A novel celecoxib derivative potently induces apoptosis of human synovial fibroblasts.
We have already demonstrated that celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, has a proapoptotic effect on synovial fibroblasts obtained from patients with rheumatoid arthritis (RA). Here we report on the development of two novel derivatives of celecoxib, N-(2-aminoethyl)-4-[5-(4-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (TT101) and 4-[5-(4-aminophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (TT201), including whether these compounds have a proapoptotic effect on synovial fibroblasts. Synovial fibroblasts were harvested from the synovial tissues of patients with RA or osteoarthritis (OA). Cell proliferation and cell viability were assessed by the incorporation of 5-bromo-2'-deoxyuridine and by the 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt assay, respectively. Apoptosis was detected by the identification of DNA fragmentation, and activation of caspase-3 was detected by the addition of a caspase-3 substrate to cell lysates. Production of prostaglandin E(2) by RA synovial fibroblasts was analyzed by enzyme-linked immunosorbent assay. TT101 inhibited the proliferation of RA and OA synovial fibroblasts in a concentration-dependent manner. It caused a marked decrease of cell viability and induced DNA fragmentation more potently than either celecoxib or SC-236 (4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide). TT101 also increased caspase-3 activity. The order of potency of the COX-2 inhibitory activity of these drugs in RA synovial fibroblasts was celecoxib = SC-236 > rofecoxib > TT201 > TT101. In conclusion, we developed TT101 with about a 5- to 10-fold stronger proapoptotic effect on RA and OA synovial fibroblasts compared with that of celecoxib. Although the mechanism of action of TT101 remains unclear, it may have potential as a novel antirheumatic agent.
Kusunoki
Natsuko
N
Division of Rheumatology, Department of Internal Medicine, Toho University Omori Medical Center, 6-11-1 Omori-Nishi, Ota-ku, Tokyo 143-8541, Japan. kusunoki@med.toho-u.ac.jp
Ito
Takumi
T
Sakurai
Nobuyuki
N
Suguro
Toru
T
Handa
Hiroshi
H
Kawai
Shinichi
S
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D000068579:Celecoxib; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D053938:DNA Fragmentation / Q000187:drug effects; D015232:Dinoprostone / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects*; D019254:Genes, bcl-2 / Q000187:drug effects; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology; D013583:Synovial Membrane / Q000166:cytology* / Q000187:drug effects; D000096926:Benzenesulfonamides
D061945:Caspase Inhibitors; D020169:Caspases; D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D004791:Enzyme Inhibitors; D007783:Lactones; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; C504152:4-(5-(4-aminophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; C504153:N-(2-aminoethyl)-4-(5-(4-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; C116926:rofecoxib