Simultaneous inhibition of COX-2 and 5-LOX activities augments growth arrest and death of premalignant and malignant human lung cell lines.
The arachidonic acid-metabolizing enzymes cyclooxygenase-2 (COX-2) or 5-lipoxygenase (5-LOX) are overexpressed during lung carcinogenesis and their end products (e.g.; PGE2, 5-HETE, and LTB4) have been implicated in tumor development. Recently, COX-2 inhibitors (e.g.; celecoxib) and 5-LOX inhibitors (e.g.; MK886 and REV5901) used as single agents have shown promising activities in the treatment and chemoprevention of cancer. However, little is known about the effects of combinations of these inhibitors. We found that simultaneous treatment of premalignant and malignant human lung cell lines with celecoxib, MK886, and REV5901 is more potent in growth suppression and induction of cell death than single or dual combination of these agents. However, their sensitivity to the inhibitors was not directly associated with the expression of COX-2, 5-LOX, or 5-LOX-activating protein (FLAP), but correlated with the production of corresponding metabolites. Furthermore, partial protection of cell death was observed when PGE2 and/or 5-HETE was added to cell cultures treated with celecoxib, MK886, and REV5901 simultaneously. Our data indicate that a triple drug combination of distinct inhibitors of the eicosanoid metabolism at clinically feasible concentrations were more effective than each agent alone suggesting further investigations.
Schroeder
Claudia P
CP
Department of Thoracic, Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center Houston, TX 77030, USA.
Yang
Peiying
P
Newman
Robert A
RA
Lotan
Reuben
R
D058927:5-Lipoxygenase-Activating Proteins; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D000068579:Celecoxib; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000494:pharmacology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013449:Sulfonamides / Q000494:pharmacology*; D002722:Chlorobenzenes
D058927:5-Lipoxygenase-Activating Proteins; D002352:Carrier Proteins; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors; D015232:Dinoprostone; D006893:Hydroxyeicosatetraenoic Acids; D007211:Indoles; D007975:Leukotriene B4; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D011720:Pyrazoles; D011804:Quinolines; D013449:Sulfonamides; C548592:ALOX5AP protein, human; C060893:MK-886; D002722:Chlorobenzenes; C049740:alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid