Proanthocyanidins: Novel Skin Cancer Preventive Agent

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DESCRIPTION (provided by applicant): Chronic exposure of solar ultraviolet (UV) radiation, particularly UVB (290-320 nm), to human skin is primarily responsible for more than one million new cases of nonmelanoma skin cancer each year in the USA, making it the most prevalent environmental carcinogen known for humans. It is well documented that UV radiation is a potent producer of reactive oxygen species (ROS) and can act as both rumor initiator and promoter. UV-induced oxidative stress plays a crucial role in activation of cellular signal transduction pathways, which are implicated in various skin diseases including cancer. There have been concerted efforts to identify newer and effective chemopreventive agents that can protect against the adverse effects of UV radiation overexposure. In preliminary studies, we observed that dietary feeding of procyanidins isolated from grape seeds (GSP) resulted in significant prevention of photocarcinogenesis in animal model. The current proposal is therefore designed to define the mechanism of prevention of photocarcinogenesis by GSP treatment in SKH-1 hairless mouse model. The hypothesis to be tested in this proposal is that UVB exposure to skin induces oxidative stress, which causes activation of epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK) signaling pathways leading to the induction of photocarcinogenic events. The corollary to this hypothesis is that dietary feeding of GSP to mice will prevent UVB radiation induced oxidative stress, and thus oxidative stress-mediated activation of EGFR and MAPK signaling pathways which will result in reduction of skin cancer incidence. Following specific aims are proposed to test this hypothesis. In Specific Aim-1, we will examine whether dietary feeding of GSP will prevent UVB radiation induced: (a) depletion of cutaneous antioxidant defense enzymes, such as glutathione peroxidase, catalase, superoxide dismutase and glutathione level, and (b) markers of oxidative stress, such as H2C>2 and nitric oxide production, lipid peroxidation and protein oxidation in mouse skin. In Specific Aim-II, we will examine whether dietary feeding of GSP prevents UVB-induced oxidative stress-mediated phosphorylation of EGFR, and MAPK proteins such as extracellular signal-regulated kinase (ERK1/2), c-Jun-N-terminal kinase (INK) and p38 signaling pathways in vivo mouse skin, and in vitro system. The results obtained from this study may lead to the generation of new knowledge by which GSP exert its photoprotective effects, and will identify new dietary botanical supplement which can be used as a complementary approach for the prevention of solar UV radiation-induced skin cancer in humans. Prevention of skin cancer risk will result to protect and prolong the human health and lives.