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- Title
Celecoxib enhances the inhibitory effect of 5-FU on human squamous cell carcinoma proliferation by ROS production.
- Authors
Sung, Myung‐Whun; Lee, Doh Young; Park, Seok‐Woo; Oh, Sang‐Mi; Choi, Jun‐Jae; Shin, Eun Sil; Kwon, Seong Keun; Ahn, Soon‐Hyun; Kim, Young Ho
- Abstract
<bold>Objectives: </bold>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.<bold>Study Design: </bold>Animal study and basic research.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>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.<bold>Level Of Evidence: </bold>N/A. Laryngoscope, 127:E117-E123, 2017.
- Subjects
CYCLOOXYGENASE 2 inhibitors; ANTIARTHRITIC agents; CELECOXIB; NIMESULIDE; ROFECOXIB; REACTIVE oxygen species; ANIMAL experimentation; ANTINEOPLASTIC agents; APOPTOSIS; BIOLOGICAL models; CELL physiology; COMPARATIVE studies; DRUG interactions; FLUOROURACIL; RESEARCH methodology; MEDICAL cooperation; MICE; NONPARAMETRIC statistics; OXIDOREDUCTASES; REFERENCE values; RESEARCH; STATISTICAL sampling; SKIN tumors; SQUAMOUS cell carcinoma; SURVIVAL; XENOGRAFTS; EVALUATION research; CANCER cell culture; PHARMACODYNAMICS
- Publication
Laryngoscope, 2017, Vol 127, Issue 4, pE117
- ISSN
0023-852X
- Publication type
journal article
- DOI
10.1002/lary.26309