Lipoxygenase inhibition induced apoptosis, morphological changes, and carbonic anhydrase expression in human pancreatic cancer cells

Epidemiologic and animal studies have linked pancreatic cancer growth with fat intake, especially unsaturated fats. Arachidonic acid release from memb rane phospholipids is essential for tumor cell proliferation. Lipoxygenases (LOX) constitute one pathway for arachidonate metabolism. We previously re ported that 5-LOX and 12-LOX are upregulated in human pancreatic cancer cel ls and that blockade of these enzymes abolishes pancreatic cancer cell grow th. The present study was aimed at evaluating the effect of LOX inhibition on differentiation and apoptosis in pancreatic cancer cells in parallel wit h growth inhibition. Four human pancreatic cancer cell lines, PANC-1, MiaPa ca2, Capan2, and HPAF, mere used. Apoptosis was evaluated by three separate methods, including DNA propidium iodide staining, DNA fragmentation, and t he TUNEL assay. Morphological changes and carbonic anhydrase activity were used to determine the effect of LOX inhibitors on differentiation. The gene ral LOX inhibitor NDGA, the 5-LOX inhibitor Rev5901, and the 12-LOX inhibit or baicalein all induced apoptosis in all four pancreatic cancer cell lines , as confirmed by all three methods, suggesting that both the 5-LOX and 12- LOX pathways are important for survival of these cells. Furthermore, NDGA, Rev5901, or baicalein resulted in marked cellular morphological changes in parallel with increased intracellular carbonic anhydrase activity, indicati ng that LOX blockade induced a more differentiated phenotype in human pancr eatic cancer cells. Together with our previous findings, this study suggest s that perturbations of LOX activity affect pancreatic cancer cell prolifer ation and survival. Blockade of LOX enzymes may be valuable for the treatme nt of human pancreatic cancer, (C) 1999 Academic Press.