Silibinin inhibits ultraviolet B radiation-induced mitogenic and survival signaling, and associated biological responses in SKH-1 mouse skin.
Ultraviolet B (UVB) radiation is a complete skin carcinogen causing DNA damage as a tumor-initiating event and activating signaling cascades that play a critical role in its tumor-promoting potential. Recently we reported that a naturally occurring flavonoid, silibinin, protects UVB-induced skin damages and prevents photocarcinogenesis. Here we examined silibinin efficacy on acute and chronic UVB-caused mitogen-activated protein kinases (MAPKs) and AKT activation and associated biological responses in SKH-1 hairless mouse skin. A single UVB exposure at 180 mJ/cm2 dose resulted in varying degrees of ERK1/2, JNK1/2, MAPK/p38 and AKT phosphorylation at various time-points in mouse skin; however, topical application of silibinin prior to or immediately after UVB exposure, or its dietary feeding strongly inhibited the activation of these molecules at all the time-points examined. Stronger effects of silibinin towards inhibition of UVB-caused phosphorylation of MAPKs and AKT were also observed in a chronic UVB (180 mJ/cm2/day for 5 days) exposure protocol. Immunohistochemical analysis of chronically exposed skin sections showed that silibinin treatment in all three protocols increases UVB-induced p53-positive cells and decreases UVB-caused cell proliferation, apoptotic and sunburn cells. These findings suggest that silibinin inhibits UVB-induced MAPK and AKT signaling and increases p53 in mouse skin, and that these effects of silibinin possibly lead to a decrease in UVB-caused proliferation and apoptosis, which might, in part, be responsible for its overall efficacy against photocarcinogenesis.
Gu
Mallikarjuna
M
Department of Pharmaceutical Sciences, School of Pharmacy and University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Dhanalakshmi
Sivanandhan
S
Mohan
Sarumathi
S
Singh
Rana P
RP
Agarwal
Rajesh
R
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D005260:Female; D020287:In Situ Nick-End Labeling; D051379:Mice; D008812:Mice, Hairless; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000528:radiation effects; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000528:radiation effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000528:radiation effects; D051057:Proto-Oncogene Proteins c-akt; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology; D012867:Skin / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D014466:Ultraviolet Rays
D018809:Proliferating Cell Nuclear Antigen; D011518:Proto-Oncogene Proteins; D011837:Radiation-Protective Agents; D012838:Silymarin; D016159:Tumor Suppressor Protein p53; D000077385:Silybin; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases