Selective inhibitors of 5-lipoxygenase reduce CML blast cell proliferation and induce limited differentiation and apoptosis

Inhibitors of the arachidonic acid metabolizing enzyme, 5-lipoxygenase, reduce the rate of proliferation of chronic myelogenous leukemia blast cells. The inhibitory agents studied were ETYA, A63162 and SC41661A. These reagents induced differentiation of cultured chronic myelogenous leukemia cells from blast to promyelocytic morphology. Promyelocytic cells then underwent apoptosis, which was identified by nuclear and cytoplasmic morphological features and by DNA laddering. Proliferation of monoblastoid U937 and myelomonocytic HL60 cell lines, known to contain 5-lipoxygenase and synthesize leukotrienes, was reduced by these inhibitors. U937 cells cultured with ETYA, A63162 or SC41661A for 48 h exhibited apoptosis as assessed by DNA laddering and morphology. Characteristic ultrastructural changes of apoptosis were seen at 120 h, MK886, an inhibitor of 5-lipoxygenase with a mechanism of action distinct from oxidation/reduction reagents, at 20-40 mu M also inhibited CML and U937 cell proliferation and induced apoptosis, as shown by DNA laddering and ultrastructure.