Citations 2
Targeting NF-κB in Waldenstrom macroglobulinemia
Leleu, Xavier , Eeckhoute, Jérôme , Jia, Xiaoying , Roccaro, Aldo M. , Moreau, Anne-Sophie, Sacco, Antonio , Ngo, Hai T., Runnels, Judith, Melhem, Molly, Burwick, Nicolas, Azab, Abdelkareem, Azab, Feda, Hunter, Zachary R. , Hatjiharissi, Evdoxia , Carrasco, Daniel R., Hideshima, Teru , Brown, Myles , Farag, Mena S. , Treon, Steven P. , Witzig, Thomas E. , Anderson, Kenneth C. , Ghobrial, Irene M. , Roccaro, Aldo M , Hunter, Zachary R , Brown, Myles
Blood | March 12, 2008 | Volume: 111 | Issue: 10 | Pages: 5068-5077
Abstract The nuclear factor-κB (NF-κB) path-way has been implicated in tumor B-cell survival, growth, and resistance to therapy. Because tumor cells overcome single-agent antitumor activity, we hypothesized that combination of agents that target differentially NF-κB pathway will induce significant cytotoxicity. Therapeutic agents that target proteasome and Akt pathways should induce significant activity in B-cell malignancies as both pathways impact NF-κB activity. We demonstrated that perifosine and bortezomib both targeted NF-κB through its recruitment to the promoter of its target gene IκB using chromatin immunoprecipitation assay. This combination led to synergistic cytotoxicity in Waldenstrom macroglobulinemia (WM) cells that was mediated through a combined reduction of the PI3K/Akt and ERK signaling pathways, found to be critical for survival of WM cells. Moreover, a combination of these drugs with the CD20 monoclonal antibody rituximab further increased their cytotoxic activity. Thus, effective WM therapy may require combination regimens targeting the NF-κB pathway.
Protein kinase C inhibitor enzastaurin induces in vitro and in vivo antitumor activity in Waldenström macroglobulinemia
Moreau, Anne-Sophie, Jia, Xiaoying , Ngo, Hai T., Leleu, Xavier , O’Sullivan, Garrett, Alsayed, Yazan, Leontovich, Alexey A. , Podar, Klaus , Kutok, Jeffrey L., Daley, John, Lazo-Kallanian, Suzan, Hatjiharissi, Evdoxia , Xu, Lian, Hideshima, Teru , Raab, Marc S. , Treon, Steven P. , Anderson, Kenneth C. , Ghobrial, Irene M.
Blood | February 7, 2007 | Volume: 109 | Issue: 11 | Pages: 4964-4972
AbstractWaldenström 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.