Anti-tumoral effect of a celecoxib low dose on a model of human medullary thyroid cancer in nude mice.
BACKGROUND
Medullary thyroid carcinoma (MTC) is a C cell neoplasm secreting calcitonin (CT). Surgery remains the only treatment as MTC is resistant to radio- and chemotherapies. Anti-tumoral effects of nonsteroidal anti-inflammatory drugs have been observed in various cancers. Thus, we tested the anti-tumoral action of an nonsteroidal anti-inflammatory drug, celecoxib, on MTC development.


METHODS
We studied the expression of prostaglandin (PG) metabolism enzymes in our in vitro (TT cells) and in vivo (TT tumors) models and in human MTCs by Western blot. We checked the effect of celecoxib on xenografted subcutaneous tumors in nude mice. Celecoxib was administrated in powder food during 9 weeks from day 1 after TT cell injection. At the end of the experiment plasma CT was measured by radioimmunoassay, the number of proliferating cells in tumor tissues was detected by Ki67 immunocytochemistry and apoptotic nuclei by caspase 3 ad Bcl-2 expression and terminal-deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) method. PGE(2) concentrations in TT cell medium were evaluated by an enzyme immunoassay kit.


RESULTS
Our in vitro and in vivo models were validated: the status of PG metabolism enzymes was comparable in these models and in human MTCs. A very low dose of celecoxib, 120 ppm in food, inhibited tumor volume by 71% and reduced plasma CT level. Although no proapoptotic effect was detectable in tumors, a decrease of proliferating cells was revealed. The inducible PG synthesis enzyme, cyclooxygenase 2, was only detectable in rare stromal cells. The expression of the constitutive PG synthesis enzyme, cyclooxygenase 1, was diminished, while the level of the catabolism enzyme, 15-PG dehydrogenase, was decreased. In vitro, TT cells treated for 12 days with 25 muM celecoxib reproduced these changes, and PGE(2) secretion was not significantly modified by the treatment, in these conditions.


CONCLUSIONS
Celecoxib has a good therapeutic potential for MTC to prevent metastasis growth, and its anti-tumoral effect is, at least in part, independent of PGE(2).
Quidville
Virginie
V
Laboratoire de Recherche Translationelle, Institut Gustave Roussy, Villejuif, France.
Segond
Nadine
N
Tebbi
Ali
A
Cohen
Regis
R
Jullienne
Annick
A
Lepoivre
Michel
M
Lausson
Sylvie
S
D000818:Animals; D015153:Blotting, Western; D018276:Carcinoma, Medullary / Q000188:drug therapy*; D053148:Caspase 3 / Q000096:biosynthesis; D000068579:Celecoxib; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D015232:Dinoprostone / Q000502:physiology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D011720:Pyrazoles / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D013964:Thyroid Neoplasms / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
D052246:Cyclooxygenase 2 Inhibitors; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D013449:Sulfonamides; D053148:Caspase 3; D000068579:Celecoxib; D015232:Dinoprostone