Date on Master's Thesis/Doctoral Dissertation

8-2017

Document Type

Master's Thesis

Degree Name

M.S.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, MS

Committee Chair

Gupta, Ramesh C.

Committee Co-Chair (if applicable)

Egilmez, Nejat K.

Committee Member

Egilmez, Nejat K.

Committee Member

Hein, David W.

Committee Member

Munagala, Radha

Committee Member

Schultz, David J.

Committee Member

Sharma, Vivek R.

Author's Keywords

colon; cancer; familial adenomatous polyposis; anthocyanidin; exosome

Abstract

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths within the United States. Familial adenomatous polyposis (FAP) is an inherited disorder which if left untreated will develop into colon cancer. The family of plant-derived compounds, anthocyanins, show significant therapeutic potential against a variety of diseases, however, they are limited by their instability and poor bioavailability. The goal of my Master’s research project was to determine whether anthocyanidins (non-glycosylated anthocyanins) are more effective than the native anthocyanins, and whether exosomal formulation of anthocyanidins (ExoAnthos) can enhance therapeutic potency compared with free Anthos against both FAP and CRC. The antiproliferative effects of the native mixture of Anthos isolated from bilberry, with and without exosomal formulation, as well as individual Anthos against APC mutant (HT-29, Caco2), APC wild-type (HCT116) colon cancer cells and CCD-18Co normal colon cells were assessed using an MTT assay. To assess chemopreventive effects, the impact of the Anthos on polyp number was investigated in the APCMin/+ mouse model for FAP. While therapeutic efficacy of the Anthos treatment on colorectal tumor number was assessed in vivo using an APCMin/+ ETBF mouse tumor model. Early mechanistic work was undertaken to assess the impact of Anthos treatment on EGFR and Src phosphorylation using western blot analysis. Antiproliferation studies showed that ExoAnthos significantly lowered the IC50 compared to free Anthos against colon cancer cells. Anthos treatment led to significant reductions in polyp and tumor counts in vivo. Reduced Src and EGFR phosphorylation was also observed. These results provide a promising outlook on the future of the berry Anthos for treatment and prevention for both FAP and CRC.

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