S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Medicine (의학과) Theses (Ph.D. / Sc.D._의학과)
The role of reactive oxygen species in combination therapy of 5-FU and celecoxib in head and neck squamous cell carcinoma
두경부 편평상피세포암에 대한 5-FU와 celecoxib 병합치료의 효과에서 활성산소의 역할에 대한 연구
- 의과대학 의학과
- Issue Date
- 서울대학교 대학원
- celecoxib; 5-FU; AKT pathway; reactive oxygen species; head and neck cancer; squamous cell carcinoma
- 학위논문 (박사)-- 서울대학교 대학원 : 의학과, 2017. 2. 김영호.
- Introduction: 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-FU on proliferation of squamous cell carcinoma cells in vivo and in vitro.
Methods: 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 (DCFH-DA). 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.
Results: ROS 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%. Co-treatment 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.
Conclusions: Celecoxib may have an enhanced anticancer effect in combination with 5-FU. ROS production may be a key mechanisms in this combination therapy by inhibiting the AKT pathway.