title: Inhibition of COX-2 expression by topical diclofenac enhanced radiation sensitivity via enhancement of TRAIL in human prostate adenocarcinoma xenograft model.
abstract: BACKGROUND
  COX-2 inhibitors have an antitumor potential and have been verified by many researchers. Treatment of cancer cells with external stressors such as irradiation can stimulate the over-expression of COX-2 and possibly confer radiation resistance. In this study, we tested if topical diclofenac, which inhibits both COX-1 and COX-2, administration rendered prostate tumor cells sensitize to the effects of radiation.
  
  
  METHODS
  LNCaP-COX-2 and LNCaP-Neo cells were treated with 0 to 1000 μM diclofenac. Next, a clonogenic assay was performed in which cells were subjected to irradiation (0 to 4 Gy) with or without diclofenac. COX-2 expression and other relevant molecules were measured by real-time PCR and immunohistochemistry after irradiation and diclofenac treatment. In addition, we assessed the tumor volumes of xenograft LNCaP-COX-2 cells treated with topical diclofenac with or without radiation therapy (RT).
  
  
  RESULTS
  LNCaP-COX-2 and LNCaP-Neo cell lines experienced cytotoxic effects of diclofenac in a dose related manner. Clonogenic assays demonstrated that LNCaP-COX-2 cells were significantly more resistant to RT than LNCaP-Neo cells. Furthermore, the addition of diclofenac sensitized LNCaP-COX-2 not but LNCaP-Neo cells to the cytocidal effects of radiation. In LNCaP-COX-2 cells, diclofenac enhanced radiation-induced apoptosis compared with RT alone. This phenomenon might be attributed to enhancement of RT-induced TRAIL expression as demonstrated by real-time PCR analysis. Lastly, tumor volumes of LNCaP-COX-2 cells xenograft treated with diclofenac or RT alone was >4-fold higher than in mice treated with combined diclofenac and radiation (p<0.05).
  
  
  CONCLUSIONS
  These in vitro and in vivo findings suggest that conventional COX inhibitor, diclofenac enhances the effect of RT on prostate cancer cells that express COX-2. Thus, diclofenac may have potential as radiosensitizer for treatment of prostate cancer.
authors.affiliation: Department of Urology, Nara Medical University, Nara, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inoue
authors.forename: Satoshi
authors.initials: S
authors.lastname: Anai
authors.forename: Sayuri
authors.initials: S
authors.lastname: Onishi
authors.forename: Makito
authors.initials: M
authors.lastname: Miyake
authors.forename: Nobumichi
authors.initials: N
authors.lastname: Tanaka
authors.forename: Akihide
authors.initials: A
authors.lastname: Hirayama
authors.forename: Kiyohide
authors.initials: K
authors.lastname: Fujimoto
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hirao
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D000287:Administration, Topical; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D051546:Cyclooxygenase 2 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D004008:Diclofenac / Q000627:therapeutic use*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D011838:Radiation-Sensitizing Agents; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D004008:Diclofenac; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human