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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 (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 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 Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 26, 2006 Accepted January 31, 2007 Protein kinase C inhibitor enzastaurin induces in vitro and in vivo antitumor activity in Waldenstrom's Macroglobulinemia Anne-Sophie Moreau, Xiaoying Jia, Hai T. Ngo, Xavier Leleu, Garrett O'Sullivan, Yazan Alsayed, Alexey Leontovich, Klaus Podar, Jeffrey Kutok, John Daley, Suzan Lazo-Kallanian, Evdoxia Hatjiharisi, Marc S. Raab, Lian Xu, Steven P. Treon, Teru Hideshima, Kenneth C. Anderson, and Irene M. Ghobrial* Dana-Farber Cancer Institute, Boston, MA, United States Service des maladies du sang, Faculte de Medecine de Lille, CHRU de Lille, Lille, France Department of Internal Medicine, University of Pittsburgh, Pittsburgh, PA, United States Mayo Clinic College of Medicine, United States Harvard Medical School, Boston, MA, United States * Corresponding author; email: irene_ghobrial{at}dfci.harvard.edu. Waldenstrom's Macroglobulinemia (WM) is an incurable lymphoplasmacytic lymphoma with limited options of therapy. Protein Kinase C (PKC) regulates cell survival and growth in many B-cell malignancies. In this study, we demonstrate upregulation of PKC protein in WM using protein array techniques and immunohistochemistry. Enzastaurin, a PKC inhibitor blocked PKC activity and induced a significant decrease of proliferation at 48h in WM cell lines (IC50 2.5-10µM). 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 co-culture of WM cells with bone marrow stromal cells. Enzastaurin induced dose-dependent apoptosis at 48h mediated via induction of caspases-3,-8,-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=0.028). 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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