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A few in vivo studies have also evaluated the potential of resveratrol for skin conditions. In a study from this laboratory, we have shown that a topical application of resveratrol to SKH-1 hairless mice results in significant inhibitions of UVB-mediated increases in (i) skin edema, (ii) inflammation, (iii) cyclooxygenase (COX) and ornithine decarboxylase (ODC) induction, and (iv) generation of hydrogen peroxide (H2O2) and lipid peroxidation, in the skin, In another study, we determined the photoprotective effects of resveratrol against multiple UVB exposure mediated damages to the skin of SKH-1 hairless mouse. Our data demonstrated that a topical pre-application of resveratrol (10 µ mole/0.2 ml/mouse) 30 minutes prior to UVB-exposures (180 mJ/cm2 × 7 exposures on alternate days) to mouse skin resulted in a significant decrease in UVB mediated increases i) in skin edema and hyperplasia, ii) infiltration of leukocytes into the epidermis and dermis, and iii) protein levels of PCNA in epidermis.
We also found that UVB-exposures to mouse skin resulted in significant i) increases in cdk-2, cdk-4, cdk-6 and cyclin D2 protein levels in epidermis; whereas, resveratrol pre-treatment significantly reversed these effects. Interestingly, resveratrol pre-treatment was found to result in a further enhancement in UVB-exposure mediated increase in WAF1/p21 and p53 proteins. Finally, we also found that repeated UVB exposures resulted in an upregulation of mitogen activated protein-kinase (MAPK) 1/2 and MAPK kinase (MEK)-1; whereas topical application of resveratrol prior to UVB exposures significantly reversed the UVB-mediated responses in these proteins. Taken together, this study suggested that the anti-proliferative effects of resveratrol might be mediated via modulation in i) cki-cyclin-cdk network, and ii) MAPK-pathway.
In a follow up study, we evaluated the involvement of IAP protein Survivin during the protective effects of resveratrol against multiple UVB exposure mediated damages in SKH-1 hairless mouse skin. The data from this study demonstrated that topical pre-treatment of resveratrol (10 µmol in 200 µl acetone per mouse) resulted in significant inhibition of UVB exposure-mediated increases in i) cellular proliferations (Ki-67 immunostaining), ii) protein levels of epidermal cyclooxygenase (COX)-2 and ornithine decarboxylase (ODC), established markers of tumor promotion, iii) protein and mRNA levels of Survivin, and iv) phosphorylation of Survivin; in the skin of SKH-1 hairless mouse. Resveratrol pre-treatment also resulted in i) reversal of UVB-mediated decrease of Smac/DIABLO, and ii) enhancement of UVB-mediated induction of apoptosis, in mouse skin. Taken together, this study suggested that resveratrol imparts chemopreventive effects against UVB exposure-mediated damages in SKH-1 hairless mouse skin via inhibiting Survivin-pathway.
In another recent study, we evaluated the skin cancer chemopreventive effects of resveratrol in a photocarcinogenesis model of skin cancer. In this study, we employed a UVB initiation-promotion protocol in which the control mice were subjected to chronic UVB exposure (180 mJ/cm2, twice weekly, for 28 weeks). The experimental animals received either a pretreatment (30 min before each UVB) or post-treatment (5 min after UVB) of resveratrol (25 or 50 µmole/0.2 ml acetone/mouse). The mice were followed for skin tumorigenesis and were killed at 24 h after the last UVB exposure, for further studies. Our data demonstrated that the topical application of skin with resveratrol (both pre- and post- treatment) resulted in a highly significant 1) inhibition in tumor incidence, and 2) delay in the onset of tumorigenesis. Interestingly, the posttreatment of resveratrol was found to impart equal protection than the pretreatment; suggesting that resveratrol-mediated responses may not be sunscreen effects.
Further, our data also demonstrated a significant i) up-regulation of Survivin (both at protein- and mRNA- levels), ii) up-regulation of phospho-Survivin protein, and iii) down-regulation of proapoptotic Smac/DIABLO protein in skin tumors; whereas treatment with resveratrol resulted in the attenuation of these responses. Our study also suggested that resveratrol enhanced apoptosis in UVB-exposure-mediated skin tumors. This study, for the first time, suggested that i) resveratrol imparts strong chemopreventive effects against UVB exposure-mediated skin carcinogenesis, and ii) the chemopreventive effects of resveratrol may, at least in part, be mediated via modulations in Survivin and other associated events.
In a recent study, Kim et al demonstrated that oral administration of resveratrol to p53(+/−)/SKH-1 mice delayed UV-induced skin tumorigenesis and reduced the malignant conversion of benign papillomas to squamous cell carcinomas (SCCs). This study also showed the involvement of transforming growth factor-beta2 (TGF-β2) signaling as a mechanism of resveratrol’s action. Kundu et al demonstrated that resveratrol pretreatment resulted in a decrease in the phosphorylation of extracellular signal-regulated protein kinase (ERK) as well as the catalytic activity of ERK and p38 MAPK (mitogen activated protein kinase). Further, resveratrol prevented TPA-induced DNA binding of activator protein-1 (AP-1). This study suggested that suppression of COX-2 expression by blocking the activation of MAPKs and AP-1 may represent possible molecular mechanisms responsible for previously reported anti-tumor promoting effects of resveratrol on mouse skin carcinogenesis.
Another in vivo study by Van Ginkel and colleagues demonstrated that peritumoral injection of resveratrol inhibited tumor growth in animal models of uveal melanoma via early mitochondrial dysfunction. In this study, in vitro experiments with uveal melanoma cell lines showed that resveratrol causes apoptosis through a mitochondrial pathway i.e. decrease in mitochondrial membrane potential associated with an activation of caspase-3. The authors suggested that the nontoxic nature of the drug makes resveratrol an attractive candidate for the treatment of uveal melanoma.
Article Produced By
Department of Dermatology, University of Wisconsin, University of Wisconsin Carbone Cancer Center, Corresponding author: Nihal Ahmad, Medical Sciences Center,
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060966/
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