In recent studies, we found that grape seed extract (GSE) significantly inhibits DU145 xenograft growth in nude mice. Mechanistic studies showed that GSE inhibits erbB1-ERKI/2-AP1 and NF-kB activation, b) alters cell cycle regulators and c) activates caspases, and that these events are associated with human prostate cancer (PCA) DU145 cell growth inhibition, G1 arrest and apoptotic death. In an attempt to conduct detailed mechanistic studies with active compound in GSE, we were able to isolate procyanidin B3 that showed even stronger DU145 cell growth inhibitory, and S and/or G2-M arrest and apoptotic death inducing efficacy than GSE in DU145 cells. In this grant, we propose in depth mechanistic followed by tumor efficacy studies with procyanidin B3 in cell culture and tumor xenografts. The central hypothesis is that procyanidin B3 inhibits a) mitogenic and cell survival signaling, b) induces S and/or G2-M arrest depending on its concentration via alteration in cell cycle regulators, and c) causes apoptosis via inhibition of survival signal, mitochondrial damage and Caspases activation. Collectively, these effects lead to its preventive and therapeutic efficacy against PCA. Following specific aims are proposed that will utilize normal human prostate epithelial and PCA LNCaP and DU145 cells. 1) To assess and define the effect of procyanidin B3 on mitogenic and cell survival signaling. 2) To assess and define the effect of procyanidin B3 on S and G2-M cell cycle regulators. 3) To assess and define the effect of procyanidin B3 on apoptosis regulators. 4) To assess and establish the efficacy of procyanidin B3 in nude mice tumor xenografts. 5) To continue identification of biologically active fraction(s) in GSE, and characterize individual compounds present therein. As a practical and translational approach, outcome of the proposed studies will form a basis for additional studies in pre-clinical PCA models followed by clinical trials in PCA patients to further define and establish the preventive and therapeutic efficacy of procyanidin B3 isolated from GSE.
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