Mitochondria Are Direct Targets of the Lipoxygenase Inhibitor MK886

We have investigated the mitochondrial and cellular effects of the lipoxygenase inhibitor MK886. Low concentrations (1 μ m ) of MK886 selectively sensitized the permeability transition pore (PTP) to opening, whereas higher concentrations of MK886 (10 μ m ) caused depolarization through combination...

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Veröffentlicht in:The Journal of biological chemistry 2002-08, Vol.277 (35), p.31789-31795
Hauptverfasser: Gugliucci, Arianna, Ranzato, Laura, Scorrano, Luca, Colonna, Raffaele, Petronilli, Valeria, Cusan, Claudia, Prato, Maurizio, Mancini, Mariangela, Pagano, Francesco, Bernardi, Paolo
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Sprache:eng
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Zusammenfassung:We have investigated the mitochondrial and cellular effects of the lipoxygenase inhibitor MK886. Low concentrations (1 μ m ) of MK886 selectively sensitized the permeability transition pore (PTP) to opening, whereas higher concentrations of MK886 (10 μ m ) caused depolarization through combination of an ionophoretic effect with inhibition of respiration. MK886 killed prostate cancer PC3 cells only at the higher, toxic concentration (10 μ m ), whereas the lower concentration (1 μ m ) had no major effect on cell survival. However, 1 μ m MK886 alone demonstrably induced PTP-dependent mitochondrial dysfunction; and it caused cell death through the mitochondrial pathway when it was used in combination with the cyclooxygenase inhibitor, indomethacin, which had no effects per se . Treatment with 1 μ m MK886 plus indomethacin sensitized cells to killing by exogenous arachidonic acid, which induces PTP opening and cytochrome c release (Scorrano, L., Penzo, D., Petronilli, V., Pagano, F., and Bernardi, P. (2001) J. Biol. Chem. 276, 12035–12040). Combination of MK886 and cyclooxygenase inhibitors may represent a viable therapeutic strategy to force cell death through the mitochondrial pathway. This approach should be specifically useful to kill cells possessing a high flux of arachidonic acid and its metabolites like prostate and colon cancer cells.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M204450200