TY - JOUR
T1 - Cytotoxicity of NF-κB inhibitors Bay 11-7085 and caffeic acid phenethyl ester to Ramos and other human B-lymphoma cell lines
AU - Berger, Nir
AU - Ben Bassat, Hannah
AU - Klein, Benjamin Y.
AU - Laskov, Reuven
PY - 2007/10
Y1 - 2007/10
N2 - Objective: The viability of normal and malignant B-cells was shown to depend on the constitutive activation of the nuclear factor (NF)- κB pathway. Thus, attempts to find efficient inhibitors of NF-κB play a central role in the search for novel anti-B lymphoma therapies. We studied the effects of two NF-κB 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-κB 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 μM and 4 μM, 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-κB binding to its κB 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-κB 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.
AB - Objective: The viability of normal and malignant B-cells was shown to depend on the constitutive activation of the nuclear factor (NF)- κB pathway. Thus, attempts to find efficient inhibitors of NF-κB play a central role in the search for novel anti-B lymphoma therapies. We studied the effects of two NF-κB 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-κB 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 μM and 4 μM, 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-κB binding to its κB 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-κB 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.
UR - http://www.scopus.com/inward/record.url?scp=34548727373&partnerID=8YFLogxK
U2 - 10.1016/j.exphem.2007.07.006
DO - 10.1016/j.exphem.2007.07.006
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 17889719
AN - SCOPUS:34548727373
SN - 0301-472X
VL - 35
SP - 1495
EP - 1509
JO - Experimental Hematology
JF - Experimental Hematology
IS - 10
ER -