Celecoxib enhances the inhibitory effect of 5-FU on human squamous cell carcinoma proliferation by ROS production.
The role of celecoxib in preventing and treating tumors has attracted broad attention in recent years because of its selective and specific inhibition of COX-2 activity. We investigated the inhibitory effects and mechanisms of celecoxib combined with 5-fluorouracil (5-FU) on proliferation of squamous cell carcinoma cells in vivo and in vitro.



Animal study and basic research.



SNU-1041 and SNU-1076 squamous cell lines and an orthotopic tongue cancer mouse model were used to study growth inhibition with 5-FU enhanced by celecoxib. Sensitivity of cells to drug treatment was analyzed by the MTT assay, and generation of reactive oxygen species (ROS) was measured using dichlorofluorescein diacetate. Phosphorylation of AKT was detected by Western blotting. Survival analysis in the mouse model was assessed according to combination treatment with 5-FU and celecoxib.



Reactive oxygen species production in vitro was highest when celecoxib was administered 48 hours after 5-FU treatment. 5-FU-induced inhibition of cell proliferation was enhanced when combined with celecoxib, which was positively correlated with ROS production. Antioxidant treatment reversed 5-FU-inhibited cell proliferation by up to 60%. Cotreatment with celecoxib and 5-FU partially blocked AKT phosphorylation, although no significant changes in total AKT protein levels were detected. An increased survival time was observed in an orthotopic mouse model treated with a combination of celecoxib and 5-FU compared to treatment with either agent alone.



Celecoxib may have an enhanced anticancer effect in combination with 5-FU. Reactive oxygen species production may be a key mechanism in this combination therapy by inhibiting the AKT pathway.



N/A. Laryngoscope, 127:E117-E123, 2017.
Department of Otorhinolaryngology Head and Neck Surgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul.|Cancer Research Institute, Seoul.|Sheikh Khalifa Specialty Hospital, Ras Al Khaimah, United Arab Emirates.
Myung-Whun
MW
Sung
Cancer Research Institute, Seoul.|Department of Otorhinolaryngology-Head and Neck Surgery, Korea University Anam Hostpital, Seoul.
Doh Young
DY
Lee
Cancer Research Institute, Seoul.
Seok-Woo
SW
Park
Cancer Research Institute, Seoul.
Sang-Mi
SM
Oh
Department of Otorhinolaryngology Head and Neck Surgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul.
Jun-Jae
JJ
Choi
Department of Otorhinolaryngology Head and Neck Surgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul.
Eun Sil
ES
Shin
Department of Otorhinolaryngology Head and Neck Surgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul.|Cancer Research Institute, Seoul.
Seong Keun
SK
Kwon
Department of Otorhinolaryngology Head and Neck Surgery, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea.
Soon-Hyun
SH
Ahn
Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul.
Young Ho
YH
Kim
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000401:mortality; D000068579:Celecoxib / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004347:Drug Interactions; D005472:Fluorouracil / Q000494:pharmacology*; D064593:Heterografts; D051379:Mice; D008819:Mice, Nude; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012016:Reference Values; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000401:mortality; D018709:Statistics, Nonparametric; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D017382:Reactive Oxygen Species; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D005472:Fluorouracil
5-FU; AKT pathway; Celecoxib; reactive oxygen species; squamous cell carcinoma