Protein kinase C inhibitor enzastaurin induces in vitro and in vivo antitumor activity in Waldenström macroglobulinemia
- 1 June 2007
- journal article
- Published by American Society of Hematology in Blood
- Vol. 109 (11), 4964-4972
- https://doi.org/10.1182/blood-2006-10-054577
Abstract
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.This publication has 25 references indexed in Scilit:
- Targeting PKC in multiple myeloma: in vitro and in vivo effects of the novel, orally available small-molecule inhibitor enzastaurin (LY317615.HCl)Blood, 2006
- B-cell receptor signaling in chronic lymphocytic leukemia cells is regulated by overexpressed active protein kinase CβIIBlood, 2006
- Update on treatment recommendations from the Third International Workshop on Waldenstrom's MacroglobulinemiaBlood, 2006
- Expression of PKC-beta or cyclin D2 predicts for inferior survival in diffuse large B-cell lymphomaLaboratory Investigation, 2005
- The Protein Kinase Cβ–Selective Inhibitor, Enzastaurin (LY317615.HCl), Suppresses Signaling through the AKT Pathway, Induces Apoptosis, and Suppresses Growth of Human Colon Cancer and Glioblastoma XenograftsCancer Research, 2005
- Waldenström macroglobulinaemiaThe Lancet Oncology, 2003
- Treatment recommendations in Waldenstrom's macroglobulinemia: Consensus Panel Recommendations from the Second International Workshop on Waldenstrom's MacroglobulinemiaSeminars in Oncology, 2003
- Clinicopathological definition of Waldenstrom's macroglobulinemia: Consensus Panel Recommendations from the Second International Workshop on Waldenstrom's MacroglobulinemiaSeminars in Oncology, 2003
- Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learningNature Medicine, 2002
- Protein kinase C inhibitors as novel anticancer drugsExpert Opinion on Investigational Drugs, 2001