Abstract
We have investigated the mitochondrial and cellular effects of the lipoxygenase inhibitor MK886. Low concentrations (1 microM) of MK886 selectively sensitized the permeability transition pore (PTP) to opening, whereas higher concentrations of MK886 (10 microM) 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 microM), whereas the lower concentration (1 microM) had no major effect on cell survival. However, 1 microM 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 microM 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.
Highlights
We have investigated the mitochondrial and cellular effects of the lipoxygenase inhibitor MK886
An important link between arachidonic acid metabolism and the mitochondrial proapoptotic pathway is suggested by the findings that apoptosis induction by arachidonic acid involved activation of caspase-3, a process that is amplified by release of mitochondrial cytochrome c [2] and Smac/DIABLO [4]; and that Bax, which kills cells via the mitochondrial pathway [17,18,19,20,21,22], is essential for the apoptotic response of cells to nonsteroidal anti-inflammatory drugs [23]
MK886 is unique among inhibitors of 5-LOX in that it acts on an arachidonic acid transfer protein, FLAP, which delivers the substrate to LOX [38]
Summary
We have investigated the mitochondrial and cellular effects of the lipoxygenase inhibitor MK886. 1 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. Combination of MK886 and cyclooxygenase inhibitors may represent a viable therapeutic strategy to force cell death through the mitochondrial pathway This approach should be useful to kill cells possessing a high flux of arachidonic acid and its metabolites like prostate and colon cancer cells. Combination of low concentrations of MK886 with a COX inhibitor may represent a viable therapeutic strategy to force cell death through the mitochondrial pathway, and this approach should be useful to kill cells possessing a high flux of arachidonic acid and its metabolites like prostate and colon cancer cells
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