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Blood, 1 May 2008, Vol. 111, No. 9, pp. 4752-4763. Prepublished online as a Blood First Edition Paper on March 3, 2008; DOI 10.1182/blood-2007-11-120972. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2007-11-120972v1 111/9/4752    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 CrossRef Google Scholar Articles by Roccaro, A. M. Articles by Ghobrial, I. M. PubMed PubMed Citation Articles by Roccaro, A. M. Articles by Ghobrial, I. M. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Dual targeting of the proteasome regulates survival and homing in Waldenström macroglobulinemia Aldo M. Roccaro13, Xavier Leleu1, Antonio Sacco1, Xiaoying Jia1, Molly Melhem1, Anne-Sophie Moreau1, Hai T. Ngo1, Judith Runnels1, Abdelkareem Azab1, Feda Azab1, Nicholas Burwick1, Mena Farag1, Steven P. Treon1, Michael A. Palladino4, Teru Hideshima1, Dharminder Chauhan1, Kenneth C. Anderson1, and Irene M. Ghobrial1 1 Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA; 2 Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy; 3 Unit of Blood Diseases and Cell Therapies, University of Brescia Medical School, Brescia, Italy; and 4 Nereus Pharmaceuticals, San Diego, CA Waldenström macroglobulinemia (WM) is an incurable low-grade B-cell lymphoma characterized by high protein turnover. We dissected the biologic role of the proteasome in WM using 2 proteasome inhibitors, NPI-0052 and bortezomib. We found that NPI-0052 inhibited proliferation and induced apoptosis in WM cells, and that the combination of NPI-0052 and bortezomib induced synergistic cytotoxicity in WM cells, leading to inhibition of nuclear translocation of p65NF-B and synergistic induction of caspases-3, -8, and -9 and PARP cleavage. These 2 agents inhibited the canonical and noncanonical NF-B pathways and acted synergistically through their differential effect on Akt activity and on chymotrypsin-like, caspaselike, and trypsinlike activities of the proteasome. We demonstrated that NPI-0052–induced cytotoxicity was completely abrogated in an Akt knockdown cell line, indicating that its major activity is mediated through the Akt pathway. Moreover, we demonstrated that NPI-0052 and bortezomib inhibited migration and adhesion in vitro and homing of WM cells in vivo, and overcame resistance induced by mesenchymal cells or by the addition of interleukin-6 in a coculture in vitro system. Theses studies enhance our understanding of the biologic role of the proteasome pathway in WM, and provide the preclinical basis for clinical trials of combinations of proteasome inhibitors in WM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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