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, Irene M Ghobrial

Publikation: Beitrag in Fachzeitschrift (peer-reviewed)Artikel in Fachzeitschrift

92 Zitate (Scopus)

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 (IC 50, 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.

OriginalspracheEnglisch
Seiten (von - bis)4964-4972
Seitenumfang9
FachzeitschriftBlood
Jahrgang109
Ausgabenummer11
DOIs
PublikationsstatusVeröffentlicht - 01 Juni 2007
Extern publiziertJa

ASJC Scopus Sachgebiete

  • Hämatologie
  • Biochemie
  • Zellbiologie
  • Immunologie

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