MK-886 enhances tumour necrosis factor-alpha-induced differentiation and apoptosis

Abstract

We investigated the role of the 5-lipoxygenase (5-LOX) pathway of arachidonic acid metabolism in tumour necrosis factor-alpha (TNF-alpha)-induced differentiation of human leukemic HL-60 cells using MK-886, an inhibitor of 5-LOX activating protein. MK-886 augmented cell cycle arrest and differentiation induced by TNF-alpha; however. both effects were probably 5-LOX-independent, because a general LOX inhibitor, NDGA, had no effect. Apoptosis was significantly elevated after combined TNF-alpha and MK-886 treatment, which could be partially associated with changes of Mcl-1 protein expression. NF-kappa B signalling or activation of JNKs were not modulated by MK-886. Thus, in addition to apoptosis, MK-886 can enhance TNF-alpha-induced differentiation. (c) 2005 Elsevier Ireland Ltd. All rights reserved.