Date of Award

Spring 2020

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

E. Angela Murphy

Abstract

5 Fluorouracil (5FU) chemotherapy is widely used in the treatment of colorectal cancer (CRC), and has been the first-choice chemotherapy drug for CRC for many years. However, nearly 10% of patients receiving chemotherapy die during the first 30 days of treatment. Further, it is estimated that 70% of surviving patients will develop non-specific toxicities as a result of chemotherapy treatment. We characterize these toxicities in an animal model of chemotherapy treatment and show that perturbations in the gut microbiome might be exacerbate the prolonged effects of chemotherapy. A compound that could attenuate the multiple non-selective toxicities associated with chemotherapy could have great clinical potential. Emodin is a trihydroxy-anthraquinone found in several Chinese herbs, including Rheum palmatum and Polygonum multiflorum. Emodin has been shown to attenuate the severity of multiple experimental disease models including arthritis, liver damage, atherosclerosis, myocardial ischemia, and cancer by reducing the inflammatory cascades associated with these conditions. We illustrate that emodin is poorly absorbed when given orally or intraperitoneally and is cleared from systemic circulation by 12 hours. However, we did discover that emodin is more bioavailable in female mice 1 hour after dosing. We also demonstrate that emodin is safe in mice when given through the diet for 3 months and does not cause any physiological or pathological perturbations. When pairing emodin with 5FU, we were able to attenuate functional toxicities associated with chemotherapy and ameliorate the lymphocytopenia associated with chronic and acute chemotherapy. Further, we demonstrate that emodin can improve gut resilience to 5FU and reduce aberrations in bacterial spatial arrangement. In addition, we examined the ability for emodin to be used as a preventative treatment for colorectal and intestinal cancer. We show that emodin treatment reduces tumor burden in both the AOM/DSS and Apcmin/+ models of sporadic cancer development. In the AOM/DSS model we show that emodin reduces pro-tumorigenic M2-type macrophages in the colon. Further, we show that there is amelioration of the pro-inflammatory niche that exists in the bone marrow which might contribute to the improved survival outcome and quality of life during cancer treatment. The findings presented in this document show significant promise for the potential use of emodin as a primary and complementary therapeutic in the treatment of colorectal cancer.

Rights

© 2020, Alexander-Jacques Theodore Sougiannis

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