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

Abstract

Epidemiologic and animal studies have linked pancreatic cancer growth with fat intake, especially unsaturated fats. Arachidonic acid release from membrane phospholipids is essential for tumor cell proliferation. Lipoxygenases (LOX) constitute one pathway for arachidonate metabolism. We previously reported that 5-LOX and 12-LOX are upregulated in human pancreatic cancer cells and that blockade of these enzymes abolishes pancreatic cancer cell growth. The present study was aimed at evaluating the effect of LOX inhibition on differentiation and apoptosis in pancreatic cancer cells in parallel with growth inhibition. Four human pancreatic cancer cell lines, PANC-1, MiaPaca2, Capan2, and HPAF, were used. Apoptosis was evaluated by three separate methods, including DNA propidium iodide staining, DNA fragmentation, and the TUNEL assay. Morphological changes and carbonic anhydrase activity were used to determine the effect of LOX inhibitors on differentiation. The general LOX inhibitor NDGA, the 5-LOX inhibitor Rev5901, and the 12-LOX inhibitor 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, indicating that LOX blockade induced a more differentiated phenotype in human pancreatic cancer cells. Together with our previous findings, this study suggests that perturbations of LOX activity affect pancreatic cancer cell proliferation and survival. Blockade of LOX enzymes may be valuable for the treatment of human pancreatic cancer.

• Authors: X Z Ding, C A Kuszynski, T H El-Metwally, T E Adrian
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 266 Issue 2 Pg. 392-9 (Dec 20 1999) ISSN: 0006-291X [Print] United States
• PMID: 10600514 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright 1999 Academic Press.

Chemical References

• Flavanones
• Flavonoids
• Lipoxygenase Inhibitors
• Quinolines
• alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol
• Propidium
• baicalein
• Masoprocol
• Carbonic Anhydrases

Topics

• Apoptosis (drug effects)
• Carbonic Anhydrases (metabolism)
• Cell Differentiation (drug effects)
• Cell Division (drug effects)
• Cell Size (drug effects)
• DNA Fragmentation (drug effects)
• Flavanones
• Flavonoids (pharmacology)
• Gene Expression Regulation, Enzymologic (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• In Situ Nick-End Labeling
• Lipoxygenase Inhibitors (pharmacology)
• Masoprocol (pharmacology)
• Pancreatic Neoplasms
• Propidium
• Quinolines (pharmacology)
• Tumor Cells, Cultured