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Blood, 15 February 2007, Vol. 109, No. 4, pp. 1669-1677. Prepublished online as a Blood First Edition Paper on October 5, 2006; DOI 10.1182/blood-2006-08-042747. This Article Full Text Full Text (PDF) Supplemental Table All Versions of this Article: blood-2006-08-042747v1 109/4/1669    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 Podar, K. Articles by Anderson, K. C. Search for Related Content PubMed PubMed Citation Articles by Podar, K. Articles by Anderson, K. C. Related Collections Neoplasia Signal Transduction Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Targeting PKC in multiple myeloma: in vitro and in vivo effects of the novel, orally available small-molecule inhibitor enzastaurin (LY317615.HCl) Klaus Podar1, Marc S. Raab1,2, Jing Zhang1, Douglas McMillin1, Iris Breitkreutz1, Yu-Tzu Tai1, Boris K. Lin3, Nikhil Munshi1, Teru Hideshima1, Dharminder Chauhan1, and Kenneth C. Anderson1 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; 2 Department of Internal Medicine V, University of Heidelberg, Germany; and 3 Eli Lilly and Company, Indianapolis, IN In multiple myeloma (MM) protein kinase C (PKC) signaling pathways have been implicated in cell proliferation, survival, and migration. Here we investigated the novel, orally available PKC-inhibitor enzastaurin for its anti-MM activity. Enzastaurin specifically inhibits phorbol ester–induced activation of PKC isoforms, as well as phosphorylation of downstream signaling molecules MARCKS and PKCµ. Importantly, it also inhibits PKC activation triggered by growth factors and cytokines secreted by bone marrow stromal cells (BMSCs), costimulation with fibronectin, vascular endothelial growth factor (VEGF), or interleukin-6 (IL-6), as well as MM patient serum. Consequently, enzastaurin inhibits proliferation, survival, and migration of MM cell lines and MM cells isolated from multidrug-resistant patients and overcomes MM-cell growth triggered by binding to BMSCs and endothelial cells. Importantly, strong synergistic cytotoxicity is observed when enzastaurin is combined with bortezomib and moderate synergistic or additive effects when combined with melphalan or lenalidomide. Finally, tumor growth, survival, and angiogenesis are abrogated by enzastaurin in an in vivo xenograft model of human MM. Our results therefore demonstrate in vitro and in vivo efficacy of the orally available PKC inhibitor enzastaurin in MM and strongly support its clinical evaluation, alone or in combination therapies, to improve outcome in patients with MM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Protein kinase C inhibitor enzastaurin induces in vitro and in vivo antitumor activity in Waldenström 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 Hatjiharissi, Marc S. Raab, Lian Xu, Steven P. Treon, Teru Hideshima, Kenneth C. Anderson, and Irene M. Ghobrial Blood 2007 109: 4964-4972. [Abstract] [Full Text] [PDF] This article has been cited by other articles: A.-R. Hanauske, M. Lahn, L. C. Musib, K. Weigang-Kohler, E. Yilmaz, T. Graefe, B. Kuenen, D. Thornton, P. McNealy, and G. Giaccone Phase Ib safety and pharmacokinetic evaluation of daily and twice daily oral enzastaurin in combination with pemetrexed in advanced/metastatic cancer Ann. Onc., September 1, 2009; 20(9): 1565 - 1575. [Abstract] [Full Text] [PDF] J. Zhang, M. Sattler, G. Tonon, C. Grabher, S. Lababidi, A. Zimmerhackl, M. S. Raab, S. Vallet, Y. Zhou, M.