The goals of the proposed studies are to: (1) Identify the mechanisms by which silymarin, a phytochemical obtained from milk thistle (Silybum marianum L.), ameliorates ultraviolet (UV) radiation-induced immunosuppression and DNA damage;and (2) Determine the contribution of these mechanisms to silymarin-mediated prevention of skin cancer. Both UV-induced DNA damage, in the form of cyclobutane pyrimidine dimers (CPDs), and immune suppression have been shown to be associated with an increased risk of skin cancer. We have demonstrated that topical treatment with silymarin provides significant protection against both UV-induced immunosuppression and carcinogenesis in an in vivo mouse model. UV irradiation is known to impair the function of dendritic cells and effector T cells but induce suppressor T cells. Furthermore, UV-induced DNA damage, predominantly the formation of CPDs, is an important molecular trigger for UV-mediated immunosuppression. We have demonstrated that silymarin has the ability to enhance the removal or repair of CPD+ cells in UV-exposed skin, and inhibits UVB-induced suppression of the contact hypersensitivity response in mice. Our preliminary data further indicate that silymarin can enhance the removal of CPDs in UV-exposed dendritic cells and restore dendritic cell-mediated activities including stimulation of T cells. However, silymarin mediated inhibition of UV-induced immunosuppression is abolished in mice that have defect in DNA repair. Collectively, these data implicate key links between the ability of silymarin to inhibit UV-induced immunosuppression and its ability to prevent photocarcinogenesis. Our hypothesis is that the repair of UVB-induced DNA damage by silymarin is critical for its chemopreventive effects on UV-induced immunosuppression and photocarcinogenesis. We propose four inter-related Specific Aims in which we will use genetically modified mouse model, including nucleotide excision repair-deficient mice: (1) Determine whether silymarin inhibits the development of UV-induced tolerogenic dendritic cells through restoration of dendritic cell activity;(2) Determine whether silymarin- induced inhibition of UV-induced immunosuppression occurs through enhancement of T-cell activation, (3) Determine whether silymarin inhibits the development of UV-induced regulatory T cells;and (4) Determine whether silymarin inhibition of photocarcinogenesis is mediated through DNA repair. The proposed studies should identify the mechanisms by which silymarin acts to correct UV-induced immunosuppression in photocarcinogenesis. We address a major public health concern as overexposure of the human skin to solar UV radiation is the major etiologic factor for the development of melanoma and non-melanoma skin cancers in the United States. The development of new strategies using silymarin may help to reduce the risk of skin cancer in humans.

Public Health Relevance

Chronic exposure of the skin to solar ultraviolet (UV) radiation induces multiple adverse effects including the risk of skin cancer development. In vitro and in vivo studies have indicated that silymarin, a plant flavonoid obtained from milk thistle, possesses potent anti-photocarcinogenic activity. In the current application, we will determine the molecular mechanism of prevention of photocarcinogenesis by silymarin. This study will also highlight that rapid repair of UVB-induced DNA damage by silymarin will result in the enhancement or restoration of immune system and that will lead to the prevention of UV-carcinogenesis. The generation of new knowledge will provide novel insights into the mechanisms by which silymarin can either correct, or compensate for, the UV-induced damage that triggers or promotes photocarcinogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA140197-03
Application #
8210888
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Seifried, Harold E
Project Start
2010-07-01
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$331,728
Indirect Cost
$105,293
Name
University of Alabama Birmingham
Department
Dermatology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Katiyar, Santosh K (2015) Proanthocyanidins from grape seeds inhibit UV-radiation-induced immune suppression in mice: detection and analysis of molecular and cellular targets. Photochem Photobiol 91:156-62
Shukla, Samriddhi; Meeran, Syed M; Katiyar, Santosh K (2014) Epigenetic regulation by selected dietary phytochemicals in cancer chemoprevention. Cancer Lett 355:9-17
Singh, Tripti; Katiyar, Santosh K (2013) Green tea polyphenol, (-)-epigallocatechin-3-gallate, induces toxicity in human skin cancer cells by targeting ?-catenin signaling. Toxicol Appl Pharmacol 273:418-24
Vaid, Mudit; Prasad, Ram; Singh, Tripti et al. (2013) Silymarin inhibits ultraviolet radiation-induced immune suppression through DNA repair-dependent activation of dendritic cells and stimulation of effector T cells. Biochem Pharmacol 85:1066-76
Vaid, Mudit; Singh, Tripti; Prasad, Ram et al. (2013) Bioactive grape proanthocyanidins enhance immune reactivity in UV-irradiated skin through functional activation of dendritic cells in mice. Cancer Prev Res (Phila) 6:242-52
Prasad, Ram; Katiyar, Santosh K (2013) Prostaglandin E2 Promotes UV radiation-induced immune suppression through DNA hypermethylation. Neoplasia 15:795-804
Sun, Qian; Prasad, Ram; Rosenthal, Eben et al. (2011) Grape seed proanthocyanidins inhibit the invasive potential of head and neck cutaneous squamous cell carcinoma cells by targeting EGFR expression and epithelial-to-mesenchymal transition. BMC Complement Altern Med 11:134
Katiyar, Santosh K; Mantena, Sudheer K; Meeran, Syed M (2011) Silymarin protects epidermal keratinocytes from ultraviolet radiation-induced apoptosis and DNA damage by nucleotide excision repair mechanism. PLoS One 6:e21410
Katiyar, Santosh K; Raman, Chander (2011) Green tea: a new option for the prevention or control of osteoarthritis. Arthritis Res Ther 13:121