5-Fluorouracil (5-FU) is widely used in the treatment of head and neck squamous cell carcinoma (HNSCC). However, development of drug resistance is one of the major causes of HNSCC treatment failure. The goal of this study was to investigate the mechanism of 5-FU resistance and to develop a novel combination therapy with another agent which sensitizes cells to 5-FU. A 5-FU-resistant cell line, UM-SCC-23F/R, was developed from UM-SCC-23 cells. We determined sensitivities to 5-FU, etodolac and a combination treatment and also analyzed the expressions of cyclooxygenase-2 (COX-2) and thymidylate synthase (TS). Selective COX-2 inhibitor, etodolac, sensitized UM-SCC-23F/R cells to 5-FU. Expression of COX-2 decreased after etodolac treatment in both cell lines. While overexpression of TS was observed in UM-SCC-23F/R cells, etodolac inhibited TS expression, suggesting that the sensitizing effect induced by etodolac depends on TS suppression. We demonstrate for the first time an important inhibitory effect of etodolac on TS expression leading to sensitization to 5-FU in 5-FU-resistant cells. Our data suggest that TS inhibition can be accomplished by this routinely used nonsteroidal anti-inflammatory drug, and this may have a role as novel effective cancer treatment for 5-FU-resistant cancer.
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