Silibinin inhibits inflammatory and angiogenic attributes in photocarcinogenesis in SKH-1 hairless mice

Cancer Res. 2007 Apr 1;67(7):3483-91. doi: 10.1158/0008-5472.CAN-06-3955.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Cell Growth Processes / drug effects
  • Cell Growth Processes / radiation effects
  • Cell Nucleus / metabolism
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / pathology
  • Cell Transformation, Neoplastic / radiation effects
  • Cyclooxygenase 2 / biosynthesis
  • Female
  • Inflammation / drug therapy
  • Inflammation / pathology
  • Mice
  • Mice, Hairless
  • NF-kappa B / metabolism
  • Neovascularization, Pathologic / drug therapy
  • Nitric Oxide Synthase Type II / biosynthesis
  • Phosphorylation
  • STAT3 Transcription Factor / metabolism
  • Silybin
  • Silymarin / pharmacology
  • Skin / enzymology
  • Skin / pathology
  • Skin / radiation effects*
  • Skin Neoplasms / blood supply
  • Skin Neoplasms / enzymology
  • Skin Neoplasms / etiology
  • Skin Neoplasms / prevention & control*
  • Ultraviolet Rays


  • Antioxidants
  • NF-kappa B
  • STAT3 Transcription Factor
  • Silymarin
  • Stat3 protein, mouse
  • Silybin
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Cyclooxygenase 2