The anti-proliferative potency of celecoxib is not a class effect of coxibs.
Celecoxib, a COX-2 (cyclooxygenase-2)-selective inhibitor (coxib), is the only NSAID (non-steroidal anti-inflammatory drug) that has been approved for adjuvant treatment of patients with familial adenomatous polyposis. To investigate if the anti-proliferative effect of celecoxib extends to other coxibs, we compared the anti-proliferative potency of all coxibs currently available (celecoxib, rofecoxib, etoricoxib, valdecoxib, lumiracoxib). Additionally, we used methylcelecoxib (DMC), a close structural analogue of celecoxib lacking COX-2-inhibitory activity. Due to the fact that COX-2 inhibition is the main characteristic of these substances (with exception of methylcelecoxib), we conducted all experiments in COX-2-overexpressing (HCA-7) and COX-2-negative (HCT-116) human colon cancer cells, in order to elucidate whether the observed effects after coxib treatment depend on COX-2 inhibition. Cell survival was assessed using the WST proliferation assay. Apoptosis and cell cycle arrest were determined using flow cytometric and Western blot analysis. The in vitro results were confirmed in vivo using the nude mouse model. Among all coxibs tested, only celecoxib and methylcelecoxib decreased cell survival by induction of cell cycle arrest and apoptosis and reduced the growth of tumor xenografts in nude mice. None of the other coxibs (rofecoxib, etoricoxib, valdecoxib, lumiracoxib) produced anti-proliferative effects, indicating the lack of a class effect and of a role for COX-2. Our data emphasize again the outstanding anti-proliferative activity of celecoxib and its close structural analogue methylcelecoxib in colon carcinoma models in vitro and in vivo.
Pharmazentrum frankfurt/ZAFES, Institute for Clinical Pharmacology, Johann Wolfgang Goethe-University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt/Main, Germany. susanne.schiffmann@med.uni-frankfurt.de
Susanne
S
Schiffmann
Thorsten Jürgen
TJ
Maier
Ivonne
I
Wobst
Astrid
A
Janssen
Heike
H
Corban-Wilhelm
Carlo
C
Angioni
Gerd
G
Geisslinger
Sabine
S
Grösch
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis; D000068579:Celecoxib; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; C495270:CTNNB1 protein, human; D056741:Cyclin D; D016213:Cyclins; D052246:Cyclooxygenase 2 Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D011720:Pyrazoles; D013449:Sulfonamides; D051176:beta Catenin; C413374:p27 antigen; D011065:Poly(ADP-ribose) Polymerases; D000068579:Celecoxib; D015232:Dinoprostone