-A. Cartron, et al. Targeting Angiogenesis via a c-Myc/Hypoxia-Inducible Factor-1{alpha}-Dependent Pathway in Multiple Myeloma Cancer Res., June 15, 2009; 69(12): 5082 - 5090. [Abstract] [Full Text] [PDF] A. P. Fields, S. R. Calcagno, M. Krishna, S. Rak, M. Leitges, and N. R. Murray Protein Kinase C{beta} Is an Effective Target for Chemoprevention of Colon Cancer Cancer Res., February 15, 2009; 69(4): 1643 - 1650. [Abstract] [Full Text] [PDF] M. S. Raab, I. Breitkreutz, G. Tonon, J. Zhang, P. J. Hayden, T. Nguyen, J. H. Fruehauf, B. K. Lin, D. Chauhan, T. Hideshima, et al. Targeting PKC: a novel role for beta-catenin in ER stress and apoptotic signaling Blood, February 12, 2009; 113(7): 1513 - 1521. [Abstract] [Full Text] [PDF] Y. Okawa, T. Hideshima, P. Steed, S. Vallet, S. Hall, K. Huang, J. Rice, A. Barabasz, B. Foley, H. Ikeda, et al. SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumors by abrogating signaling via Akt and ERK Blood, January 22, 2009; 113(4): 846 - 855. [Abstract] [Full Text] [PDF] M. GUAN, L. ZHU, G. SOMLO, A. HUGHES, B. ZHOU, and Y. YEN Bortezomib Therapeutic Effect is Associated with Expression of FGFR3 in Multiple Myeloma Cells Anticancer Res, January 1, 2009; 29(1): 1 - 9. [Abstract] [Full Text] [PDF] B. A. Teicher In Vivo/Ex Vivo and In Situ Assays Used in Cancer Research: A Brief Review Toxicol Pathol, January 1, 2009; 37(1): 114 - 122. [Abstract] [Full Text] [PDF] F. Morgillo, E. Martinelli, T. Troiani, G. Laus, S. Pepe, C. Gridelli, and F. Ciardiello Sequence-dependent, synergistic antiproliferative and proapoptotic effects of the combination of cytotoxic drugs and enzastaurin, a protein kinase C{beta} inhibitor, in non-small cell lung cancer cells Mol. Cancer Ther., June 1, 2008; 7(6): 1698 - 1707. [Abstract] [Full Text] [PDF] W. Koh, R. D. Mahan, and G. E. Davis Cdc42- and Rac1-mediated endothelial lumen formation requires Pak2, Pak4 and Par3, and PKC-dependent signaling J. Cell Sci., April 1, 2008; 121(7): 989 - 1001. [Abstract] [Full Text] [PDF] K.-W. Lee, S. G. Kim, H.-P. Kim, E. Kwon, J. You, H.-J. Choi, J.-H. Park, B.-C. Kang, S.-A. Im, T.-Y. Kim, et al. Enzastaurin, a Protein Kinase C{beta} Inhibitor, Suppresses Signaling through the Ribosomal S6 Kinase and Bad Pathways and Induces Apoptosis in Human Gastric Cancer Cells Cancer Res., March 15, 2008; 68(6): 1916 - 1926. [Abstract] [Full Text] [PDF] A. C. Spalding, R. Watson, M. E. Davis, A. C. Kim, T. S. Lawrence, and E. Ben-Josef Inhibition of Protein Kinase C{beta} by Enzastaurin Enhances Radiation Cytotoxicity in Pancreatic Cancer Clin. Cancer Res., November 15, 2007; 13(22): 6827 - 6833. [Abstract] [Full Text] [PDF] R. S. Herbst, Y. Oh, A. Wagle, and M. Lahn Enzastaurin, a Protein Kinase C{beta} Selective Inhibitor, and Its Potential Application as an Anticancer Agent in Lung Cancer Clin. Cancer Res., August 1, 2007; 13(15): 4641s - 4646s. [Abstract] [Full Text] [PDF] H. Younes, X. Leleu, E. Hatjiharissi, A.-S. Moreau, T. Hideshima, P. Richardson, K. C. Anderson, and I. M. Ghobrial Targeting the Phosphatidylinositol 3-Kinase Pathway in Multiple Myeloma Clin. Cancer Res., July 1, 2007; 13(13): 3771 - 3775. [Abstract] [Full Text] [PDF] A.-S. Moreau, X. Jia, H. T. Ngo, X. Leleu, G. O'Sullivan, Y. Alsayed, A. Leontovich, K. Podar, J. Kutok, J. Daley, et al. Protein kinase C inhibitor enzastaurin induces in vitro and in vivo antitumor activity in Waldenstrom macroglobulinemia Blood, June 1, 2007; 109(11): 4964 - 4972. [Abstract] [Full Text] [PDF]

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