Abstract
Solar ultraviolet (UV) radiation is a well recognized epidemiologic risk factor for melanoma and non-melanoma skin cancers. This observation has been linked to the accumulation of UVB radiation-induced DNA lesions in cells, and that finally lead to the development of skin cancers. Earlier, we have shown that topical treatment of skin with silymarin, a plant flavanoid from milk thistle (Silybum marianum), inhibits photocarcinogenesis in mice; however it is less understood whether chemopreventive effect of silymarin is mediated through the repair of DNA lesions in skin cells and that protect the cells from apoptosis. Here, we show that treatment of normal human epidermal keratinocytes (NHEK) with silymarin blocks UVB-induced apoptosis of NHEK in vitro. Silymarin reduces the amount of UVB radiation-induced DNA damage as demonstrated by reduced amounts of cyclobutane pyrimidine dimers (CPDs) and as measured by comet assay, and that ultimately may lead to reduced apoptosis of NHEK. The reduction of UV radiation-induced DNA damage by silymarin appears to be related with induction of nucleotide excision repair (NER) genes, because UV radiation-induced apoptosis was not blocked by silymarin in NER-deficient human fibroblasts. Cytostaining and dot-blot analysis revealed that silymarin repaired UV-induced CPDs in NER-proficient fibroblasts from a healthy individual but did not repair UV-induced CPD-positive cells in NER-deficient fibroblasts from patients suffering from xeroderma pigmentosum complementation-A disease. Similarly, immunohistochemical analysis revealed that silymarin did not reduce the number of UVB-induced sunburn/apoptotic cells in the skin of NER-deficient mice, but reduced the number of sunburn cells in their wild-type counterparts. Together, these results suggest that silymarin exert the capacity to reduce UV radiation-induced DNA damage and, thus, prevent the harmful effects of UV radiation on the genomic stability of epidermal cells.
Highlights
Ultraviolet (UV) radiation is a well established etiologic risk factor for the incidence of melanoma and non-melanoma skin cancers, and these skin cancers are a major burden on the health care system
Our study reveals that the repair of UV-induced DNA damage or genomic instability by silymarin is mediated through the nucleotide excision repair (NER) mechanism, which was verified by using NER-proficient and NER-deficient human fibroblasts, and NER-deficient mouse model
Our data indicated that treatment of cells with silymarin at the concentration of 10 mg/mL and 20 mg/mL significantly blocked UVB radiation-induced apoptosis and that is by 58% (P,0.01) and 84% (P,0.005) respectively
Summary
Ultraviolet (UV) radiation is a well established etiologic risk factor for the incidence of melanoma and non-melanoma skin cancers, and these skin cancers are a major burden on the health care system. The molecular pathways leading to UVB radiation-induced apoptosis include the formation of cyclobutane pyrimidine dimers (CPDs) and (6–4) photoproducts [3,4], the activation of death receptors including CD95 (Fas/APO-1) [3,5], and the formation of reactive oxygen species [6]. These pathways are orchestrated by positive and negative factors that act within the epidermis in an autocrine and/or paracrine manner. Because of its protective function, alterations in UVB-induced apoptosis may have a profound impact in the induction of skin cancer, the most common cutaneous malignancy in Caucasians
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