Jornal de Pesquisa em Dermatologia Clínica e Experimental
Acesso livre

Abstrato

Topical Nutlin-3 Potentiates the UVB-induced p53 Response and Reduces DNA Photodamage and Apoptosis in Mouse Epidermal Keratinocytes in Vivo

Catharina M. Lerche, Birthe Mørch Thomsen, Hans Christian Wulf and Robert Gniadecki

Background/Aims: (-)-Nutlin-3 (nutlin) is a cis-imidazoline analog, which activates p53 by antagonizing murine double minute (Mdm2) protein. To our knowledge, no studies have assessed the effect of topical nutlin on cyclobutane pyrimidine dimers (CPD) repair and apoptosis. We therefore conducted a study in hairless mice to investigate the effect of topical nutlin on murine epidermis after UVB-radiation.
Methods: Female C3.Cg/TifBomTac immunocompetent mice were treated with 100 μl 43 mM nutlin 30 min before and after irradiation with 3 SED (100 mJ/cm²) UVB. Animals were euthanized 24 hours after irradiation, the dorsal, treated skin was biopsied and fixed in 4% formalin. Sections were incubated with the antibodies against p53, thymine dimers and terminal deoxynucleotidyl transferase-mediated dUTP nick and labelling (TUNEL).
Results: We showed here that nutlin was active after topical application in hairless mice and potentiated the p53 nuclear translocation in epidermal keratinocytes after ultraviolet B irradiation. Moreover, topical treatment with nutlin resulted in a decrease in the number of keratinocytes exhibiting positive nuclear staining for thymine dimers (P<0.05 compared with the vehicle control) and decreased the frequency of apoptotic, TUNEL-positive cells (P=0.02).
Conclusion: We hypothesize that nutlin stimulates DNA photodamage repair in the epidermis and may prove useful for the chemoprevention of skin cancer.