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Modification of eicosanoid profile in human blood treated by dual COX/LOX inhibitors
J Pommery1, N Pommery, J-P Hénichart
1Institut de Chimie Pharmaceutique Albert Lespagnol, EA 2692, Lille, France.
Abstract:
The arachidonic acid metabolizing enzymes, the cyclooxygenases (COXs) and lipoxygenases (LOXs), have been implicated in the development of a variety of cancers and numerous new therapeutic inhibitors are currently under investigation. However, given the interdependence of the two pathways, the effect of inhibiting one pathway with relatively selective agents can only be appreciated in the in vivo situation. Clearly then, because of their potential beneficial or deleterious effects, it is important to understand the nature and levels of the resulting arachidonic acid metabolites when treating patients with relatively selective inhibitor drugs. In this study, using reference COX-2, 5-LOX and dual COX-2/5-LOX inhibitors, we devised a protocol which permitted the simultaneous quantification of eicosanoid metabolites formed during stimulation of human peripheral venous blood samples with the calcium ionophore, A23187, in the absence and presence of lipopolysaccharide (LPS). Not surprisingly, the end products of both COX and LOX pathways were affected depending on the inhibitor, or combination of inhibitors, used and the concentrations of drug tested. In conclusion, the method described permits the rapid screening of novel compounds for potentially positive and/or negative effects upon the products of arachidonic acid metabolism.
Insights
This study developed a method to measure arachidonic acid metabolites, crucial for understanding cancer drug effects. The technique helps screen new inhibitors by analyzing how they impact cyclooxygenase (COX) and lipoxygenase (LOX) pathways.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Cyclooxygenases (COX) and lipoxygenases (LOX) are key enzymes in arachidonic acid metabolism, implicated in cancer development.
- Interdependence of COX and LOX pathways necessitates in vivo evaluation of selective inhibitors.
- Understanding metabolite profiles is crucial for assessing therapeutic effects and potential side effects of COX/LOX inhibitors.
Purpose of the Study:
- To develop and validate a protocol for simultaneous quantification of eicosanoid metabolites.
- To assess the impact of selective COX-2, 5-LOX, and dual COX-2/5-LOX inhibitors on arachidonic acid metabolism.
- To enable rapid screening of novel compounds affecting these pathways.
Main Methods:
- Human peripheral venous blood samples were stimulated with calcium ionophore (A23187) and lipopolysaccharide (LPS).
- Reference COX-2, 5-LOX, and dual COX-2/5-LOX inhibitors were used.
- Simultaneous quantification of eicosanoid metabolites was performed in the presence and absence of inhibitors.
Main Results:
- Inhibitor type and concentration influenced the levels of both COX and LOX pathway end products.
- The study demonstrated the differential effects of selective and dual inhibitors on metabolite profiles.
- The developed method allowed for observation of pathway interdependence.
Conclusions:
- The described method enables rapid screening of novel compounds for their effects on arachidonic acid metabolism.
- This technique is valuable for evaluating potential positive and negative impacts of inhibitors.
- Understanding these metabolic effects is vital for cancer drug development and patient treatment.
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