Lipoxygenase inhibitor-induced apoptosis in Madin-Darby canine kidney cells

Both cyclooxygenase (COX) and lipoxygenase (LOX), as well as their metabolites, are suggested to play a dual role in regulating cell survival and apoptosis in various types of cells. However, their mechanism remains unclear. When Madin-Darby canine kidney (MDCK) cells were treated with 12-O-tetradecanoylphorbol beta-acetate (TPA) and nordihydroguaiaretic acid (NDGA), a LOX inhibitor, we detected a synergistic stimulation of apoptosis as determined by hallmarks such as DNA ladder formation and chromatin condensation. The apoptosis was slightly induced by TPA alone. The effect of TPA was markedly stimulated along with NDGA. NDGA on its own did not have the ability to induce apoptosis. Aspirin, a COX inhibitor, was not effective. Alternatively, hydrogen peroxide-induced apoptosis was not promoted by the addition of NDGA. These two types of apoptosis would be regulated by a different mechanism. Although NDGA-induced apoptosis might be associated with the depletion of intracellular reduced glutathione in some kinds of tumor cells, N-acetyl cysteine (NAC), a thiol agent, had no inhibitory effect on the NDGA-induced apoptosis. To determine the further mechanism of NDGA-induced apoptosis in MDCK cells, we are examining the involvement of apoptosis-specific signaling molecules and the effect of lipoxygenase metabolites on NDGA-induced apoptosis. (C) 2002 Elsevier Science B.V. All rights reserved.