Inhibition of nuclear factor κB activation attenuates apoptosis resistance in lymphoid cells

Death-inducing ligands (DILs) such as tumor necrosis factor alpha (TNF alpha) or the cytotoxic drug doxorubicin have been shown to activate a nuclear factor kappa B (NF kappa B)-dependent program that may rescue cells from apoptosis induction. We demonstrate here that TRAIL (TNF-related apoptosis-inducing ligand), a recently identified DIL, also activates NF kappa B in lymphoid cell lines in a kinetic similar to TNF alpha. NF kappa B activity is independent from FADD, caspases, and apoptosis induction. To study the influence of NF kappa B activity on apoptosis mediated by TRAIL, CD95, TNF alpha, or doxorubicin, NF kappa B activation was inhibited using the proteasome inhibitor N-acetyl-L-leucinyl-L-leucinyl-L-norleuc or transient overexpression of mutant I kappa B alpha. Sensitivity for induction of apoptosis was markedly increased by these treatments in apoptosis sensitive cell lines. Moreover, both in cell lines and in primary leukemia cells that are resistant towards induction of apoptosis by DILs and doxorubicin, antagonization of NF kappa B activity partially restored apoptosis sensitivity. These data suggest that inhibition of NF kappa B activation may provide a molecular approach to increase apoptosis sensitivity in anticancer treatment. (C) 1998 by The American Society of Hematology.