Background: Epidemiological studies continue to support the premise that increased consumption of allium vegetables, such as garlic, may be protective against the risk of certain types of cancers including prostate cancer. Recent studies have revealed that human prostate cancer cells as well as a cell line derived from prostate adenocarcinoma of a transgenic mouse (transgenic adenocarcinoma mouse prostate; TRAMP-C1 cell line) are highly sensitive to growth inhibition by diallyl trisulfide (DATS), a garlic-derived organosulfur compound (OSC). Interestingly, viability of a normal prostate epithelial cell line (PrEC, Clonetics) was minimally affected by DATS even at concentrations that were highly cytotoxic to the prostate cancer cells. These results are encouraging since selective killing of cancer cells is a highly desirable property of potential cancer preventive/therapeutic agents. Objective/Hypothesis: The underlying hypothesis driving this project is that DATS elevates the intracellular level of reactive oxygen species (ROS) and subsequently activates INK and caspases. The activation of the apoptotic pathway leads to the chemopreventive efficacy of DATS.
Specific Aims :
The specific aims of this project are to examine (1) whether DATS elevates the intracellular level of ROS by either increasing production of ROS through the mitochondrial electron transport chain or decreasing elimination of ROS through the glutathione peroxidase/glutathione reductase system, (2) whether redox-regulatory proteins such as thioredoxin (TRX) and glutaredoxin (GRX) recognize DATS-induced oxidative stress and activate the ASKl-MEK-JNK-Bim-Bax signal transduction pathway, and (3) whether intrinsic and extrinsic caspase pathways are involved in DATS- induced apoptotic death. Study design: In the proposed studies, the first aim will use a spectrofluorometer to measure the intracellular level of ROS.
The second aim will be use of biochemical assays to investigate the ASK1-MEK-JNK signal transduction pathway.
The third aim will use pharmacological and molecular genetic approaches to attenuate the activity/expression of caspase. Relevance: We believe that the successful outcome of this study will support the development and clinical application of DATS for the chemoprevention of human prostate cancer. ? ? ?
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