Curcumin synergistically potentiates the growth-inhibitory and pro-apoptotic effects of celecoxib in osteoarthritis synovial adherent cells.
OBJECTIVE
Osteoarthritis (OA) is the Western world's leading cause of disability. Cyclo-oxygenase-2 (COX-2) inhibitors are efficient anti-inflammatory agents commonly used in the treatment of osteoarthritis. However, recent studies have shown that their long-term use may be limited due to cardiovascular toxicity. The anti-inflammatory efficacy of the phytochemical curcumin has been demonstrated in several in vitro and animal models. This study was undertaken to investigate whether curcumin augments the growth-inhibitory and pro-apoptotic effects of celecoxib in OA synovial adherent cells.


METHODS
OA synovial adherent cells were prepared from human synovial tissue collected during total knee replacement surgery. The cells were exposed to different concentrations of celecoxib (0-40 mum), curcumin (0-20 mum) and their combination. Flow cytometric analysis was used to measure the percentage of cells with a subdiploid DNA content, the hallmark of apoptosis. COX-2 activity was assessed by measuring production of prostaglandin E(2) by enzyme-linked immunoassay.


RESULTS
A synergistic effect was observed in inhibition of cell growth when the cells were exposed to various concentrations of celecoxib combined with curcumin. The inhibitory effect of the combination on cell growth was associated with an increased induction of apoptosis. The synergistic effect was mediated through a mechanism that involves inhibition of COX-2 activity.


CONCLUSIONS
This effect may enable the use of celecoxib at lower and safer concentrations, and may pave the way for a novel combination treatment in osteoarthritis and other rheumatological disorders.
Lev-Ari
S
S
Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel.
Strier
L
L
Kazanov
D
D
Elkayam
O
O
Lichtenberg
D
D
Caspi
D
D
Arber
N
N
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000068579:Celecoxib; D002448:Cell Adhesion; D002455:Cell Division / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D020370:Osteoarthritis, Knee / Q000378:metabolism / Q000473:pathology*; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D013583:Synovial Membrane / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D052246:Cyclooxygenase 2 Inhibitors; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D003474:Curcumin; D000068579:Celecoxib; D015232:Dinoprostone