akiyama, C. Mitsiades, N. MItsiades, B. Gong, L. Bonham, P. de Vries, et al.
Antitumor Activity of Lysophosphatidic Acid Acyltransferase-{beta} Inhibitors, a Novel Class of Agents, in Multiple Myeloma
Cancer Res., December 1, 2003; 63(23): 8428 - 8436.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
V. Poulaki, C. S. Mitsiades, C. McMullan, D. Sykoutri, G. Fanourakis, V. Kotoula, S. Tseleni-Balafouta, D. A. Koutras, and N. Mitsiades
Regulation of Vascular Endothelial Growth Factor Expression by Insulin-Like Growth Factor I in Thyroid Carcinomas
J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5392 - 5398.
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Cancer Res.Home page
C. S. Mitsiades, N. S. Mitsiades, R. T. Bronson, D. Chauhan, N. Munshi, S. P. Treon, C. A. Maxwell, L. Pilarski, T. Hideshima, R. M. Hoffman, et al.
Fluorescence Imaging of Multiple Myeloma Cells in a Clinically Relevant SCID/NOD in Vivo Model: Biologic and Clinical Implications
Cancer Res., October 15, 2003; 63(20): 6689 - 6696.
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Clin. Cancer Res.Home page
J. C. Pahler, S. Ruiz, I. Niemer, L. R. Calvert, M. Andreeff, M. Keating, S. Faderl, and D. J. McConkey
Effects of the Proteasome Inhibitor, Bortezomib, on Apoptosis in Isolated Lymphocytes Obtained from Patients with Chronic Lymphocytic Leukemia
Clin. Cancer Res., October 1, 2003; 9(12): 4570 - 4577.
[Abstract] [Full Text] [PDF]


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NEJMHome page
P. G. Richardson, B. Barlogie, J. Berenson, S. Singhal, S. Jagannath, D. Irwin, S. V. Rajkumar, G. Srkalovic, M. Alsina, R. Alexanian, et al.
A Phase 2 Study of Bortezomib in Relapsed, Refractory Myeloma
N. Engl. J. Med., June 26, 2003; 348(26): 2609 - 2617.
[Abstract] [Full Text] [PDF]


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Cancer Res.Home page
L. F. Zerbini, Y. Wang, J.-Y. Cho, and T. A Libermann
Constitutive Activation of Nuclear Factor {kappa}B p50/p65 and Fra-1 and JunD Is Essential for Deregulated Interleukin 6 Expression in Prostate Cancer
Cancer Res., May 1, 2003; 63(9): 2206 - 2215.
[Abstract] [Full Text] [PDF]


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BloodHome page
Y.-T. Tai, K. Podar, N. Mitsiades, B. Lin, C. Mitsiades, D. Gupta, M. Akiyama, L. Catley, T. Hideshima, N. C. Munshi, et al.
CD40 induces human multiple myeloma cell migration via phosphatidylinositol 3-kinase/AKT/NF-kappa B signaling
Blood, April 1, 2003; 101(7): 2762 - 2769.
[Abstract] [Full Text] [PDF]


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BloodHome page
S. K. Ghosh, C. Wood, L. H. Boise, A. M. Mian, V. V. Deyev, G. Feuer, N. L. Toomey, N. C. Shank, L. Cabral, G. N. Barber, et al.
Potentiation of TRAIL-induced apoptosis in primary effusion lymphoma through azidothymidine-mediated inhibition of NF-kappa B
Blood, March 15, 2003; 101(6): 2321 - 2327.
[Abstract] [Full Text] [PDF]


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BloodHome page
N. Mitsiades, C. S. Mitsiades, P. G. Richardson, V. Poulaki, Y.-T. Tai, D. Chauhan, G. Fanourakis, X. Gu, C. Bailey, M. Joseph, et al.
The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications
Blood, March 15, 2003; 101(6): 2377 - 2380.
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Clin. Cancer Res.Home page
F. Ravandi, M. Talpaz, and Z. Estrov
Modulation of Cellular Signaling Pathways: Prospects for Targeted Therapy in Hematological Malignancies
Clin. Cancer Res., February 1, 2003; 9(2): 535 - 550.
[Abstract] [Full Text] [PDF]


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BloodHome page
J. F. Garcia, F. I. Camacho, M. Morente, M. Fraga, C. Montalban, T. A. C. Bellas, A. Castano, A. Diez, T. Flores, C. Martin, et al.
Hodgkin and Reed-Sternberg cells harbor alterations in the major tumor suppressor pathways and cell-cycle checkpoints: analyses using tissue microarrays
Blood, January 15, 2003; 101(2): 681 - 689.
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Cancer Res.Home page
M. Akiyama, T. Hideshima, T. Hayashi, Y.-T. Tai, C. S. Mitsiades, N. Mitsiades, D. Chauhan, P. Richardson, N. C. Munshi, and K. C. Anderson
Nuclear Factor-{kappa}B p65 Mediates Tumor Necrosis Factor {alpha}-induced Nuclear Translocation of Telomerase Reverse Transcriptase Protein
Cancer Res., January 1, 2003; 63(1): 18 - 21.
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J. Immunol.Home page
J. Ursini-Siegel, W. Zhang, A. Altmeyer, E. N. Hatada, R. K. G. Do, H. Yagita, and S. Chen-Kiang
TRAIL/Apo-2 Ligand Induces Primary Plasma Cell Apoptosis
J. Immunol., November 15, 2002; 169(10): 5505 - 5513.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
N. Mitsiades, C. S. Mitsiades, V. Poulaki, D. Chauhan, G. Fanourakis, X. Gu, C. Bailey, M. Joseph, T. A. Libermann, S. P. Treon, et al.
Molecular sequelae of proteasome inhibition in human multiple myeloma cells
PNAS, October 29, 2002; 99(22): 14374 - 14379.
[Abstract] [Full Text] [PDF]


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Mol. Pathol.Home page
G Pratt
Molecular aspects of multiple myeloma
Mol. Pathol., October 1, 2002; 55(5): 273 - 283.
[Abstract] [Full Text] [PDF]


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Cancer Res.Home page
R. LeBlanc, L. P. Catley, T. Hideshima, S. Lentzsch, C. S. Mitsiades, N. Mitsiades, D. Neuberg, O. Goloubeva, C. S. Pien, J. Adams, et al.
Proteasome Inhibitor PS-341 Inhibits Human Myeloma Cell Growth in Vivo and Prolongs Survival in a Murine Model
Cancer Res., September 1, 2002; 62(17): 4996 - 5000.
[Abstract] [Full Text] [PDF]



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