MOLECULAR CHEMOPREVENTION MECHANISMS OF TEA POLYPHENOLS

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DESCRIPTION: (Applicant's Description) Prevention is the most efficient way to reduce the incidence, morbidity, Nd mortality of cancer. Thus, development of new investigators in cancer prevention research is imperative. Steven P. Stratton, Ph.D. is a junior investigator in the field of cancer prevention; with training in analytical chemistry, toxicology, pharmacology, cancer therapeutics, cancer drug development, and cancer prevention epidemiology. The mentored training supported by this award will facilitate the development of Dr. Stratton into a fully independent investigator. This project will be conducted at the Arizona Cancer Center, a National Cancer Institute-designated comprehensive cancer center with an international reputation for excellence in cancer prevention research. The proposed studies will be performed under the aegis of the Chemoprevention of Skin Cancer Program Project at the University of Arizona. This project will focus on skin cancer chemoprevention mechanisms with polyphenolic derivatives of tea, Camellia sinensis. Green tea is one of the most widely consumed beverages in the world. Many studies both in vivo and in vitro suggest that polyphenolic compounds present in tea inhibit skin carcinogenesis, though the mechanism of action is still unknown. An understanding of this mechanism is crucial to the development of chemopreventive strategies using these compounds. This project will test the hypothesis that green tea polyphenols prevent UV radiation-induced skin carcinogenesis by modulating reactive oxygen-mediated alterations of normal cell function. Markers of reactive oxygen and secondary membrane damage will be used to explore the role of tea polyphenols in UV-induced skin cell transformation using human keratinocytes in vitro and an in vivo mouse skin model. The specific aims of this project include analyzing the effects of green tea polyphenols on: (1) Cell membrane lipid peroxidation using new sensitive and specific GC/MS assays to quantify levels of oxidized biomolecules; (2) Cell cycle progression and expression of cell cycle control genes using flow cytometry and RNase protection techniques; (3) Regulation of transcription factor activation using an alkaline phosphatase reporter system; and (4) Apoptosis and translocation of relevant transcription factors using in situ molecular imaging techniques. Changes in levels of these markers will be used to establish links between antioxidant effects of tea polyphenols and possible direct effects on redox-sensitive downstream events. The overall goal of this project is to promote the development of an academic research career in cancer prevention within a framework of molecular chemoprevention mechanistic studies and training. Immediate goals include acquiring the scientific and technical expertise necessary for independent investigations of secondary cancer prevention mechanisms. Long-term career goals include development of new methods, assays, and expertise in redox-modulated biochemical processes; establishment of a molecular chemoprevention laboratory; development of collaborative research programs in molecular mechanisms of cancer prevention; and ultimately, development of chemopreventive therapies that reduce cancer morbidity and mortality.