Cytotoxicity of NF-kappaB 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)- kappaB pathway. Thus, attempts to find efficient inhibitors of NF-kappaB play a central role in the search for novel anti-B lymphoma therapies. We studied the effects of two NF-kappaB 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-kappaB 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 IC(50) values of 0.7 microM and 4 microM, 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-kappaB binding to its kappaB motif without reducing the level of nuclear p65.


CONCLUSIONS
Our results indicate that BAY causes a necrotic rather than apoptotic cell death, either through its effect on the NF-kappaB 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.
Berger
Nir
N
Department of Experimental Medicine and Cancer Research, Hebrew University-Hadassah Medical School, Ein Kerem, Jerusalem, Israel.
Ben Bassat
Hannah
H
Klein
Benjamin Y
BY
Laskov
Reuven
R
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D002109:Caffeic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D003593:Cytoplasm / Q000378:metabolism / Q000473:pathology; D003603:Cytotoxins / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009336:Necrosis / Q000378:metabolism / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology* / Q000627:therapeutic use; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors* / Q000378:metabolism
C416282:BAY 11-7085; D002109:Caffeic Acids; D003603:Cytotoxins; D009570:Nitriles; D013450:Sulfones; D051996:Transcription Factor RelA; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol