An IkappaBalpha inhibitor causes leukemia cell death through a p38 MAP kinase-dependent, NF-kappaB-independent mechanism.

Treatment of U937 cells with an IkappaBalpha phosphorylation inhibitor, Bay 11-7085, induced a rapid phosphorylation of p38 mitogen-activated protein (MAP) kinase, significant apoptosis, extensive necrosis, and a weak phosphorylation of MAP kinase kinase. Bay 11-7085 had no effect on the basal levels of phosphorylated IkappaBalpha but completely inhibited phorbol 12-myristate 13-acetate-induced phosphorylation of IkappaBalpha. Although Bay 11-7085 prevented phorbol 12-myristate 13-acetate-induced NF-kappaB nuclear translocation, SN50, a specific inhibitor of nuclear translocation and function of NF-kappaB, did not induce any significant nuclear/DNA fragmentation, caspase 3 activation, or cell death.