%0 Journal Article
%T Prevalence of bortezomib-resistant constitutive NF-kappaB activity in mantle cell lymphoma
%A David T Yang
%A Ken H Young
%A Brad S Kahl
%A Stephanie Markovina
%A Shigeki Miyamoto
%J Molecular Cancer
%D 2008
%I BioMed Central
%R 10.1186/1476-4598-7-40
%X Proteasome activity in the EBV-negative MCL cell lines Jeko-1 and Rec-1 is inhibited by greater than 80% after exposure to 20 nM bortezomib for 4 hours. This treatment decreased NF-¦ĘB activity in Jeko-1 cells, but failed to do so in Rec-1 cells when assessed by electrophoretic mobility shift assay (EMSA). Concurrently, Rec-1 cells were more resistant to the cytotoxic effects of bortezomib than Jeko-1 cells. Consistent with a proteasome inhibitor resistant pathway of activation described in mouse B-lymphoma cells (WEHI231) and a breast carcinoma cell line (MDA-MB-468), the bortezomib-resistant NF-¦ĘB activity in Rec-1 cells is inhibited by calcium chelators, calmodulin inhibitors, and perillyl alcohol, a monoterpene capable of blocking L-type calcium channels. Importantly, the combination of perillyl alcohol and bortezomib is synergistic in eliciting Rec-1 cell cytotoxicity. The relevance of these results is illuminated by the additional finding that a considerable fraction of primary MCL samples (8 out of 10) displayed bortezomib-resistant constitutive NF-¦ĘB activity.Our findings show that bortezomib-resistant NF-¦ĘB activity is frequently observed in MCL samples and suggest that this activity may be relevant to MCL biology as well as serve as a potential therapeutic target.Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma genetically characterized by the t(11;14)(q13;q32) translocation with overexpression of cyclin D1. [1] It typically presents as advanced disease in men over 60 years of age and accounts for approximately 5% of all non-Hodgkin lymphoma (NHL) with an incidence of approximately 3,000 cases per year in the United States [2-5]. MCL remains a therapeutic challenge, having the worst 5-year survival of any lymphoma subtype in the NHL classification project and a median survival of only 3 or 4 years [6-15].The need for new treatment strategies has led to the development of a novel class of pharmacologic agents, the proteasome inhibitors
%U http://www.molecular-cancer.com/content/7/1/40