Antiproliferative effect of a novel nitro-oxy derivative of celecoxib in human colon cancer cells: role of COX-2 and nitric oxide.
It has been shown previously that a novel nitrooxy derivative of celecoxib exerts antiproliferative and pro-apoptotic effects in human colon cancer cells. The aim of this study was to elucidate whether these biological properties depend on COX-2 inhibition and/or NO release. Therefore, the derivative was decomposed into the parent compound celecoxib and the NO donor benzyl nitrate and the biological role of each was tested in COX-2-positive (HT-29) and -negative (SW-480) colon cancer cells. The main findings were that the nitro-oxy derivative behaved like celecoxib in HT-29 cells in terms of COX-2 and ERK/MAPK inhibition, as well as induction of apoptosis, while the benzyl nitrate had no such effects. Interestingly, the beta-catenin system was activated by the nitro-oxy derivative as well as by benzyl nitrate alone more potently than by the parent compound celecoxib, suggesting a possible regulatory role for NO. In SW480 cells, these activities were substantially less pronounced, suggesting the presence of COX-2-dependent mechanisms in the modulation of these parameters.
Bocca
Claudia
C
Department of Experimental Medicine and Oncology University of Torino, Cso Raffaello, 30-10125 Torino, Italy. claudia.bocca@unito.it
Bozzo
Francesca
F
Bassignana
Andrea
A
Miglietta
Antonella
A
D017209:Apoptosis / Q000187:drug effects; D001593:Benzyl Compounds / Q000494:pharmacology*; D000068579:Celecoxib; D048708:Cell Growth Processes / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009566:Nitrates / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D051176:beta Catenin / Q000378:metabolism
D001593:Benzyl Compounds; C495270:CTNNB1 protein, human; D052246:Cyclooxygenase 2 Inhibitors; D009566:Nitrates; D020030:Nitric Oxide Donors; D011720:Pyrazoles; D013449:Sulfonamides; C482654:benzylnitrate; D051176:beta Catenin; D009569:Nitric Oxide; D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D000068579:Celecoxib