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: Mallikarjuna Gu, Rana P Singh, Sivanandhan Dhanalakshmi, Chapla Agarwal, Rajesh Agarwal
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 7 Pg. 3483-91 (Apr 01 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17409458 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

• Animals
• Antioxidants (pharmacology)
• Cell Growth Processes (drug effects, radiation effects)
• Cell Nucleus (metabolism)
• Cell Transformation, Neoplastic (drug effects, pathology, radiation effects)
• Cyclooxygenase 2 (biosynthesis)
• Female
• Inflammation (drug therapy, 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, pathology, radiation effects)
• Skin Neoplasms (blood supply, enzymology, etiology, prevention & control)
• Ultraviolet Rays