Investigating the multi-targeted anti-cancer and chemopreventive potential of GSE in pre-clinical models of colorectal cancer

Colorectal cancer (CRC) is the third leading cause of cancer-associated deaths in the world; in this regard, there is an interest in cancer prevention and treatment strategies. Colon carcinogenesis involves a number of etiological factors, and thus to create effective preventive and treatment strategies, molecular targets need to be identified and targeted prior to disease progression.;Non-toxic chemoprevention strategies need to be developed; Grape seed extract (GSE) is one such agent, whose beneficial effects have been well documented in multiple cancer models. The present studies examine the chemopreventive and anti-cancer efficacy of GSE treatment through in-vitro and in-vivo pre-clinical models of CRC. In-vitro studies elute GSE efficacy and mechanisms of apoptotic death in human CRC cell lines. In-vivo studies assessed GSE efficacy as a chemoprevention agent against azoxymethane (AOM)-induced colon tumorigenesis in the A/J mouse model. Furthermore, these studies characterized the metastasis of azoxymethane-induced colon tumors to lung mouse model and evaluated grape seed extract (GSE) efficacy against this pre-clinical metastatic CRC model.;GSE is a complex mixture of polyphenolic compounds, including catechin and epicatechin; we aimed to identify potential targets of this extract utilizing Drug Affinity Response Target Stability (DARTS). This DARTS technique involves separation of proteins from GSE-treated and control-treated human CRC cells. Altered protein bands that are enriched due to GSE treatment were isolated and analyzed via LC/MS; the resulting peptides were then identified via MASCOT. These results revealed an overall downregulation of proteins involved in the ER stress response.;Overall the completed studies in this thesis indicated that GSE is a non toxic pleiotropic agent that targets multiple protein pathways involved in the development of colon carcinogenesis; these pathways included: ER stress pathway; intrinsic and extrinsic apoptotic pathways; proliferation pathways and inflammation. The pre-clinical efficacy studies have indicated that GSE would be a safe, effective, long-term treatment for the prevention and treatment of human CRC and should be further investigated in Phase I clinical trials.