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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1654-1664. Prepublished online as a Blood First Edition Paper on November 15, 2007; DOI 10.1182/blood-2007-08-105601. This Article Full Text (PDF) All Versions of this Article: blood-2007-08-105601v1 111/3/1654    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 August 6, 2007 Accepted November 9, 2007 Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma Dharminder Chauhan*, Ajita Singh, Mohan Brahmandam, Klaus Podar, Teru Hideshima, Paul Richardson, Nikhil Munshi, Michael A. Palladino, and Kenneth C. Anderson Department of Medical Oncology, the LeBow Institute for Myeloma Therapeutics, and Jerome Lipper Center for Myeloma Research, Dana Farber Cancer Institute, Boston, MA, United States Nereus Pharmaceuticals, San Diego, CA, United States * Corresponding author; email: dharminder_chauhan{at}dfci.harvard.edu. Our recent study demonstrated that a novel proteasome inhibitor NPI-0052 triggers apoptosis in multiple myeloma (MM) cells; and importantly, is distinct from bortezomib (VelcadeTM) in its chemical structure, effects on proteasome activities, and mechanisms of action. Here, we demonstrate that combining NPI-0052 and bortezomb induces synergistic anti-MM activity both in vitro using MM cell lines or patient CD138+ MM cells and in vivo in a human plasmacytoma xenograft mouse model. NPI-0052 + bortezomib-induced synergistic apoptosis is associated with: 1) activation of caspase-8, caspase-9, caspase-3, and PARP; 2) induction of ER-stress response and JNK; 3) inhibition of migration of MM cells and angiogenesis; 4) suppression of chymotrypsin-like (CT-L), caspase-like (C-L) and trypsin-like (T-L) proteolytic activities; and 5) blockade of NF-B signaling. Studies in a xenograft model show that low dose combinations of NPI-0052 and bortezomib is well tolerated, triggers synergistic inhibition of tumor growth, and CT-L, C-L and T-L proteasome activities in tumor cells. Immununostaining of MM tumors from NPI-0052 + bortezomib-treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Taken together, our study provides the preclinical rationale for clinical protocols evaluating bortezomib together with NPI-0052 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: D. Malhotra, R. Thimmulappa, N. Vij, A. Navas-Acien, T. Sussan, S. Merali, L. Zhang, S. G. Kelsen, A. Myers, R. Wise, et al. Heightened Endoplasmic Reticulum Stress in the Lungs of Patients with Chronic Obstructive Pulmonary Disease: The Role of Nrf2-Regulated Proteasomal Activity Am. J. Respir. Crit. Care Med., December 15, 2009; 180(12): 1196 - 1207. [Abstract] [Full Text] [PDF] S. Baritaki, K. Yeung, M. Palladino, J. Berenson, and B. Bonavida Pivotal Roles of Snail Inhibition and RKIP Induction by the Proteasome Inhibitor NPI-0052 in Tumor Cell Chemoimmunosensitization Cancer Res., November 1, 2009; 69(21): 8376 - 8385. [Abstract] [Full Text] [PDF] F. Parlati, S. J. Lee, M. Aujay, E. Suzuki, K. Levitsky, J. B. Lorens, D. R. Micklem, P. Ruurs, C. Sylvain, Y. Lu, et al. Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome Blood, October 15, 2009; 114(16): 3439 - 3447. [Abstract] [Full Text] [PDF] T. Hideshima, H. Ikeda, D. Chauhan, Y. Okawa, N. Raje, K. Podar, C. Mitsiades, N. C. Munshi, P. G. Richardson, R. D. Carrasco, et al. Bortezomib induces canonical nuclear factor-{kappa}B activation in multiple myeloma cells Blood, July 30, 2009; 114(5): 1046 - 1052. [Abstract] [Full Text] [PDF] R. E. Tiedemann, J. Schmidt, J. J. Keats, C.-X. Shi, Y. X. Zhu, S. E. Palmer, X. Mao, A. D. Schimmer, and A. K. Stewart Identification of a potent natural triterpenoid inhibitor of proteosome chymotrypsin-like activity and NF-{kappa}B with antimyeloma activity in vitro and in vivo Blood, April 23, 2009; 113(17): 4027 - 4037. [Abstract] [Full Text] [PDF] U. VALENTINER, C. HAANE, N. NEHMANN, and U. SCHUMACHER Effects of Bortezomib on Human Neuroblastoma Cells In Vitro and in a Metastatic Xenograft Model Anticancer Res, April 1, 2009; 29(4): 1219 - 1225. [Abstract] [Full Text] [PDF] D. M. Schewe and J. A. Aguirre-Ghiso Inhibition of eIF2{alpha} Dephosphorylation Maximizes Bortezomib Efficiency and Eliminates Quiescent Multiple Myeloma Cells Surviving Proteasome Inhibitor Therapy Cancer Res., February 15, 2009; 69(4): 1545 - 1552. [Abstract] [Full Text] [PDF] G. Pagnan, D. Di Paolo, R. Carosio, F. Pastorino, D. Marimpietri, C. Brignole, A. Pezzolo, M. Loi, L. J.V. Galietta, F. Piccardi, et al. The Combined Therapeutic Effects of Bortezomib and Fenretinide on Neuroblastoma Cells Involve Endoplasmic Reticulum Stress Response Clin. Cancer Res., February 15, 2009; 15(4): 1199 - 1209. [Abstract] [Full Text] [PDF] G. Bisping, D. Wenning, M. Kropff, D. Gustavus, C. Muller-Tidow, M. Stelljes, G. Munzert, F. Hilberg, G. J. Roth, M. Stefanic, et al. Bortezomib, Dexamethasone, and Fibroblast Growth Factor Receptor 3-Specific Tyrosine Kinase Inhibitor in t(4;14) Myeloma Clin. Cancer Res., January 15, 2009; 15(2): 520 - 531. [Abstract] [Full Text] [PDF] C. Lopez-Otin and J. S. Bond Proteases: Multifunctional Enzymes in Life and Disease J. Biol. Chem., November 7, 2008; 283(45): 30433 - 30437. [Full Text] [PDF] J. Kirshner, K. J. Thulien, L. D. Martin, C. Debes Marun, T. Reiman, A. R. Belch, and L. M. Pilarski A unique three-dimensional model for evaluating the impact of therapy on multiple myeloma Blood, October 1, 2008; 112(7): 2935 - 2945. [Abstract] [Full Text] [PDF] P. Lunghi, N. Giuliani, L. Mazzera, G. Lombardi, M. Ricca, A. Corradi, A. M. Cantoni, L. Salvatore, R. Riccioni, A. Costanzo, et al. Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways Blood, September 15, 2008; 112(6): 2450 - 2462. [Abstract] [Full Text] [PDF] A. M. Roccaro, X. 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