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-lipoxygenase, active at nanomolar concentrations. At micromolar concentrations, it inhibited the proliferation of U937 monoblastoid cells and of cultured malignant cells from patients with chronic myelogenous leukemia. These cells became morphologically apoptotic, a form of physiologic cell death. U937 cell apoptosis was assessed by flow cytometry, ultrastructure, DNA laddering and immuno-histology for free 3'OH-DNA. MK886-induced apoptosis developed over time as cells were recruited in concert with reduction in their numbers. Some CML cells exhibited cytoplasmic changes of apoptosis without typical nuclear changes. Under conditions used for measuring Ca2+ with Fura 2, 10 micromolar MK886 increased U937 intracellular Ca2+ 4-fold or more over the 8 minute period of measurement. Since MK886 inhibits the association of arachidonic acid with the 5-lipoxygenase activating protein, altered arachidonic acid metabolism may have contributed to these results.
Anderson
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Department of Medicine, Rush Medical College, Chicago, IL 60612, USA.
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D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002452:Cell Count / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D016859:Lipoxygenase Inhibitors; D008938:Mitosis / Q000187:drug effects; D014407:Tumor Cells, Cultured; D002722:Chlorobenzenes
D002118:Calcium; D004273:DNA, Neoplasm; D004121:Dimethyl Sulfoxide; D007211:Indoles; D016859:Lipoxygenase Inhibitors; C060893:MK-886; D002722:Chlorobenzenes