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 multi drug resistance (MDR) 1 gene, encoding a transmembrane glycoprotein (P-gp), that antagonizes intracellular accumulation of cytotoxic agents. P-gp protein expression and function in a rat model has been demonstrated to depend on cyclooxygenase 2 (COX-2) isoform levels, that are found elevated in many human cancers. The aim of our study is to investigate the role of 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 PGE₂ 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 PGE₂, but possibly implicating the synthesis of other COX-2 products.