Novel nitro-oxy derivatives of celecoxib for the regulation of colon cancer cell growth.
Celecoxib is a non-steroidal anti-inflammatory drug (NSAID) developed as a selective inhibitor of cyclooxygenase-2 (COX-2). Despite the associated cardiovascular toxicity risk, celecoxib has been found to be effective in reducing cancer risk in animal and human studies. In the present study the antiproliferative activity of novel nitro-oxy-methyl substituted analogues of celecoxib (NO-cel), potentially less cardiotoxic, has been investigated in vitro on human colon cancer cells and compared with action of the parent drug. Moreover, experiments were performed in order to evaluate whether COX-2 pharmacological inhibition may affect beta-catenin/E-cadherin signalling pathway. All the tested analogues of celecoxib exerted a significant antiproliferative activity on COX-2 positive HT-29 human colon cancer cells, being less effective on the COX-2 negative SW-480 human colon cancer cell line. In particular, the analogue displaying two nitro-oxy functions fully mimicked the known inhibitory properties of celecoxib, including inhibition of COX-2, as well as of ERK/MAPK and beta-catenin signalling pathways. Interestingly, the latter compound also elicited a strong reorganization of the beta-catenin/E-cadherin complex, which has been suggested to be relevant for colon carcinogenesis. On these premises, NO-cel analogues of celecoxib can represent promising colon cancer chemopreventive agents potentially able to affect colon cancer development.
Bozzo
Francesca
F
Dipartimento di Medicina e Oncologia Sperimentale, University of Torino, C. Raffaello 30, 10125 Turin, Italy.
Bassignana
Andrea
A
Lazzarato
Loretta
L
Boschi
Donatella
D
Gasco
Alberto
A
Bocca
Claudia
C
Miglietta
Antonella
A
D015820:Cadherins / Q000378:metabolism; D000068579:Celecoxib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051176:beta Catenin / Q000378:metabolism
D015820:Cadherins; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D051176:beta Catenin; D051546:Cyclooxygenase 2; D000068579:Celecoxib