Abstract
Micromolar MK886, a selective inhibitor of 5-lipoxygenase at nanomolar concentration, induces physiologic cell death in U937 and chronic myelogenous leukemia blast cells. When U937 cells were challenged with 10 μM MK886, an acute, biphasic and sustained rise in intracellular Ca 2+ occurred, as determined with Fura-2. The initial increase was followed by a transient decline and a larger rise due to an influx of external Ca 2+. The first increase and part of the subsequent rise also developed in Ca 2+-free medium, identifying their origin from intracellular stores. The intracellular Ca 2+ concentration of U937 cells that remained after culture for 24 or 48 h with 5 or 10 μm MK886 was not reliably altered from the control values of 130 ± 8.3 nM. Under similar conditions MK886 did not increase cytosol Ca 2+ of a human prostate (PC3) cell line examined in suspension. The increase in intracellular CA 2+ in response to MK886 in calcium-containing medium was confirmed with an ACAS laser spectrometer. U937 cytosol pH was measured with the fluorescent probe BCECF, but no persistent acute or chronic change was induced by MK886. The rapid and sustained rise in Ca 2+ induced by MK886 is an early event in U937 cells which subsequently undergo physiologic cell death characterized in many by apoptosis.
Published Version
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