Mitochondria are direct targets of the lipoxygenase inhibitor MK886 - A strategy for cell killing by combined treatment with MK886 and cyclooxygenase inhibitors

We have investigated the mitochondrial and cellular effects of the lipoxygenase inhibitor MK886. Low concentrations (1 mu(M)) of MK886 selectively sensitized the permeability transition pore (PTP) to opening, whereas higher concentrations of MK886 (10 mu(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 mu(M)), whereas the lower concentration (1 mu(M)) had no major effect on cell survival. However, 1 mu(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 mu(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.