Molecular networks in melanoma invasion and metastasis.

Metastatic melanoma accounts for approximately 80% of skin cancer-related deaths. Up to now there has been no effective treatment for stage IV melanoma patients due to the complexity and dissemination potential of this disease. Melanomas are heterogeneous tumors in which conventional therapies fail to improve overall survival. Targeted therapies are being developed, but the final outcome can be hampered by the incomplete knowledge of the process of melanoma progression. Even if the intracellular pathways are similar, the interaction of the cells with the surrounding environment should be taken into consideration. This article seeks to highlight some of the advances in the understanding of the molecular mechanisms underlying melanoma dissemination.

Nitroxides and a nitroxide-based UV filter have the potential to photoprotect UVA-irradiated human skin fibroblasts against oxidative damage.

BACKGROUND: Antioxidants are now being incorporated into sunscreens as additional topical measure for delaying the aging process and reducing photo-damage to skin induced by excessive UVA exposure. UVA radiation reaching the skin leads to the generation of ROS (reactive oxygen species) implicated in DNA damage and activation of matrix metalloproteinase-1 (MMP-1) responsible for collagen damage and photo-aging. Nitroxides are a class of compounds endowed with versatile antioxidant activity and recently, nitroxide-based UV filters in which a nitroxide moiety has been attached to the most popular UV filter present in sunscreens have been developed. OBJECTIVE: This study explores the potential photo-protective effects of these compounds on ROS production and induction of MMP-1 in cultured human dermal fibroblasts exposed to UVA. For comparison, vitamin E was also tested. METHODS: The effects were assessed by measuring intracellular ROS production using a ROS-index probe and MMP-1 mRNA expression levels using quantitative real-time PCR (qPCR). RESULTS: Exposure of fibroblasts to 18J/cm(2) UVA lead to a two-fold increase in ROS production which was reduced to non-irradiated control levels in the presence of 50µM nitroxide compounds and vitamin E. Under the same conditions, a ten-fold increase in MMP-1 mRNA expression levels was observed 24h post-UVA treatment which was significantly reduced by all nitroxide compounds but not vitamin E. CONCLUSION: The results of this study support the potential use of nitroxide compounds, including novel nitroxide-based UV filters, as a useful and alternative strategy for improving the efficacy of topical formulations against photo-aging and possibly photo-carcinogenesis.

Modified TiO(2) particles differentially affect human skin fibroblasts exposed to UVA light.

Numerous sunscreens contain titanium dioxide (TiO(2)) because of its ability to reflect, scatter, and absorb UV radiation, thus preventing sunlight-related skin disorders. Since TiO(2) is well known to generate reactive oxygen species (ROS) under photoexcitation, it is chemically modified when used in sunscreens. In the present study, five modified TiO(2) particles, specifically developed and marketed for sunscreens, were tested using different in vitro models, including cultured human skin fibroblasts (HuDe), to investigate their possible photocatalytic effects following UVA exposure. The results obtained show that the type of modification and crystal form determine their ability to (a) induce photobleaching of the DPPH radical, (b) photodegrade deoxyribose, (c) reduce cell viability, (d) increase/decrease DNA damage, and (e) increase/decrease intracellular ROS. This research concludes that some modified TiO(2) particles still retain photocatalytic activity under the experimental conditions employed, especially those in which the anatase crystal form of TiO(2) is present. The penetration of TiO(2) nanosized particles into the viable epidermis of skin is still under debate; thus, the results presented here contribute to gaining further knowledge on the potential effects of TiO(2) particles at the cellular level, in the worst possible case that they do penetrate.

Nitroxides are more efficient inhibitors of oxidative damage to calf skin collagen than antioxidant vitamins.

Reactive oxygen species generated upon UV-A exposure appear to play a major role in dermal connective tissue transformations including degradation of skin collagen. Here we investigate on oxidative damage to collagen achieved by exposure to (i) UV-A irradiation and to (ii) AAPH-derived radicals and on its possible prevention using synthetic and natural antioxidants. Oxidative damage was identified through SDS-PAGE, circular dichroism spectroscopy and quantification of protein carbonyl residues. Collagen (2 mg/ml) exposed to UV-A and to AAPH-derived radicals was degraded in a time- and dose-dependent manner. Upon UV-A exposure, maximum damage was observable at 730 kJ/m2 UV-A, found to be equivalent to roughly 2 h of sunshine, while exposure to 5 mM AAPH for 2 h at 50 degrees C lead to maximum collagen degradation. In both cases, dose-dependent protection was achieved by incubation with muM concentrations of nitroxide radicals, where the extent of protection was shown to be dictated by their structural differences whereas the vitamins E and C proved less efficient inhibitors of collagen damage. These results suggest that nitroxide radicals may be able to prevent oxidative injury to dermal tissues in vivo alternatively to commonly used natural antioxidants.