title: Celecoxib reduces the effects of acute and chronic UVB exposure in mice treated with therapeutically relevant immunosuppressive drugs.
abstract: Solid organ transplant recipients have a greatly increased risk for the development of non-melanoma skin cancers. We have previously shown in our mouse model that sirolimus given in combination with cyclosporine A resulted in fewer and smaller tumors than cyclosporine A alone. In the current study, we tested the hypothesis that an anti-inflammatory agent celecoxib applied topically after UVB exposure would further reduce UVB induced skin cancer in mice treated with cyclosporine A and sirolimus. The effect of celecoxib treatment on acute inflammation, initiation/promotion and tumor development was examined through a set of four experiments. Delayed tumor onset was observed in both tumor development experiments. Reduced tumor size and number compared to vehicle was observed when CX was administered concurrently with UVB and when CX was administered after cessation of UVB treatments, respectively. Prostaglandin E2 was confirmed to be significantly reduced in the dorsal skin of mice concurrently treated with immunosuppressants, CX and UVB for 13 weeks, suggesting a reduction in the inflammatory response could be the mechanism by which CX reduced tumorigenesis. Furthermore, topical celecoxib treatment following acute UVB exposure reduced dermal neutrophil number and activity compared to vehicle. In all of these experiments, unirradiated and vehicle treated mice were utilized as controls. In conclusion, these data suggest that even in the presence of cyclosporine A and sirolimus, topical celecoxib treatment can result in reduced inflammation, tumor number and size; properties which may be beneficial in the therapeutic reduction of skin cancer development in solid organ transplant recipients.
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Wulff
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Thomas-Ahner
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Schick
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Oberyszyn
mesh_terms: D000818:Animals; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016572:Cyclosporine / Q000008:administration & dosage; D015232:Dinoprostone / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D051379:Mice; D009381:Neoplasms, Radiation-Induced / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D011720:Pyrazoles / Q000494:pharmacology*; D020123:Sirolimus / Q000008:administration & dosage; D012878:Skin Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D013449:Sulfonamides / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D016861:Cyclooxygenase Inhibitors; D007166:Immunosuppressive Agents; D011720:Pyrazoles; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; D016572:Cyclosporine; D053148:Caspase 3; D000068579:Celecoxib; D015232:Dinoprostone; D020123:Sirolimus