Inhibition of Solar Simulator-Induced p53 Mutations and Protection Against Skin Cancer Development in Mice by Sunscreens

Abstract

We demonstrated previously that p53 mutations can be detected in ultraviolet B-irradiated mouse skin months before the gross appearance of skin tumors and that applying sun protection factor 15 sunscreens to mouse skin before each Kodacel-filtered FS40 sunlamp irradiation resulted in the reduction of such mutations. To determine whether there is an association between reduction of ultraviolet-induced p53 mutations by sunscreens and protection against skin cancer using an environmentally relevant light source, we applied sunscreens (sun protection factors 15-22) on to the shaved dorsal skin of C3H mice 30 min before each exposure to 4.54 kJ ultraviolet B (290-400 nm) radiation per m2 from a solar simulator. Control mice were treated 5 d per wk with ultraviolet only or vehicle plus ultraviolet. p53 mutation analysis indicated that mice exposed to ultraviolet only or vehicle plus ultraviolet for 16 wk (cumulative exposure to 359 kJ ultraviolet B per m2) developed p53 mutations at a frequency of 56%-69%, respectively, but less than 5% of mice treated with sunscreens plus ultraviolet showed evidence of p53 mutations. More importantly, 100% of mice that received a cumulative dose of 1000 kJ ultraviolet B per m2 only, or vehicle plus ultraviolet B developed skin tumors, whereas, the probability of tumor development in all the mice treated with the sunscreens plus 1000 kJ ultraviolet B per m2 was 2% and mice treated with sunscreens plus 1500 kJ ultraviolet B per m2 was 15%. These results demonstrate that the sunscreens used in this study not only protect mice against ultraviolet-induced p53 mutations, but also against skin cancers induced with solar-simulated ultraviolet. Because of this association, we conclude that inhibition of p53 mutations is a useful early biologic endpoint of photoprotection against an important initiating event in ultraviolet carcinogenesis.

Reduction of IKKα Expression Promotes Chronic Ultraviolet B Exposure-Induced Skin Inflammation and Carcinogenesis

“…5 These early genetic events have been demonstrated to be important for UVB carcinogenesis because these mutations can interrupt the tumor suppressor function of p53. 6 We detected more early UVB-induced signature p53 mutations in Ikk␣ ϩ/Ϫ than in Ikk␣ ϩ/ϩ skin specimens ( Figure 2A Figure S2, A-D, see http://ajp.amjpathol.org), the method used in this study was only able to monitor those photoproducts within 24 hours after UVB irradiation because cellular DNA duplication occurred. We previously reported that loss of IKK␣ reduces the G 2 /M cell cycle checkpoint in response to DNA damage, which can also amplify cells carrying DNA damage because cells deficient in the G 2 /M cell cycle checkpoint do not have enough time to repair DNA damage.…”

Reproducibility and Expression of Skin Biomarkers in Sun-Damaged Skin and Actinic Keratoses

“…Animal studies have shown that sunscreens can inhibit UVinduced skin carcinogenesis (45)(46)(47). In addition, Ananthaswamy et al (47), showed that sunscreens inhibit UV-induced p53 mutations as well as skin cancer development in mice. When incorporating biomarkers like p53 expression into skin cancer chemoprevention trials, potential confounding factors must be considered in the design of the trial.…”

Alternative methods to evaluate the protective ability of sunscreen against photo-genotoxicity

“…To date, the biological activity of sunscreens in offering protection against erythema has been represented through the use of a Sun Protection Factor (SPF). Some investigators have recently shown that SPF is not an adequate gauge when evaluating a sunscreen's ability to protect against UV-induced biological activity, and they propose estimating the protective activity of sunscreen through the use of other categories [10,11,[22][23][24]. In this study we examined Drosophila systems to determine if a genotoxicity protection factor could be utilized as an alternative evaluation of the efficacy of a sunscreen.…”

“…Ananthaswamy et al proposed the Mutation Protection Factor (MPF) as an estimate of a sunscreen's protective activity, as obtained through the measurement of p53 mutation in the skin of mice irradiated with UVB [10]. It has also been shown that treatment with sunscreen reduced the incidence of tumors in the skin of mice irradiated by a solar simulator [11]. We also suggest that a sunscreen's ability to protect against sunlight-induced mutation should be taken into account.…”