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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 Apoptosis Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 June 2002, Vol. 99, No. 12, pp. 4525-4530 NEOPLASIA Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications Nicholas Mitsiades, Constantine S. Mitsiades, Vassiliki Poulaki, Dharminder Chauhan, Paul G. Richardson, Teru Hideshima, Nikhil C. Munshi, Steven P. Treon, and Kenneth C. Anderson From the Department of Adult Oncology, Dana-Farber Cancer Institute, the Department of Medicine, Harvard Medical School, and the Retina Research Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA. 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)-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-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. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. S. Mitsiades, E. M. Ocio, A. Pandiella, P. Maiso, C. Gajate, M. 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Preclinical Antilymphoma Activity of a Humanized Anti-CD40 Monoclonal Antibody, SGN-40 Cancer Res., September 15, 2005; 65(18): 8331 - 8338. [Abstract] [Full Text] [PDF] T. Hideshima, D. Chauhan, P. Richardson, and K. C. Anderson Identification and Validation of Novel Therapeutic Targets for Multiple Myeloma J. Clin. Oncol., September 10, 2005; 23(26): 6345 - 6350. [Abstract] [Full Text] [PDF] H. Yasui, T. Hideshima, N. Raje, A. M. Roccaro, N. Shiraishi, S. Kumar, M. Hamasaki, K. Ishitsuka, Y.-T. Tai, K. Podar, et al. FTY720 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Drug Resistance Cancer Res., August 15, 2005; 65(16): 7478 - 7484. [Abstract] [Full Text] [PDF] T. Nakazato, K. Ito, Y. Ikeda, and M. Kizaki Green Tea Component, Catechin, Induces Apoptosis of Human Malignant B Cells via Production of Reactive Oxygen Species Clin. Cancer Res., August 15, 2005; 11(16): 6040 - 6049. [Abstract] [Full Text] [PDF] A. Vacca, C. Scavelli, V. Montefusco, G. Di Pietro, A. Neri, M. Mattioli, S. Bicciato, B. Nico, D. Ribatti, F. Dammacco, et al. Thalidomide Downregulates Angiogenic Genes in Bone Marrow Endothelial Cells of Patients With Active Multiple Myeloma J. Clin. Oncol., August 10, 2005; 23(23): 5334 - 5346. [Abstract] [Full Text] [PDF] M. Hamasaki, T. Hideshima, P. Tassone, P. Neri, K. Ishitsuka, H. Yasui, N. Shiraishi, N. Raje, S. Kumar, D. H. Picker, et al. Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine) inhibits human multiple myeloma cell growth in the bone marrow milieu in vitro and in vivo Blood, June 1, 2005; 105(11): 4470 - 4476. [Abstract] [Full Text] [PDF] R. Z. Orlowski The Ubiquitin Proteasome Pathway from Bench to Bedside Hematology, January 1, 2005; 2005(1): 220 - 225. [Abstract] [Full Text] [PDF] R. A. Kyle and S. V. Rajkumar Multiple Myeloma N. Engl. J. Med., October 28, 2004; 351(18): 1860 - 1873. [Full Text] [PDF] V. Poulaki, A. M. Joussen, N. Mitsiades, C. S. Mitsiades, E. F. Iliaki, and A. P. Adamis Insulin-Like Growth Factor-I Plays a Pathogenetic Role in Diabetic Retinopathy Am. J. Pathol., August 1, 2004; 165(2): 457 - 469. [Abstract] [Full Text] [PDF] T. Hideshima, P. L. Bergsagel, W. M. Kuehl, and K. C. Anderson Advances in biology of multiple myeloma: clinical applications Blood, August 1, 2004; 104(3): 607 - 618. [Abstract] [Full Text] [PDF] Y.-T. Tai, L. P. Catley, C. S. Mitsiades, R. Burger, K. Podar, R. Shringpaure, T. Hideshima, D. Chauhan, M. Hamasaki, K. Ishitsuka, et al. Mechanisms by which SGN-40, a Humanized Anti-CD40 Antibody, Induces Cytotoxicity in Human Multiple Myeloma Cells: Clinical Implications Cancer Res., April 15, 2004; 64(8): 2846 - 2852. [Abstract] [Full Text] [PDF] K. C. Anderson Proteasome inhibitor therapy of multiple myeloma. AACR Meeting Abstracts, March 1, 2004; 2004(1): 1316 - 1316. [Abstract] R. LeBlanc, T. Hideshima, L. P. Catley, R. Shringarpure, R. Burger, N. Mitsiades, C. Mitsiades, P. Cheema, D. Chauhan, P. G. Richardson, et al. 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Phase II Study of SU5416, a Small Molecule Vascular Endothelial Growth Factor Tyrosine Kinase Receptor Inhibitor, in Patients with Refractory Multiple Myeloma Clin. Cancer Res., January 1, 2004; 10(1): 88 - 95. [Abstract] [Full Text] [PDF] 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] M. A. Dimopoulos, A. Anagnostopoulos, and D. Weber Treatment of Plasma Cell Dyscrasias With Thalidomide and Its Derivatives J. Clin. Oncol., December 1, 2003; 21(23): 4444 - 4454. [Abstract] [Full Text] [PDF] V. Poulaki, C. S. Mitsiades, C. McMullan, D. Sykoutri, G. Fanourakis, V. Kotoula, S. Tseleni-Balafouta, D. A. Koutras, and N. 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