Abstract
Ultraviolet radiation B (UVB) is the main cause of DNA damage in epidermal cells; and if not repaired, this DNA damage leads to skin cancer. In earlier studies, we have reported that natural flavonolignan silibinin exerts strong chemopreventive efficacy against UVB-induced skin damage and carcinogenesis; however mechanistic studies are still being actively pursued. Here, we investigated the role of nucleotide excision repair (NER) pathway in silibinin's efficacy to repair UVB-induced DNA damage. Normal human dermal fibroblasts (NHDFs) were exposed to UVB (1 mJ/cm2) with pre- or post- silibinin (100 μM) treatment, and cyclobutane pyrimidine dimers (CPDs) formation/repair was measured. Results showed that post-UVB silibinin treatment accelerates DNA repair via activating the NER pathway including the expression of XPA (xeroderma pigmentosum complementation group A), XPB, XPC, and XPG. In UVB exposed fibroblasts, silibinin treatment also increased p53 and GADD45α expression; the key regulators of the NER pathway and DNA repair. Consistently, post-UVB silibinin treatment increased the mRNA transcripts of XPA and GADD45α. Importantly, silibinin showed no effect on UVB-induced DNA damage repair in XPA- and XPB-deficient human dermal fibroblasts suggesting their key role in silibinin-mediated DNA damage repair. Moreover, in the presence of pifithrin-α, an inhibitor of p53, the DNA repair efficacy of silibinin was compromised associated with a reduction in XPA and GADD45α transcripts. Together, these findings suggest that silibinin's efficacy against UVB-induced photodamage is primarily by inhibiting NER and p53; and these findings further support silibinin's usage as a potential inexpensive, effective, and non-toxic agent for skin cancer chemoprevention.
Highlights
Skin cancer is the most common cancer with more than 3 million cases diagnosed annually in the United States
Post-ultraviolet B (UVB) silibinin treatment resulted in an accelerated DNA repair response with a 55% (p < 0.05) reduction in cyclobutane pyrimidine dimers (CPDs) levels compared to UVB alone after 8 hrs (Figure 1B)
These findings are important because silibinin increased the spatial-temporal presence of nucleotide excision repair (NER) factors in UVB exposed cells and stimulated mRNA production of some of the factors involved in DNA damage repair
Summary
Skin cancer is the most common cancer with more than 3 million cases diagnosed annually in the United States. This is roughly equivalent to the annual incidence of all other malignancies combined. Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), together known as non-melanoma skin cancers (NMSCs), account for about 95% of all skin cancer cases in the United. The primary lesions caused by UVB are cyclobutane pyrimidine dimers (CPDs) and 6–4 photoproducts (6–4 PPs). These lesions, if not repaired or removed, could give rise to mutations and cancer initiation. Subsequent selection and multiplication of these initiated cells results in further accumulation of mutations, leading to the development of skin tumors [2]
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