Pancreatic cancer is the fourth leading cause of cancer-related death in the United States. It is one of the most aggressive human malignancies with poor prognosis. Epidemiological studies from different geographical locations have suggested that increased consumption of cruciferous vegetables reduces the risk of pancreatic cancer. Several studies have established that cancer preventive effects of cruciferous vegetables are attributable to isothiocyanates (ITCs), which are generated upon cutting or chewing of these vegetables. ITCs are known to offer significant protection against chemically induced cancer in animal models. Despite compelling epidemiological correlation, however, effect of cruciferous vegetable Iconstituents on growth of human pancreatic cancer has not been determined. Our preliminary studies demonstrate that benzyl isothiocyanate (BITC), a prototypical and best studied member of the ITC family, inhibits proliferation of human pancreatic cancer BxPC-3 and Capan-2 cells by causing G2/M arrest and inducing apoptosis, whereas growth of normal human acinar and ductal cells is minimally affected by BITC. Our studies have also demonstrated that the key survival molecules NF-kappaB, cyclin D1 and Bcl-2 that are overexpressed in pancreatic cancer are significantly inhibited by BITCtreatment. Based on these interesting findings, we hypothesize that human pancreatic cancer cells would be highly sensitive to growth inhibition by BITC in vitro and in vivo due to its ability to (a) cause cell cycle arrest, and (b) induce apoptosis via inhibition of NF-kappaB signaling pathway. Following are the specific aims to test our hypothesis:
Specific aim 1 will investigate the effects of orally administered BITC on growth of BxPC-3 and Capan-2 xenografts in nude mice.
Specific aim 2 will investigate the molecular mechanism(s) of BITC-mediated G21M arrest in both the cell lines.
Specific aim 3 will determine the mechanism(s) of BITC-mediated attenuation of NF-kappaB signaling pathway in above cells through analysis of the expression and activity of upstream and downstream signaling molecules of protein kinase C (PKC) and mitogen activated protein kinases (MAPK) pathways, which are the regulators of NF-kappaB, and the cross-talk between these signaling molecules.
Specific aim 4 will investigate the involvement of PI3K/PKB signaling pathway in BITC-mediated inhibition of NFkB in pancreatic cancer cells using genetic (transfection) and pharmacological (inhibitors) approaches. The experiments proposed in this application will lay the pre-clinical foundation for future clinical studies directed at a novel strategy to delay the onset and/or progression of pancreatic cancer by dietary agent targeting NF-kappaB pathway.
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