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In this report, we investigated the effects of the natural product parthenolide on human B-lymphoma cell lines. We show that parthenolide inhibited NF-κB transcription factor c-Rel (REL). In addition, the sensitivity of several human B-lymphoma cell lines to parthenolide-induced apoptosis inversely correlated with their levels of anti-apoptosis protein Bcl-X(L). Furthermore, ectopic expression of Bcl-X(L) (but not Bcl-2) in two B-lymphoma cell lines decreased their sensitivity to parthenolide-induced apoptosis. Finally, over-expression of a transforming mutant of REL, which increased expression of endogenous Bcl-X(L), decreased the sensitivity of BJAB B-lymphoma cells to parthenolide-induced apoptosis. These results demonstrate that the NF-κB target gene products Bcl-X(L) and Bcl-2 can play different roles in protecting B-lymphoma cells from chemical-induced apoptosis. [ABSTRACT FROM AUTHOR]