title: Etodolac improves 5-FU sensitivity of head and neck cancer cells through inhibition of thymidylate synthase.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Murata
authors.forename: Makoto
authors.initials: M
authors.lastname: Adachi
authors.forename: Mitomu
authors.initials: M
authors.lastname: Kioi
authors.forename: Soichiro
authors.initials: S
authors.lastname: Torigoe
authors.forename: Kei
authors.initials: K
authors.lastname: Ijichi
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ogawa
authors.forename: Mihir K
authors.initials: MK
authors.lastname: Bhayani
authors.forename: Stephen Y
authors.initials: SY
authors.lastname: Lai
authors.forename: Kenji
authors.initials: K
authors.lastname: Mitsudo
authors.forename: Iwai
authors.initials: I
authors.lastname: Tohnai
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017308:Etodolac / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology*; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D017308:Etodolac; D051546:Cyclooxygenase 2; D013940:Thymidylate Synthase; D005472:Fluorouracil