Selective Cyclo-oxygenase 2 inhibitors revert chemoresistance In Medullary thyroid carcinoma by a mechanism mediated by P-gp and PGH2

Medullary thyroid carcinoma (MTC) is a malignant tumour deriving from parafollicular C cells, with a highly chemoresistant phenotype. Failure of medical therapy has been ascribed, at least in part, to multi drug resistance (MDR1) gene over-expression. MDR1 encodes for a transmembrane glycoprotein, P-gp, which hampers intracellular accumulation of cytotoxic drugs. It has been demonstrated that P-gp expression and function depend on cyclo-oxygenase 2 (COX-2) expression, which is elevated in many human tumours We have previously demonstrated that a human MTC cell line, TT, expresses MDR1 and COX-2. In this model, selective COX-2 inhibitors, such as Rofecoxib and NS-398, sensitize TT cells to the cytotoxic effects of doxorubicin (a well known chemotherapic drug), reducing P-gp expression and function. The aim of our study was to verify which prostaglandin mediate the effect of COX-2 on TT cells. TT cell were therefore treated with a selective COX-2 inhibitor (NS-398) with or without two COX-2 products, PGE2 and PGH2. P-gp expression was then evaluated by Western blot. P-gp levels were reduced by treatment with NS-398, while PGE2 and PGH2 did not significantly modify protein expression. Combined treatment with NS-398 and PGE2 did not restore P-gp expression, while combined treatment with NS-398 and PGH22 restored P-gp protein to normal levels. Our data suggest that the effects of COX-2 inhibitors on P-gp expression are mediated by PGH2, an intermediate product in prostaglandin synthesis, and not by PGE2, a final product. Moreover, these results confirm the hypothesis that selective COX-2 inhibitors might be employed to inhibit P-gp expression and function, reducing chemoresistance in MTC.