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9932807 
Journal Article 
Cyclooxygenase-2 inhibitors reverse chemoresistance phenotype in medullary thyroid carcinoma by a permeability glycoprotein-mediated mechanism 
Zatelli, MC; Luchin, A; Piccin, D; Tagliati, F; Bottoni, A; Vignali, C; Bondanelli, M; Degli Uberti, EC 
2005 
Yes 
Journal of Clinical Endocrinology and Metabolism
ISSN: 0021-972X
EISSN: 1945-7197 
90 
10 
5754-5760 
English 
16091477 
OBJECTIVE: Medullary thyroid carcinoma (MTC) is a highly chemoresistant malignant neoplasia deriving from parafollicular C cells. Chemotherapy failure has been ascribed, at least in part, to the overexpression by MTC of the multidrug resistance 1 (MDR1) gene, encoding a transmembrane glycoprotein [permeability glycoprotein (P-gp)] that antagonizes intracellular accumulation of cytotoxic agents. P-gp expression and function in a rat model have been demonstrated to depend on cyclooxygenase (COX)-2 isoform levels, which are found elevated in many human cancers. The aim of our study was to investigate the role of the COX-2 pathway in modulating chemoresistance.

DESIGN AND RESULTS: We investigated P-gp and COX-2 expression and then evaluated the sensitizing effects of COX-2 inhibitors on the cytotoxic effects of doxorubicin in the presence or in the absence of prostaglandin E2 in primary cultures and in a human MTC cell line, TT. Moreover, P-gp function has been studied. Our data show that TT cells express both MDR1 and COX-2 and that rofecoxib, a selective COX-2 inhibitor, sensitizes TT cells to the cytotoxic effects of doxorubicin, reducing P-gp expression and function.

CONCLUSIONS: Our data suggest that these effects are mediated by a mechanism not involving the generation of prostaglandin E2, possibly implicating the synthesis of other COX-2 products.