title: Silibinin inhibits inflammatory and angiogenic attributes in photocarcinogenesis in SKH-1 hairless mice.
abstract: Sunscreens partially filter UVB and, therefore, could partially prevent skin cancer; however, efficient approaches are desired to effectively prevent photocarcinogenesis. It is hypothesized that nontoxic pharmacologically active natural compounds can increase photoprotective effects. Our completed studies suggest that silibinin, a bioactive phytochemical, strongly prevents photocarcinogenesis; however, its mechanism is not fully understood. Herein, for the first time, we used a clinically relevant UVB dose (30 mJ/cm(2)/day) to examine the photoprotective effect and associated mechanisms of silibinin in SKH1 hairless mice. Topical or dietary silibinin treatment caused a strong protection against photocarcinogenesis in terms of delay in tumor appearance, multiplicity, and volume. Analyses of normal skin, uninvolved skin from tumor-bearing mice, and skin tumors showed a statistically significant decrease (P < 0.05-0.001) in inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) levels by silibinin. Concomitantly, phospho-signal transducers and activators of transcription 3 (Tyr(705)) and phospho-p65(Ser(536)) were also decreased by silibinin, which are potential up-stream regulators of iNOS and COX-2. Simultaneously, silibinin also decreased UVB-caused increase in cell proliferation and microvessel density. In tumors, hypoxia-inducible factor 1alpha (HIF-1alpha) and vascular endothelial growth factor protein levels were decreased by silibinin. Further analysis showed that silibinin inhibited UVB-caused phosphorylation and nuclear translocation of STAT3 and p65, as well as nuclear factor kappaB (NF-kappaB) DNA binding activity. Together, these results suggest that silibinin causes a strong protective effect against photocarcinogenesis via down-regulation of inflammatory and angiogenic responses, involving HIF-1alpha, STAT3, and NF-kappaB transcription factors, as well as COX2 and iNOS.
authors.affiliation: Department of Pharmaceutical Sciences, and University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado, USA.
authors.forename: Mallikarjuna
authors.initials: M
authors.lastname: Gu
authors.forename: Rana P
authors.initials: RP
authors.lastname: Singh
authors.forename: Sivanandhan
authors.initials: S
authors.lastname: Dhanalakshmi
authors.forename: Chapla
authors.initials: C
authors.lastname: Agarwal
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects / Q000528:radiation effects; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D005260:Female; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008812:Mice, Hairless; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology; D012867:Skin / Q000201:enzymology / Q000473:pathology / Q000528:radiation effects*; D012878:Skin Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D014466:Ultraviolet Rays
chemical_list: D000975:Antioxidants; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D012838:Silymarin; C494087:Stat3 protein, mouse; D000077385:Silybin; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051546:Cyclooxygenase 2