A Novel Celecoxib Derivative Potently Induces Apoptosis of Human Synovial Fibroblasts

Abstract

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,, 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-2Ј-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 ϭ SC-236 Ͼ rofecoxib Ͼ TT201 Ͼ 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.

Celecoxib induces anoikis in human colon carcinoma cells associated with the deregulation of focal adhesions and nuclear translocation of p130Cas

“…Thus, other authors have chemically dissociated the antitumor and COX-2 inhibitory activities, synthesizing derivatives with the same basic structure as celecoxib. [62][63][64][65] In conclusion, we have demonstrated that celecoxib induces anoikis by deregulating focal adhesion signaling. This deregulation includes, in all tested colon carcinoma cells, the cleavage of p130Cas to generate a 31 kDa fragment, which is translocated to the nucleus, leading to the activation of the mitochondrial apoptotic pathway.…”

Chandipura Virus Induces Neuronal Death through Fas-Mediated Extrinsic Apoptotic Pathway

“…The CDDE kit is based on the principle of identifying mono-or oligonucleosomes in a "sandwich enzyme immunoassay" from a fraction of cell lysates of apoptotic cells where fragmentation of DNA happens before membrane blebbing. Thus, it can specifically distinguish between apoptosis and necrosis, since in necrosis fragmented DNA is released in the growth medium due to premature rupture of the plasma membrane (31).…”

Pro-apoptotic effect of nonsteroidal anti-inflammatory drugs on synovial fibroblasts

“…Therefore, we tried to develop potent inducer of apoptosis by modification of the structure of celecoxib. We synthesized two celecoxib derivatives (TT101 and TT201) and analyzed their proapoptotic effect on RA synovial fibroblasts [36]. We summarized properties of several NSAIDs from the view point of bioactivities and structures ( Table 1).…”

“…8) in RA synovial fibroblasts when compared to celecoxib. NSAIDs without sulfonamide group, Reprinted from Kusunoki et al [36], with kind permission from American Society for Pharmacology and Experimental Therapeutics such as indomethacin, diclofenac, oxaprozin, zaltoprofen, also induced apoptosis in RA synovial fibroblasts. However, they activated PPARc in the cells, while celecoxib did not.…”