title: Role of p53 in silibinin-mediated inhibition of ultraviolet B radiation-induced DNA damage, inflammation and skin carcinogenesis.
abstract: Non-melanoma skin cancers (NMSC) are a growing problem given that solar ultraviolet B (UVB) radiation exposure is increasing most likely due to depletion of the atmospheric ozone layer and lack of adequate sun protection. Better preventive methods are urgently required to reduce UV-caused photodamage and NMSC incidence. Earlier, we have reported that silibinin treatment activates p53 and reduces photodamage and NMSC, both in vitro and in vivo; but whether silibinin exerts its protective effects primarily through p53 remains unknown. To address this question, we generated p53 heterozygous (p53+/-) and p53 knockout (p53-/-) mice on SKH-1 hairless mouse background, and assessed silibinin efficacy in both short- and long-term UVB exposure experiments. In the chronic UVB-exposed skin tumorigenesis study, compared to p53+/+mice, p53+/-mice developed skin tumors earlier and had higher tumor number, multiplicity and volume. Silibinin topical treatment significantly reduced the tumor number, multiplicity and volume in p53+/+mice but silibinin' protective efficacy was significantly compromised in p53+/-mice. Additionally, silibinin treatment failed to inhibit precursor skin cancer lesions in p53-/-mice but improved the survival of the mice. In short-term studies, silibinin application accelerated the removal of UVB-induced DNA damage in p53+/+mice while its efficacy was partially compromised in p53-/-mice. Interestingly, silibinin treatment also inhibited the UVB-induced inflammatory markers in skin tissue. These results further confirmed that absence of the p53 allele predisposes mice to photodamage and photocarcinogenesis, and established that silibinin mediates its protection against UVB-induced photodamage, inflammation and photocarcinogenesis partly through p53 activation.
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Rigby
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences.|Present address: Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Srirupa
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences.|University of Colorado Cancer Center and.
authors.forename: Gagan
authors.initials: G
authors.lastname: Deep
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences.
authors.forename: Ruth
authors.initials: R
authors.lastname: Guillermo-Lagae
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Jain
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences.
authors.forename: Deepanshi
authors.initials: D
authors.lastname: Dhar
authors.affiliation: Department of Pathology, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Orlicky
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences.|University of Colorado Cancer Center and.
authors.forename: Chapla
authors.initials: C
authors.lastname: Agarwal
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, rajesh.agarwal@ucdenver.edu.|University of Colorado Cancer Center and.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D004249:DNA Damage / Q000187:drug effects* / Q000528:radiation effects; D005260:Female; D007249:Inflammation / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D000975:Antioxidants; D012838:Silymarin; D016159:Tumor Suppressor Protein p53; D000077385:Silybin