title: Differential effects of selective cyclooxygenase-2 inhibitors in inhibiting proliferation and induction of apoptosis in oral squamous cell carcinoma.
abstract: Cyclooxygenase-2 (COX-2), an enzyme that catalyzes the synthesis of prostaglandins, is made inducible by various stimuli such as inflammation. Although COX-2 is commonly overexpressed in a variety of premalignant and malignant conditions including oral leukoplakia and squamous cell carcinoma, relatively little research has compared the effects of various COX-2 inhibitors (celecoxib, NS-398, nimesulide and meloxicam). Therefore, we investigated the effects of four different selective COX-2 inhibitors on the growth of KB cells, derived from oral squamous cell carcinoma (OSCC) and its mechanisms. Celecoxib and NS-398 strongly suppressed the proliferation of KB cells at 10-100 microM, whereas nimesulide and meloxicam are less potent proliferation inhibitors. Only celecoxib induced apoptosis of the KB cells, as detected on the basis of DNA fragmentation, caspase-3/7 activation and cleaved poly(ADP-ribose) polymerase (PARP) fragmentation. All four COX-2 inhibitors increased COX-2 protein expression but suppressed prostaglandin (PG) E2 production in the KB cells, suggesting that the pro-apoptotic effect of celecoxib was unrelated to the inhibition of COX-2. Mechanistically, a high level of p53 protein and a low level of multidrug-resistant protein 1 (MRP1) and breast cancer resistant protein (BCRP) mRNA in KB cells with celecoxib may explain the differential effect of these selective COX-2 inhibitors in KB cells. Taken together, celecoxib is a good therapeutic candidate for treating OSCC through the suppression of cell proliferation and the induction of apoptosis in a COX-2 independent manner.
authors.affiliation: College of Dentistry and Research Institute of Oral Science, Kangnung National University, 120 Gangneung Daehangno, Gangneung-City, Gangwon-Do, Korea.
authors.forename: Seong-Hee
authors.initials: SH
authors.lastname: Ko
authors.forename: Geun Jun
authors.initials: GJ
authors.lastname: Choi
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Lee
authors.forename: Yoon A
authors.initials: YA
authors.lastname: Han
authors.forename: Soo-Jeong
authors.initials: SJ
authors.lastname: Lim
authors.forename: So Hee
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000201:enzymology*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000187:drug effects*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D053938:DNA Fragmentation; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D009062:Mouth Neoplasms / Q000201:enzymology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D053148:Caspase 3; D053179:Caspase 7; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D015232:Dinoprostone; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; C116614:ABCG2 protein, human; C496540:PTGS2 protein, human; C421109:multidrug resistance-associated protein 1