Date on Master's Thesis/Doctoral Dissertation

12-2018

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

Gupta, Ramesh

Committee Co-Chair (if applicable)

Egilmez, Nejat

Committee Member

Egilmez, Nejat

Committee Member

Hein, David

Committee Member

Munagala, Radha

Committee Member

Schultz, David

Committee Member

Sharma, Vivek

Author's Keywords

CRC; FAP; anthos; berry; anthocyanidin

Abstract

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths within the United States. A variety of factors including exposure to environmental carcinogens, such as benzo[a]pyrene (B[a]P), dysbiosis of the gut microbiome and hereditary influences, including APC mutations, have been shown to lead to an increased risk of developing colorectal cancer. Given the recent alarming rise in cases of colorectal cancer diagnosed in individuals under the age of 40, further insight into developing novel and effective prevention and treatment strategies are warranted. The family of plant pigments known as the anthocyanins has been identified with a variety of health benefits including chemopreventive and therapeutic effects. However, a limitation to current clinical applications of anthocyanins is the high doses that are required. In order to overcome this barrier we tested the active moiety, anthocyanidins, native bilberry mixture of anthocyanidins (Anthos), at various doses for chemopreventive and therapeutic effects against colorectal cancer both in vitro and in vivo. Anthos treatment led to favorable modulation of several key contributors to the development of CRC including Src/EGFR pathway, Phase I/II enzyme expression and the inflammatory microenvironment, with special emphasis on the expression of PD-L1, a key immune checkpoint protein both in vitro and in vivo using an ApcMin/+ ETBF mouse tumor model. These results provide a promising outlook on the impact of berry Anthos for treatment and prevention of bacteria and B[a]P-driven colorectal cancer. Results from this study also provide novel mechanistic insight into the chemopreventive and therapeutic activities of Anthos.

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