title: Silibinin enhances the repair of ultraviolet B-induced DNA damage by activating p53-dependent nucleotide excision repair mechanism in human dermal fibroblasts.
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.
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Guillermo-Lagae
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, USA.|University of Colorado Cancer Center, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Gagan
authors.initials: G
authors.lastname: Deep
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, USA.
authors.forename: Harold
authors.initials: H
authors.lastname: Ting
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, USA.|University of Colorado Cancer Center, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Chapla
authors.initials: C
authors.lastname: Agarwal
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, USA.|University of Colorado Cancer Center, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004249:DNA Damage; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020405:Dermis / Q000166:cytology; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D015870:Gene Expression; D006801:Humans; D018613:Microscopy, Confocal; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays / Q000009:adverse effects*; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D000975:Antioxidants; D018797:Cell Cycle Proteins; D004265:DNA Helicases; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000077385:Silybin; D012838:Silymarin; D016159:Tumor Suppressor Protein p53; D051760:Xeroderma Pigmentosum Group A Protein; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C497314:XPA protein, human; C072022:XPBC-ERCC-3 protein
keywords: nucleotide excision repair; p53; photodamage; silibinin; ultraviolet radiation B