Grape Seed Extract as an Adjunct for Modulating Colon Carcinogenesis

Heinz-Taheny, Kathleen M.

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Description

Title

Grape Seed Extract as an Adjunct for Modulating Colon Carcinogenesis

Author(s)

Heinz-Taheny, Kathleen M.

Issue Date

2007

Doctoral Committee Chair(s)

Wallig, Matthew A.

Department of Study

Veterinary Pathobiology

Discipline

Veterinary Pathobiology

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

Health Sciences, Oncology

Language

eng

Abstract

Colon cancer is one of the leading causes of cancer deaths in the United States and increasing in incidence globally. Grape seed extract (GSE) is a nutritional supplement with claims as a chemopreventive compound. Preliminary experimental data suggests that dietary GSE may be protective against colorectal cancer. In preliminary experiments, we identified candidate protein biomarkers expressed differently in human colonic tumors compared with non-cancerous colonic tissue. In Western blot and immunohistochemical staining of human colonic tumors compared with non-cancerous colonic tissue, the tumors exhibited elevated expression of beta-catenin and iNOS and decreased expression of PPARgamma, and increased expression of COX-2 by immunohistochemistry. To carry out experimental analysis of dietary GSE in an in vivo model of human colon cancer, azoxymethane (AOM) was used to induce pre-neoplastic colonic lesions in male Fischer 344 rats. These pre-neoplastic lesions are termed aberrant crypt foci (ACF). Both ACF and ACF with multiplicity (ACF with four or more aberrant crypts within a focus) are putative pre-neoplastic lesions with the potential for development into colonic adenomas or carcinomas. Utilizing three dietary doses of GSE, low (0.005%), mid (0.01%) and high (0.05%) in AOM-induced rats, it was found that the low and mid dose groups had the greatest reduction in ACF and ACF with multiplicity compared to the high dose and positive control (AOM only) groups. PPARgamma, a putative colonic enterocyte cellular differentiation marker, was evaluated by Western blot and observed to be elevated in the mid dose group, consistent with its suggested role in colonic differentiation. Microarray analysis revealed repression of several genes involved in lipid metabolism. Evaluating the effects of dietary GSE in short term studies yielded interesting proteomic and genomic trends. It was found that at an early model of AOM effects on rats fed GSE, two weeks post-AOM, dietary GSE protected colonic enterocytes against AOM damage by reduced expression of beta-catenin and COX-2. Genetic alterations in the GSE groups included up-regulation of apoptotic inducers and lamin B1 and down-regulation of lipid metabolism. In rats GSE three weeks post-AOM, it was found that GSE protected the enterocytes against severe AOM damage that resulted in a large increase in apoptosis in the rats receiving AOM only. Genetically, in this three weeks post-AOM model, GSE up-regulated cellular ubiquitination and sensitivity to natural killer-cell mediated destruction and down-regulated cGMP activity. Dietary GSE alone (without AOM exposure) did not alter proteins differently than the negative control (rats receiving neither AOM or dietary GSE) and genomically down-regulated Jun oncogene. In conclusion, GSE protects against AOM induced colonic pre-neoplastic lesions and proteomic and genomic alterations consistent with protection against development of colonic tumors.

Graduation Semester

2007

Type of Resource

text

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