Novel vitamin D compounds and skin cancer prevention

Abstract

As skin cancer is one of the most costly health issues in many countries, particularly in Australia, the possibility that vitamin D compounds might contribute to prevention of this disease is becoming increasingly more attractive to researchers and health communities. In this article, important epidemiologic, mechanistic and experimental data supporting the chemopreventive potential of several vitamin D-related compounds are explored. Evidence of photoprotection by the active hormone, 1α,25dihydroxyvitamin D3, as well as a derivative of an over-irradiation product, lumisterol, a fluorinated analog and bufalin, a potential vitamin D-like compound, are provided. The aim of this article is to understand how vitamin D compounds contribute to UV adaptation and potentially, skin cancer prevention.

Keywords: 1α,25-dihydroxyvitaminD3; DNA damage; bufalin; photocarcinogenesis; photoimmune suppression; photoprotection; skin cancer prevention; vitamin D compounds; vitamin D photoproducts.

Figure 1. The chemical structures of the various D compounds.

Figure 2. Photoprotection against thymine dimers by 1,25(OH)₂D₃ and Bufalin in human keratinocytes. DNA damage was assessed using a monoclonal antibody to thymine dimers, immunohistochemistry and image analysis as previously described^, at 3 h after UV irradiation, in human keratinocytes treated with vehicle, 1,25(OH)₂D₃ or three concentrations of bufalin and expressed as positively stained nuclei as a percent of total nuclei. The graph illustrates pooled data from a minimum of four independent experiments. *** denotes a significant difference compared with vehicle (***p < 0.001), ^, ^^, ^^^ denotes a significant difference compared with 10⁻⁹M bufalin (^p < 0.05, ^^p < 0.01, ^^^p < 0.001).

Figure 3. Reduction of UV-induced IL-6 expression by topical application of 1,25(OH)₂D₃ in mouse skin. Immunohistochemical detection of IL-6 in Skh:hr1 hairless mice skin was with a monoclonal antibody to IL-6 and a biotinylated secondary rabbit anti-goat IgG. Figures are representative dorsal skin sections (A) non-irradiated skin or (B) after solar simulated radiation followed by 48-h treatment with vehicle or (C) after solar simulated radiation followed by 48-h treatment with 1,25D (22.8 pmol/cm²). Reprinted from The Journal of Steroid Biochemistry and Molecular Biology. R.S. Mason, V.B. Sequeira, K.M. Dixon, C. Gordon-Thomson, K. Pobre, A. Dilley, M.T. Mizwicki, A.W. Norman, D. Feldman, G.M. Halliday, V.E. Reeve (2010).

Figure 4. 1,25(OH)₂D₃ and JN protect against UV-induced edema. 1,25(OH)₂D₃ and JN reduce UV-induced edema in Skh:hr1 mouse skin. Mice were exposed to 1 × 3 MEDs (minimal erythemal doses) of solar-simulated UVR (3.98 kJ/m² UVB and 63.8 kJ/m² UVA) and were treated topically on the UV-irradiated dorsal surface immediately after UVR exposure with 100 mL of vehicle only, 1,25(OH)₂D₃, or JN. Edema was measured as dorsal skin-fold thickness in the mice 48 h after UVR exposure. Significantly different from vehicle-treated UV-irradiated mice. **p < 0.01; n = 5. Reproduced from Cancer Prevention Research. K.M. Dixon, A.W. Norman, V.B. Sequeira, R. Mohan, M.S. Rybchyn, V.E. Reeve, G.M. Halliday, R.S. Mason (2011).

Figure 5. 1,25(OH)₂D₃ and JN protect against chronic UV-induced squamous cell carcinomas (SCC). Groups of 20 mice were exposed to a suberythemal dose of UVR on 5 d/wk for 10 wk. The solar-simulated UVR source was identical to that used in previous studies, as described earlier for acute exposures, but the daily dose was lowered to mimic chronic human sunlight exposure without burning. The daily dose provided 0.658 kJ/m² UVB and 20.30 kJ/m² UVA, which is approximately one MED (minimal erythemal dose). Incidence of SCC was reduced by 1,25(OH)₂D₃ and JN at 40-wk time point. SCC incidence was calculated at each weekly time point as the percentage of mice in each group bearing at least 1 SCC. The Mantel-Haenszel log-rank test was performed to determine the difference in risk of developing an SCC between treatment groups and vehicle control. There was a significantly reduced risk of SCC development in both the 1,25(OH)₂D₃ and JN treatment groups compared with vehicle. The asterisks refer to the incidence risk assessed by the Mantel–Haenszel log-rank test over the whole time course. Significantly different from vehicle. ***p < 0.001; **p < 0.01; n = 20. Reproduced from Cancer Prevention Research. K.M. Dixon, A.W. Norman, V.B. Sequeira, R. Mohan, M.S. Rybchyn, V.E. Reeve, G.M. Halliday, R.S. Mason (2011).