Celecoxib enhances the inhibitory effect of 5-FU on human squamous cell carcinoma proliferation by ROS production

Abstract

Objectives 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. Study Design Animal study and basic research. 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. 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 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. Conclusion 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. Level of Evidence N/A. Laryngoscope, 127:E117–E123, 2017

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“…Also in cutaneous T-cell lymphoma cells, apoptosis induction by indirubin derivatives was ROS-dependent [15]. Induction of ROS in the course of celecoxib treatment has already been reported in melanoma and breast cancer cells [54], and ROS production was suggested as a key mechanism for celecoxib's anticancer activity in combination with 5-FU in head and neck cancer cells [55].…”

Tra2β silencing suppresses cell proliferation in laryngeal squamous cell carcinoma via inhibiting PI3K/AKT signaling

“…Previous studies revealed that laryngeal squamous cell carcinoma progression is associated with many signaling pathways, such as the NF-κB signaling pathway, 37 vitamin D receptor signaling pathway, 28 AKT signaling pathway, 27,33,38,39 and Notch2 signaling pathway. 40 Tra2β is involved in the activation of many signaling pathway, such as the Wnt signaling pathway 41 and HtrA/PED pathway.…”

Emerging Perspective: Role of Increased ROS and Redox Imbalance in Skin Carcinogenesis

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