l-663536 and Leukemia--Myeloid--Acute

Microsomal prostaglandin E synthase-1 (mPGES-1), an inducible enzyme that specifically catalyzes the conversion of prostaglandin H2 (PGH2) to prostaglandin E2 (PGE2), has been reported to be over-expressed in a variety of solid tumor cells and tissues, but not in normal tissues. Its association with leukemia, however, has not been fully investigated. Our study revealed, for the first time, that mPGES-1 is over-expressed in human acute myeloid leukemia HL-60 cells. Cytotoxicity assays and flow cytometry showed that MK886, an inhibitor of mPGES-1, inhibits proliferation of HL-60 cells and induces apoptosis in a dose- and time-dependent manner, which may result from down-regulation of mPGES-1 expression and PGE2 synthesis. Evaluation of mediators of apoptotic signaling revealed up-regulation of BAX expression and caspase-3 activity, as well as significant decreases in Bcl2 and P-Akt. We conclude that MK886 reduces the viability of leukemia HL-60 cells by reducing mPGES-1 expression and PGE2 synthesis in a dose-dependent manner, which strongly suggests that mPGES-1 inhibitors should be considered as promising candidates for leukemia treatment.

Topics: Cell Proliferation; Depression, Chemical; Dinoprostone; Dose-Response Relationship, Drug; Down-Regulation; Gene Expression Regulation, Enzymologic; HL-60 Cells; Humans; Indoles; Intramolecular Oxidoreductases; Leukemia, Myeloid, Acute; Lipoxygenase Inhibitors; Molecular Targeted Therapy; Prostaglandin-E Synthases; Time Factors; Tumor Cells, Cultured

We have studied the actions of inhibitors of leukotriene generation on DNA synthesis (measured by 3H-thymidine incorporation) in blast cells from patients with acute myeloid leukaemia (AML). Cells from a subset only of these patients were sensitive to MK 886, a potent selective inhibitor of leukotriene synthesis. By contrast, DNA replication in cells from all of the patients was inhibited by nordihydroguiaretic acid (NDGA), a leukotriene synthesis inhibitor of lower selectivity. DNA synthesis in normal bone marrow cells and phytohaemagglutinin-stimulated lymphocytes was sensitive to NDGA but not to MK 886. The data suggest that NDGA inhibits DNA replication by a mechanism other than the abolition of leukotriene biosynthesis, but that DNA synthesis in a subset of AML cells may be dependent on the generation of lipoxygenase products, as indicated by sensitivity to MK 886.

Topics: Adult; Aged; Child; DNA, Neoplasm; Female; Humans; Indoles; Leukemia, Myeloid, Acute; Leukotriene Antagonists; Male; Masoprocol; Middle Aged