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Blood, 1 June 2007, Vol. 109, No. 11, pp. 4964-4972. Prepublished online as a Blood First Edition Paper on February 6, 2007; DOI 10.1182/blood-2006-10-054577. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-10-054577v1 109/11/4964    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 Citing Articles via Google Scholar Google Scholar Articles by Moreau, A.-S. Articles by Ghobrial, I. M. Search for Related Content PubMed PubMed Citation Articles by Moreau, A.-S. Articles by Ghobrial, I. M. Related Collections Neoplasia Signal Transduction Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Protein kinase C inhibitor enzastaurin induces in vitro and in vivo antitumor activity in Waldenström macroglobulinemia Anne-Sophie Moreau1,2,3, Xiaoying Jia1, Hai T. Ngo1, Xavier Leleu1,2,3, Garrett O'Sullivan1, Yazan Alsayed4, Alexey Leontovich5, Klaus Podar1,2, Jeffrey Kutok1,2, John Daley1, Suzan Lazo-Kallanian1, Evdoxia Hatjiharissi1,2, Marc S. Raab1,2, Lian Xu1, Steven P. Treon1,2, Teru Hideshima1,2, Kenneth C. Anderson1,2, and Irene M. Ghobrial1,2 1 Dana-Farber Cancer Institute, Boston, MA; 2 Harvard Medical School, Boston, MA; 3 Service des maladies du sang, Faculté de Médecine de Lille, Centre Hospitalier Règional Universitaire de Lille, France; 4 Department of Internal Medicine, University of Pittsburgh, PA; 5 Mayo Clinic College of Medicine, Rochester, MN Waldenström macroglobulinemia (WM) is an incurable lymphoplasmacytic lymphoma with limited options of therapy. Protein kinase Cβ (PKCβ) regulates cell survival and growth in many B-cell malignancies. In this study, we demonstrate up-regulation of PKCβ protein in WM using protein array techniques and immunohistochemistry. Enzastaurin, a PKCβ inhibitor, blocked PKCβ activity and induced a significant decrease of proliferation at 48 hours in WM cell lines (IC50, 2.5-10 µM). Similar effects were demonstrated in primary CD19+ WM cells, without cytotoxicity on peripheral blood mononuclear cells. In addition, enzastaurin overcame tumor cell growth induced by coculture of WM cells with bone marrow stromal cells. Enzastaurin induced dose-dependent apoptosis at 48 hours mediated via induction of caspase-3, caspase-8, caspase-9, and PARP cleavage. Enzastaurin inhibited Akt phosphorylation and Akt kinase activity, as well as downstream p-MARCKS and ribosomal p-S6. Furthermore, enzastaurin demonstrated additive cytotoxicity in combination with bortezomib, and synergistic cytotoxicity in combination with fludarabine. Finally, in an in vivo xenograft model of human WM, significant inhibition of tumor growth was observed in the enzastaurin-treated mice (P = .028). Our studies therefore show that enzastaurin has significant antitumor activity in WM both in vitro and in vivo, providing the framework for clinical trials to improve patient outcome in WM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? 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[Abstract] [Full Text] [PDF] A. M. Roccaro, X. Leleu, A. Sacco, A.-S. Moreau, E. Hatjiharissi, X. Jia, L. Xu, B. Ciccarelli, C. J. Patterson, H. T. Ngo, et al. Resveratrol Exerts Antiproliferative Activity and Induces Apoptosis in Waldenstrom's Macroglobulinemia Clin. Cancer Res., March 15, 2008; 14(6): 1849 - 1858. [Abstract] [Full Text] [PDF] A. Huston, X. Leleu, X. Jia, A.-S. Moreau, H. T. Ngo, J. Runnels, J. Anderson, Y. Alsayed, A. Roccaro, S. Vallet, et al. Targeting Akt and Heat Shock Protein 90 Produces Synergistic Multiple Myeloma Cell Cytotoxicity in the Bone Marrow Microenvironment Clin. Cancer Res., February 1, 2008; 14(3): 865 - 874. [Abstract] [Full Text] [PDF] X. Leleu, X. Jia, J. Runnels, H. T. Ngo, A.-S. Moreau, M. Farag, J. A. Spencer, C. M. Pitsillides, E. Hatjiharissi, A. Roccaro, et al. The Akt pathway regulates survival and homing in Waldenstrom macroglobulinemia Blood, December 15, 2007; 110(13): 4417 - 4426. [Abstract] [Full Text] [PDF]

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