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5-Lipoxygenase inhibitors reduce PC-3 cell proliferation and initiate nonnecrotic cell death.

Anderson KM, Seed T, Vos M, Mulshine J, Meng J, Alrefai W, Ou D, Harris JE

Prostate 37: 161-173 (1998)


BACKGROUND: Products of the arachidonic acid-metabolizing enzyme, 5-lipoxygenase, stimulate the growth of several cell types. Selective inhibitors of the enzyme, including SC41661A and MK886, reduce PC-3 prostate cell proliferation. With continued culture, cells die, but the mode of death, necrotic or nonnecrotic, has not been established. METHODS: Flow cytometry, laddering after agarose electrophoresis of DNA from inhibitor-treated cells, and light and electron microscopy were employed to examine the type of death in PC-3 prostate cells cultured with either 5-lipoxygenase inhibitor. RESULTS: The inhibitors induced nonnecrotic, programmed cell death. SC41661A-treated cells exhibited 'foamy,' vacuolated cytoplasm and mitochondria with disrupted cristae and limiting membranes, while some cells contained numerous polysomes and extended hypertrophic Golgi and secretory cisternal networks. A proportion of the treated cells detached and the nuclei of these cells were characteristic of type 1 'apoptotic' programmed cell death. MK886, a 5-lipoxygenase-inhibitor with a different mechanism of action, induced nonnecrotic changes largely confined to the cytoplasm, most consistent with type 2 'autophagic' programmed cell death. In preliminary studies of mechanism, we demonstrated that PC-3 cells express mRNA for 5-lipoxygenase and for 5-lipoxygenase-activating protein. The less active inhibitor, SC45662 neither reduced proliferation nor induced DNA laddering. The antioxidant, N-acetyl-l-cysteine but not butylated hydroxy toluene or alpha tocopherol, partially reduced the inhibition of proliferation from SC41661A. CONCLUSIONS: SC41661A and MK886 inhibit PC-3 cell proliferation and induce a form of type 1 or type 2 programmed cell death, respectively. PC-3 cells contain messenger RNA for 5-lipoxygenase and 5-lipoxygenase-activating proteins. Drug-induced changes included altered redox potential, inferred from the increased survival due to the antioxidant and glutathione precursor, N-acetyl-l-cysteine. PC-3 cells are an appropriate model for studying the mechanism responsible for 5-lipoxygenase inhibitor-induced cellular suicide.