Inhibitory effects of caffeic acid phenethyl ester on the activity and expression of cyclooxygenase-2 in human oral epithelial cells and in a rat model of inflammation.
We investigated the mechanisms by which caffeic acid phenethyl ester (CAPE), a phenolic antioxidant, inhibited the stimulation of prostaglandin (PG) synthesis in cultured human oral epithelial cells and in an animal model of acute inflammation. Treatment of cells with CAPE (2.5 microg/ml) suppressed phorbol ester (12-O-tetradecanoylphorbol-13-acetate; TPA) and calcium ionophore (A23187)-mediated induction of PGE2 synthesis. This relatively low concentration of CAPE did not affect amounts of cyclooxygenase (COX) enzymes. CAPE nonselectively inhibited the activities of baculovirus-expressed hCOX-1 and hCOX-2 enzymes. TPA- and A23187-stimulated release of arachidonic acid from membrane phospholipids was also suppressed by CAPE (4-8 microg/ml). Higher concentrations of CAPE (10-20 microg/ml) suppressed the induction of COX-2 mRNA and protein mediated by TPA. Transient transfections using human COX-2 promoter deletion constructs were performed; the effects of TPA and CAPE were localized to a 124-bp region of the COX-2 promoter. In the rat carrageenan air pouch model of inflammation, CAPE (10-100 mg/kg) caused dose-dependent suppression of PG synthesis. Amounts of COX-2 in the pouch were markedly suppressed by 100 mg/kg CAPE but were unaffected by indomethacin. These data are important for understanding the anticancer and anti-inflammatory properties of CAPE.
Michaluart
P
P
Department of Medicine, Strang Cancer Prevention Center, New York, New York 10021, USA.
Masferrer
J L
JL
Carothers
A M
AM
Subbaramaiah
K
K
Zweifel
B S
BS
Koboldt
C
C
Mestre
J R
JR
Grunberger
D
D
Sacks
P G
PG
Tanabe
T
T
Dannenberg
A J
AJ
D000388:Air; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000378:metabolism; D002109:Caffeic Acids / Q000494:pharmacology*; D000001:Calcimycin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D002351:Carrageenan / Q000633:toxicity; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D007476:Ionophores / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism; D008565:Membrane Proteins; D009061:Mouth Mucosa / Q000166:cytology*; D017924:Nucleopolyhedroviruses / Q000235:genetics; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D010743:Phospholipids / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D001095:Arachidonic Acids; D002109:Caffeic Acids; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007476:Ionophores; D007527:Isoenzymes; D008563:Membrane Lipids; D008565:Membrane Proteins; D010743:Phospholipids; D011993:Recombinant Fusion Proteins; D000001:Calcimycin; D002351:Carrageenan; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C055494:caffeic acid phenethyl ester; D015232:Dinoprostone; D010626:Phenylethyl Alcohol; D013755:Tetradecanoylphorbol Acetate; D007213:Indomethacin