TY - JOUR
T1 - Protein kinase C inhibitor enzastaurin induces in vitro and in vivo antitumor activity in Waldenström macroglobulinemia
AU - Moreau, Anne-Sophie
AU - Jia, Xiaoying
AU - Ngo, Hai T
AU - Leleu, Xavier
AU - O'Sullivan, Garrett
AU - Alsayed, Yazan
AU - Leontovich, Alexey
AU - Podar, Klaus
AU - Kutok, Jeffrey
AU - Daley, John
AU - Lazo-Kallanian, Suzan
AU - Hatjiharissi, Evdoxia
AU - Raab, Marc S
AU - Xu, Lian
AU - Treon, Steven P
AU - Hideshima, Teru
AU - Anderson, Kenneth C
AU - Ghobrial, Irene M
PY - 2007/6/1
Y1 - 2007/6/1
N2 - 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.
AB - 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.
KW - Antigens, CD19/biosynthesis
KW - Antineoplastic Agents/pharmacology
KW - Biopsy
KW - Dose-Response Relationship, Drug
KW - Enzyme Activation
KW - Enzyme Inhibitors/pharmacology
KW - Humans
KW - In Vitro Techniques
KW - Indoles/pharmacology
KW - Inhibitory Concentration 50
KW - Leukocytes, Mononuclear/immunology
KW - Oligonucleotide Array Sequence Analysis
KW - Protein Kinase C/antagonists & inhibitors
KW - Protein Kinase C beta
KW - Time Factors
KW - Waldenstrom Macroglobulinemia/drug therapy
UR - http://www.scopus.com/inward/record.url?scp=34249746834&partnerID=8YFLogxK
U2 - 10.1182/blood-2006-10-054577
DO - 10.1182/blood-2006-10-054577
M3 - Journal article
C2 - 17284528
SN - 0006-4971
VL - 109
SP - 4964
EP - 4972
JO - Blood
JF - Blood
IS - 11
ER -