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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 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 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 Google Scholar Articles by Chauhan, D. Articles by Anderson, K. C. PubMed PubMed Citation Articles by Chauhan, D. Articles by Anderson, K. C. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma Dharminder Chauhan1, Ajita Singh1, Mohan Brahmandam1, Klaus Podar1, Teru Hideshima1, Paul Richardson1, Nikhil Munshi2, Michael A. Palladino3, and Kenneth C. Anderson1 1 The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Myeloma Research, Department of Medical Oncology, Dana-Farber Cancer Institute, and 2 Veterans Administration Boston Healthcare System, Harvard Medical School, Boston, MA; and 3 Nereus Pharmaceuticals, San Diego, CA Our recent study demonstrated that a novel proteasome inhibitor NPI-0052 triggers apoptosis in multiple myeloma (MM) cells, and importantly, that is distinct from bortezomib (Velcade) 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 plus bortezomib–induced synergistic apoptosis is associated with: (1) activation of caspase-8, caspase-9, caspase-3, and PARP; (2) induction of endoplasmic reticulum (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 combination of NPI-0052 and bortezomib is well tolerated and 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 plus 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: A. M. Roccaro, X. Leleu, A. Sacco, X. Jia, M. Melhem, A.-S. Moreau, H. T. Ngo, J. Runnels, A. Azab, F. Azab, et al. Dual targeting of the proteasome regulates survival and homing in Waldenstrom macroglobulinemia Blood, May 1, 2008; 111(9): 4752 - 4763. [Abstract] [Full Text] [PDF]

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