AN IN-VIVO INHIBITOR OF 5-LIPOXYGENASE, MK886, AT MICROMOLAR CONCENTRATION INDUCES APOPTOSIS IN U937 AND CML CELLS

MK886 (Merck Frosst) is a selective in vivo inhibitor of 5-lipoxygenas e, active at nanomolar concentrations. At micromolar concentrations, i t inhibited the proliferation of U937 monoblastoid cells and of cultur ed malignant cells from patients with chronic myelogenous leukemia. Th ese cells became morphologically apoptotic, a form of physiologic cell death. U937 cell apoptosis was assessed by flow cytometry, ultrastruc ture, DNA laddering and immuno-histology for free 3'OH-DNA. MK886-indu ced apoptosis developed over time as cells were recruited in concert w ith reduction in their numbers. Some CML cells exhibited cytoplasmic c hanges of apoptosis without typical nuclear changes. Under conditions used for measuring Ca2+ with Fura 2, 10 micromolar MK886 increased U93 7 intracellular Ca2+ 4-fold or more over the 8 minute period of measur ement. Since MK886 inhibits the association of arachidonic acid with t he 5-lipoxygenase activating protein, altered arachidonic acid metabol ism may have contributed to these results.