Overexposure of the human skin to solar ultraviolet (UV) radiation is the major etiologic agent for the development of melanoma and non-melanoma skin cancers in the United States, with non-melanoma skin cancer being the most common cutaneous malignancy. We have demonstrated that dietary grape seed proanthocyanidins (GSPs) provide significant protection against UV-induced skin carcinogenesis in an in vivo mouse model and have further demonstrated that dietary GSPs provide significant protection against UV- induced immunosuppression, a well-established risk factor for skin cancer. The goal of the proposed studies is to establish the mechanisms by which dietary GSPs act to correct UV-induced immunosuppression associated with photocarcinogenesis by: (i) Identifying the mechanisms by which dietary GSPs ameliorate UV radiation- induced immunosuppression and DNA damage;and (ii) Determining the contribution of these mechanisms to GSPs-mediated prevention of skin cancer. Currently, it is known that UV-induced DNA damage in the form of generation of cyclobutane pyrimidine dimers (CPDs) is a risk factor for cancer and is an important molecular trigger for UV-mediated immunosuppression and that UV-mediated immunosuppression is associated with the induction of suppressor cells and impaired function of dendritic cells and effector T cells. The critical question is therefore whether the GSPs act on multiple fronts to prevent or correct UV-induced immunosuppression or act by blocking the early events that initiate immunosuppression. Our pilot studies suggest that GSPs have the ability to enhance the removal or repair of CPD+ cells in UV-exposed skin and our preliminary data further indicate that GSPs can act to enhance the removal of CPDs in UV-exposed dendritic cells and restore dendritic cell-mediated activities, including stimulation of T cells. Notably, dietary GSPs do not inhibit UV-induced immunosuppression in those mice which have a defect in DNA repair. Together, these data suggest the hypothesis that the repair of UVB-induced DNA damage by GSPs in dendritic cells is critical for their 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 dietary GSPs inhibit the development of UV-induced tolerogenic dendritic cells through restoration of dendritic cell activity;(2) Determine whether dietary GSPs inhibit UV-induced immunosuppression through enhancement of T-cell activation, (3) Determine whether dietary GSPs inhibit the development of UV-induced regulatory T cells;and (4) Determine whether inhibition of photocarcinogenesis by dietary GSPs is mediated through DNA repair. SIGNIFICANCE: These studies address a major public health and VA healthcare concern, i.e., the growing incidence of skin cancers. The development of more effective preventive approaches, such as dietary GSPs that exhibit no toxicity in mice, requires an improved understanding of the mechanisms by which they prevent UVB-induced carcinogenesis.

Public Health Relevance

/ Significance and Relevance to Veterans Health Care Chronic exposure of the skin to solar ultraviolet (UV) radiation induces adverse effects including the risk of skin cancer development. Veterans in general are over-exposed to solar UV light, and this is particularly true for those deployed during the Persian Gulf War and currently in the Afghanistan and Iraq war. Our studies indicated that grape seed proanthocyanidins (GSPs) possess potent anti-photocarcinogenic activity. In the current application, our study will highlight that rapid repair of UVB-induced DNA damage by dietary GSPs will result in the enhancement or restoration of immune system and that will lead to the prevention of UV- carcinogenesis in laboratory animals. Successful completion of the proposed studies with GSPs may lead to the generation of new knowledge to identify newer, effective and novel chemopreventive agent and strategies that can be used to prevent solar UV radiation-induced skin cancer in general, and the VA population in particular, and that will result in a better quality of life of veterans and their caring families.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Oncology A (ONCA)
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Birmingham VA Medical Center
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Vaid, Mudit; Prasad, Ram; Singh, Tripti et al. (2017) Dietary grape seed proanthocyanidins inactivate regulatory T cells by promoting NER-dependent DNA repair in dendritic cells in UVB-exposed skin. Oncotarget 8:49625-49636
Prasad, Ram; Katiyar, Santosh K (2017) Crosstalk Among UV-Induced Inflammatory Mediators, DNA Damage and Epigenetic Regulators Facilitates Suppression of the Immune System. Photochem Photobiol 93:930-936
Pal, Harish C; Prasad, Ram; Katiyar, Santosh K (2017) Cryptolepine inhibits melanoma cell growth through coordinated changes in mitochondrial biogenesis, dynamics and metabolic tumor suppressor AMPK?1/2-LKB1. Sci Rep 7:1498
Singh, Tripti; Prasad, Ram; Katiyar, Santosh K (2016) Therapeutic intervention of silymarin on the migration of non-small cell lung cancer cells is associated with the axis of multiple molecular targets including class 1 HDACs, ZEB1 expression, and restoration of miR-203 and E-cadherin expression. Am J Cancer Res 6:1287-301
Katiyar, Santosh K (2016) Dietary proanthocyanidins inhibit UV radiation-induced skin tumor development through functional activation of the immune system. Mol Nutr Food Res 60:1374-82
Prasad, Ram; Kappes, John C; Katiyar, Santosh K (2016) Inhibition of NADPH oxidase 1 activity and blocking the binding of cytosolic and membrane-bound proteins by honokiol inhibit migratory potential of melanoma cells. Oncotarget 7:7899-912
Vaid, Mudit; Singh, Tripti; Prasad, Ram et al. (2016) Bioactive proanthocyanidins inhibit growth and induce apoptosis in human melanoma cells by decreasing the accumulation of ?-catenin. Int J Oncol 48:624-34
Vaid, Mudit; Singh, Tripti; Prasad, Ram et al. (2015) Therapeutic intervention of proanthocyanidins on the migration capacity of melanoma cells is mediated through PGE2 receptors and ?-catenin signaling molecules. Am J Cancer Res 5:3325-38
Katiyar, Santosh K (2015) Hsp90 inhibitor can inhibit UV carcinogenesis. J Invest Dermatol 135:945-947
Singh, Tripti; Gupta, Nirzari A; Xu, Su et al. (2015) Honokiol inhibits the growth of head and neck squamous cell carcinoma by targeting epidermal growth factor receptor. Oncotarget 6:21268-82

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