Inhibition of 5-lipoxygenase induces cell death in anti-inflammatory fatty acid-treated HL-60 cells.

Abstract

BACKGROUND:

Enteral nutrition containing eicosapentaenoic (20:5 omega-3) and gamma-linolenic acid (18:3 omega-6) decreases leukotriene B4 levels and neutrophils in bronchoalveolar lavage fluid of patients and animals with acute respiratory distress syndrome. Reduction in pulmonary inflammation may be caused by decreased neutrophil migration or survival. We showed that apoptosis increases in eicosapentaenoic/gamma-linolenic acid-treated HL-60 cells. We hypothesize that eicosapentaenoic/gamma-linolenic acid-induced apoptosis involves downstream metabolic products of lipoxygenase and cyclooxygenase enzymes. This study determined the effects of inhibitors of lipoxygenase and cyclooxygenase enzymes on eicosapentaenoic/gamma-linolenic acid-treated HL-60 cells.

METHODS:

Cells were incubated with 50 microM eicosapentaenoic/20 microM gamma-linolenic acid in the presence of an enzyme inhibitor (1-10 microM) for 12 hours. Compounds were used to inhibit cyclooxygenase (ibuprofen), 12-lipoxygenase (baicalein), or 5-lipoxygenase (AA-861). Flow cytometry assessed viability, apoptosis, and necrosis.

RESULTS:

5-Lipoxygenase inhibition decreased cell viability and increased cell death (apoptosis + necrosis) in eicosapentaenoic/gamma-linolenic acid-treated HL-60 cells. Inhibition of cyclooxygenase 1 and 2 and 12-lipoxygenase had no significant effect on cellular viability and death in eicosapentaenoic/gamma-linolenic acid-treated HL-60 cells. Adding leukotriene B4 counteracted the effect of 5-lipoxygenase inhibition on apoptosis in eicosapentaenoic/gamma-linolenic acid-treated HL-60 cells.

CONCLUSIONS:

These data suggest that the processing of eicosapentaenoic and gamma-linolenic acid by 5-lipoxygenase is critical to HL-60 cell survival.

• Authors: Robert C Gillis, Brian J Daley, Blaine L Enderson, Michael D Karlstad
• Journal: JPEN. Journal of parenteral and enteral nutrition (JPEN J Parenter Enteral Nutr) 2004 Sep-Oct Vol. 28 Issue 5 Pg. 308-14 ISSN: 0148-6071 [Print] United States
• PMID: 15449569 (Publication Type: Journal Article)

Chemical References

• Cyclooxygenase Inhibitors
• Drug Combinations
• Lipoxygenase Inhibitors
• gamma-Linolenic Acid
• Eicosapentaenoic Acid
• Arachidonate 5-Lipoxygenase

Topics

• Apoptosis (drug effects)
• Arachidonate 5-Lipoxygenase (metabolism)
• Cell Survival (drug effects)
• Cyclooxygenase Inhibitors
• Dose-Response Relationship, Drug
• Drug Combinations
• Eicosapentaenoic Acid (pharmacology)
• Enteral Nutrition
• Flow Cytometry
• HL-60 Cells
• Humans
• Lipoxygenase Inhibitors
• gamma-Linolenic Acid (pharmacology)