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Blood, 1 February 2007, Vol. 109, No. 3, pp. 1220-1227. Prepublished online as a Blood First Edition Paper on October 10, 2006; DOI 10.1182/blood-2006-04-015149. This Article Full Text (PDF) All Versions of this Article: blood-2006-04-015149v1 109/3/1220    most recent Alert me when this article is cited Alert me if a correction is posted 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 Chauhan, D. Articles by Anderson, K. C. Search for Related Content PubMed PubMed Citation Articles by Chauhan, D. Articles by Anderson, K. C. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 5, 2006 Accepted August 23, 2006 Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM) Dharminder Chauhan, Paola Neri, Mugdha Velankar, Klaus Podar, Teru Hideshima, Mariateresa Fulciniti, Pierfrancesco Tassone, Noopur Raje, Constantine S. Mitsiades, Nicholas Mitsiades, Paul G. Richardson, Leigh Zawel, Mary Tran, Nikhil C. Munshi, and Kenneth C. Anderson* Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA Novartis Institute of Biomedical Research, Cambridge, MA, USA * Corresponding author; email: kenneth_anderson{at}dfci.harvard.edu. Second mitochondria-derived activator of caspases (Smac) promotes apoptosis via activation of caspases. Here we show that a low molecular weight Smac mimetic LBW242 induces apoptosis in multiple myeloma (MM) cells resistant to conventional and Bortezomib therapies. Examination of purified patient MM cells demonstrated similar results, without significant cytotoxicity against normal lymphocytes and bone marrow stromal (BMSCs) cells. Importantly, LBW242 abrogates paracrine MM cell growth triggered by their adherence to BMSCs and overcomes MM cell growth and drug-resistance conferred by interleukin-6 or insulin-like growth factor-1. Overexpression of Bcl-2 similarly does not affect LBW242-induced cytotoxicity. Mechanistic studies show that LBW242-induced apoptosis in MM cells is associated with activation of caspase-8, caspase-9 and caspase-3, followed by PARP cleavage. In human MM xenograft mouse models, LBW242 is well tolerated, inhibits tumor growth, and prolongs survival. Importantly, combining LBW242 with novel agents including Tumor necrosis factor-related apoptosis inducing ligand (TRAIL), or proteasome inhibitors Bortezomib and NPI-0052; as well as with conventional anti-MM agents melphalan or dexamethasone induces additive/synergistic anti-MM activity. Our study therefore provides the rationale for clinical protocols evaluating LBW242, alone and together with other anti-MM agents, to improve patient outcome in MM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Loeder, T. Zenz, A. Schnaiter, D. Mertens, D. Winkler, H. Dohner, K.-M. Debatin, S. Stilgenbauer, and S. Fulda A Novel Paradigm to Trigger Apoptosis in Chronic Lymphocytic Leukemia Cancer Res., December 1, 2009; 69(23): 8977 - 8986. [Abstract] [Full Text] [PDF] A. M. Roccaro, A. Sacco, B. Thompson, X. Leleu, A. K. Azab, F. Azab, J. Runnels, X. Jia, H. T. Ngo, M. R. Melhem, et al. MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma Blood, June 25, 2009; 113(26): 6669 - 6680. [Abstract] [Full Text] [PDF] M. Vogler, H. Walczak, D. Stadel, T. L. Haas, F. Genze, M. Jovanovic, U. Bhanot, C. Hasel, P. Moller, J. E. Gschwend, et al. Small Molecule XIAP Inhibitors Enhance TRAIL-Induced Apoptosis and Antitumor Activity in Preclinical Models of Pancreatic Carcinoma Cancer Res., March 15, 2009; 69(6): 2425 - 2434. [Abstract] [Full Text] [PDF] G. Desplanques, N. Giuliani, R. Delsignore, V. Rizzoli, R. Bataille, and S. Barille-Nion Impact of XIAP protein levels on the survival of myeloma cells Haematologica, January 1, 2009; 94(1): 87 - 93. [Abstract] [Full Text] [PDF] J. Lu, L. Bai, H. Sun, Z. Nikolovska-Coleska, D. McEachern, S. Qiu, R. S. Miller, H. Yi, S. Shangary, Y. Sun, et al. SM-164: A Novel, Bivalent Smac Mimetic That Induces Apoptosis and Tumor Regression by Concurrent Removal of the Blockade of cIAP-1/2 and XIAP Cancer Res., November 15, 2008; 68(22): 9384 - 9393. [Abstract] [Full Text] [PDF] C. S. Mitsiades, E. M. Ocio, A. Pandiella, P. Maiso, C. Gajate, M. Garayoa, D. Vilanova, J. C. Montero, N. Mitsiades, C. J. McMullan, et al. Aplidin, a Marine Organism-Derived Compound with Potent Antimyeloma Activity In vitro and In vivo Cancer Res., July 1, 2008; 68(13): 5216 - 5225. [Abstract] [Full Text] [PDF] A. Gaither, D. Porter, Y. Yao, J. Borawski, G. Yang, J. Donovan, D. Sage, J. Slisz, M. Tran, C. Straub, et al. A Smac Mimetic Rescue Screen Reveals Roles for Inhibitor of Apoptosis Proteins in Tumor Necrosis Factor-{alpha} Signaling Cancer Res., December 15, 2007; 67(24): 11493 - 11498. [Abstract] [Full Text] [PDF] D. Vucic and W. J. Fairbrother The Inhibitor of Apoptosis Proteins as Therapeutic Targets in Cancer Clin. Cancer Res., October 15, 2007; 13(20): 5995 - 6000. [Abstract] [Full Text] [PDF] E. Weisberg, A. L. Kung, R. D. Wright, D. Moreno, L. Catley, A. Ray, L. Zawel, M. Tran, J. Cools, G. Gilliland, et al. Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells Mol. Cancer Ther., July 1, 2007; 6(7): 1951 - 1961. [Abstract] [Full Text] [PDF]

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