Cytotoxicity of NF-κB inhibitors Bay 11-7085 and caffeic acid phenethyl ester to Ramos and other human B-lymphoma cell lines

Objective. The viability of normal and malignant B-cells was shown to depend on the constitutive activation of the nuclear factor (NF)-kappa B pathway. Thus, attempts to find efficient inhibitors of NF-kappa B play a central role in the search for novel anti-B lymphoma therapies. We studied the effects of two NF-kappa B inhibitors, Bay 11-7085 (BAY) and caffeic acid phenethyl ester (CAPE), on the viability of B-lymphoma cell lines. Methods. We investigated the mechanism(s) of the cytotoxic effect of the NF-kappa B inhibitors, BAY, and CAPE on human-lymphoma and nonhematological cell lines. Results. BAY and CAPE were shown to kill Ramos-Burkitt's lymphoma cells with IC50 values of 0.7 mu M and 4 mu M, respectively. The rapid killing by BAY (h) vs the slower killing by CAPE (1-3 days), and their differential effects on the stages of the cell cycle, indicated that these drugs induce killing by different mechanisms. BAY and CAPE induced a loss of the cytoplasmic compartment and generated pyknotic nuclei, which lacked nuclear or nucleosomal fragmentation, features characteristic of necrosis rather than apoptosis. BAY also induced a rapid loss of the mitochondrial potential and rapid inhibition of p65 NF-kappa B binding to its kappa B motif without reducing the level of nuclear p65. Conclusion. Our results indicate that BAY causes a necrotic rather than apoptotic cell death, either through its effect on the NF-kappa B pathway and/or by affecting additional molecular targets. The high sensitivity of B-lymphoma cell lines to the cytotoxicity of BAY, justify further research to explore its potential therapeutic effect on human B lymphomas. (c) 2007 ISEH-Society for Hematology and Stem Cells. Published by Elsevier Inc.