This translational research project is based on the premise that diallyl trisulfide (DATS), a garlic-derived organosulfur compound, may be used to inhibit onset and/or progression of prostate cancer, which is the second leading cause of cancer related deaths among men in the United States. The rationale for a systematic preclinical evaluation of DATS against prostate cancer derives from epidemiological data and the results of our recently completed preliminary studies, which led us to hypothesize that DATS will inhibit onset and/or progression of prostate carcinogenesis due to its ability to (a) cause G2/M phase cell cycle arrest involving Ser-216 phosphorylation of Cdc25C, and (b) cause caspase-mediated apoptosis through activation of c-Jun N-terminal kinases (JNKs). We propose to test this hypothesis by: (1) determining the functional significance and mechanism of Cdc25C phosphorylation in DATS-induced G2/M phase cell cycle arrest using PC-3 and DU145 human prostate cancer cells as a cellular model, (2) determining the mechanism of DATS-induced activation of JNKs using PC-3 and DU145 cells, (3) determining the relative contribution of intrinsic (mitochondria mediated activation of caspase-9) and extrinsic (death-receptor mediated activation of caspase-8) caspase pathways in apoptosis induction by DATS using PC-3 and DU145 cells, (4) determining the effect of oral administration of DATS on growth of PC-3 and DU145 xenografts in vivo in nude mice, and (5) determining in vivo efficacy of DATS for prevention of prostate tumorigenesis in TRAMP mice.
In Specific Aims 4 and 5, the tumor tissues from control and DATS treated mice will be analyzed for apoptosis index and levels of cell cycle and apoptosis regulating proteins to determine the extent to which DATS-induced molecular changes observed in cells (Aims 1-3) correlate with its effect in vivo. In summary, the studies proposed in this application will (a) define the mechanism(s) by which DATS inhibits proliferation of human prostate cancer cells, which could lead to identification of mechanism-based biomarkers potentially useful in future clinical trials, and (b) determine efficacy of DATS against prostate cancer using appropriate animal models, which is a prerequisite for initiation of clinical trials to determine activity of DATS against prostate cancer in humans. In the long run, the results of the proposed studies could lead to DATS-based strategies for prevention and/or treatment of human prostate cancers.
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