Celecoxib leads to G2/M arrest by induction of p21 and down-regulation of cyclin B1 expression in a p53-independent manner.
A unique in vitro system has been developed in our lab that consists of normal enterocytes derived from the rat ileum (IEC-18 cells) and their transformed derivatives with c-K-ras (R1 cells), anti-sense bak (B3 cells) and cyclin D1 (D1 cells). R1 and B3 cells express high level of COX-2 protein and PGE2. IEC 18 and D1 cells express negligible amount of COX-2, and produce very low level of PGE2. A relatively low dose of celecoxib (5-10 microM) induced G2/M arrest, followed by induction of apoptosis in the transformed but not in the normal cells. Down-regulation of cyclin B1 and up-regulation of p21 expressions independent of p53 might have cause this cell cycle block. Growth inhibition was related to COX-2 function with 90-95% reduction in PGE2 production. These findings may be of clinical importance, since low concentration of celecoxib can be achieved in human serum following standard anti-inflammatory (100-200 mg bid) regime.
Dvory-Sobol
Hadas
H
Integrated Comprehensive Cancer Prevention Center, Tel Aviv Sourasky Medical Center, 6 Weizmann St., Tel Aviv 64239, Israel.
Cohen-Noyman
Efrat
E
Kazanov
Diana
D
Figer
Arie
A
Birkenfeld
Shlomo
S
Madar-Shapiro
Liora
L
Benamouzig
Robert
R
Arber
Nadir
N
D000818:Animals; D000068579:Celecoxib; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D019926:Cyclin B / Q000187:drug effects* / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D020895:Enterocytes / Q000187:drug effects; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects*; D011905:Genes, ras / Q000187:drug effects; D006801:Humans; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects
C493957:Cdkn1a protein, mouse; D019926:Cyclin B; D050759:Cyclin-Dependent Kinase Inhibitor p21; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D015232:Dinoprostone