Treatment with 5-Fluorouracil and Celecoxib Displays Synergistic Regression of Ultraviolet Light B-Induced Skin Tumors

Abstract

Standard chemotherapeutic agents used for the treatment of pre-cancerous skin lesions and non-melanoma skin cancers are not completely effective. Several studies have suggested that repeated inflammatory sunburn reactions, which include the induction of cyclooxygenase-2 (COX-2) and the subsequent production of prostaglandins, play a role in skin cancer development. COX-2 inhibition has been demonstrated to be a potent means of preventing skin cancer development in mice; however, COX-2 inhibitors alone are not effective as chemotherapeutic agents. Data in a variety of cancer types suggest greater efficacy in treating tumors with combination chemotherapies. Therefore, we hypothesized that a combination of the chemotherapeutic agent 5-fluorouracil (5-FU) and the COX-2 inhibitor and anti-inflammatory drug celecoxib would act synergistically to regress tumors in a murine model of ultraviolet light B- (UVB-) induced carcinogenesis. We found that topical treatment with 5-FU and celecoxib together was up to 70% more effective in reducing the number of UVB-induced skin tumors than 5-FU treatment alone. Our data suggest that more effective chemotherapy regimens can be developed to treat the millions of pre-cancerous and cancerous skin lesions that arise every year, which could ultimately lead to a significant reduction in costs and cosmetic defects (scarring) associated with surgical interventions.

Preventing chemoresistance of human breast cancer cell line, MCF-7 with celecoxib

“…Celecoxib has been shown to enhance clinically the antitumor eYcacy of doxorubicin (Awara et al 2004) and 5-Xuorouracil (Wilgus et al 2004). In this study, cytostatic eYcacy of doxorubicin was determined by MTT assay in MCF-7 cells, and we found that celecoxib and doxorubicin were synergistic.…”

Reduction in squamous cell carcinomas in mouse skin by dietary zinc supplementation

“…The results of this study suggest that mild Zn supplementation may be helpful for preventing the progression of NMSCs, even in Zn‐sufficient individuals, possibly in combination with other preventive treatments currently under investigation in UV or DMBA/PMA induction models, some showing promise 44, 45, 46, 47, 48, 49. Further studies are needed to define mechanisms that enable dietary Zn supplementation to reduce tumor burdens in Fhit − / − mice, perhaps with a focus on experiments aimed at evaluating differences in responses in male and female mice, since females displayed the most emphatic reductions.…”

Cyclooxygenase-dependent signaling is causally linked to non-melanoma skin carcinogenesis: pharmacological, genetic, and clinical evidence

“…Remarkably, in chronically UV Bchallenged SKH skin the inhibitors are not found to inhibit edema or inflammation [185]. Beside the chemo-preventive effects, celecoxib exhibited therapeutic efficacy inducing a partial regression of UV-induced pre-existing tumors [188,189], an inhibitory effect that can be synergistically enhanced by combination treatments of celecoxib with difluoromethylornithine or 5-fluorouracil [188,190] and an effect that depends on continuous treatment [188]. Beyond stimulation of apoptosis, a further mechanism that could contribute to the antitumorigenic effects of NSAIDs in skin is highlighted recently.…”