Neoadjuvant selective COX-2 inhibition down-regulates important oncogenic pathways in patients with esophageal adenocarcinoma.
OBJECTIVE
To evaluate the effects of neoadjuvant therapy with the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib in vitro and in patients with esophageal adenocarcinoma on COX-2 and MET expression.


BACKGROUND
High COX-2 and/or MET expression levels are negative prognostic factors for adenocarcinoma of the esophagus. Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors exert anticancer mechanisms as is evident from epidemiologic studies and from experimental models for esophageal cancer. The mechanisms and the significance of these findings in patients with adenocarcinoma of the esophagus are unknown.


METHODS
Esophageal adenocarcinoma cell lines were used to asses the effects in vitro. To study the clinical effects 12 patients with esophageal adenocarcinoma were included for neoadjuvant treatment (4 weeks) with celecoxib at 400 mg twice daily. Fifteen patients not receiving NSAIDs or celecoxib were included as a control. Effects were evaluated using the MTT-cell viability test, Western blot analysis, immunohistochemistry, and RT-PCR.


RESULTS
In vitro celecoxib administration resulted in decreased cell viability, increased apoptosis, and decreased COX-2 and MET expression levels. In patients, neoadjuvant treatment with celecoxib significantly down-regulated COX-2 and MET expression in the tumor when compared with the nontreated control group and when compared with pretreatment measurements.


CONCLUSIONS
This is the first study to show in vitro and in patients with esophageal adenocarcinoma that selective COX-2 inhibition down-regulates COX-2 and MET expression, both important proteins involved in cancer progression and dissemination. Therefore, (neo)adjuvant therapy with celecoxib might have clinical potential for patients with esophageal adenocarcinoma.
Tuynman
Jurriaan B
JB
Departments of Surgery, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. J.B.Tuynman@amc.uva.nl
Buskens
Christianne J
CJ
Kemper
Kristel
K
ten Kate
Fiebo J W
FJ
Offerhaus
G Johan A
GJ
Richel
Dirk J
DJ
van Lanschot
J Jan B
JJ
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology; D015153:Blotting, Western; D000068579:Celecoxib; D051545:Cyclooxygenase 1 / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D015536:Down-Regulation; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D020360:Neoadjuvant Therapy; D019859:Proto-Oncogene Proteins c-met / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D019859:Proto-Oncogene Proteins c-met; D000068579:Celecoxib