Date of Award

1-1-2009

Document Type

Campus Access Dissertation

Department

College of Pharmacy

Sub-Department

Pharmaceutical Science

First Advisor

Lorne J. Hofseth

Abstract

Ulcerative colitis (UC) is a heterogenous, chronic and relapsing inflammatory condition that has a significant impact on the quality of life. Millions of people world-wide have this disease and have an increased colon cancer risk. Despite a wide variety of causes (e.g. environmental factors, genetic susceptibility and imbalanced enteric bacteria), the end result is an abnormal immune response with repeated episodes of colonic inflammation. While not everyone with colitis will develop colon cancer, risk increases when length of disease exceeds 10 years, on the order of 0.5-1.0% per year. Conventional treatment of colitis can reduce periods of active disease and help to maintain remission, but these treatments often bring marginal results, there are side effects, and patients become refractory. For this reason, many colitis sufferers turn to unconventional treatments in hopes of abating symptoms of active disease and it is estimated that ~40% of UC patients use some form of megavitamin therapy of herbal/dietary supplement basing on current records.

Many reports suggest that the natural herbal American ginseng (Panax quinquefolius) improves mental performance, immune-reaction and detrimental end points associated with diseases such as cardiovascular disease, diabetes, influenza and cancer. These diseases are all associated with inflammation, and American ginseng (AG) is a putative antioxidant in that it targets many of the key players involved in inflammation.

Furthermore, apoptosis of inflammatory cells is a key mechanism regulating UC. AG is a putative anti-oxidant with an ability to suppress hyperactive immune cells. As a part of this thesis, we show AG can prevent and treat mouse colitis, as well as suppress oxidative stress and DNA damage in vitro and in vivo (Chapter II). Because p53 levels are elevated in inflammatory cells in both mouse and human colitis, we also hypothesized and show that AG protects from colitis by driving inflammatory cell apoptosis through a p53 mechanism (Chapter III).

Moreover, chronic inflammation contributes a high cancer risk. The hypothesis has been tested that AG can prevent colon cancer associated with colitis (Chapter IV). Using the azoxymethane (AOM)/dextran sulfate sodium (DSS) mouse model of UC, we show that AG can suppress colon cancer associated with colitis. To explore the molecular mechanisms of the anti-cancer effects of ginseng, we also carried out antibody array experiments, and found there were 82 protein endpoints that were either significantly higher (41 proteins), or significantly lower (41 proteins) in the AOM + DSS group compared with the AOM alone (control) group. In contrast, there were only 19 protein endpoints that were either significantly higher (10 proteins), or significantly lower (9 proteins) in the AOM + DSS + AG group compared with the AOM alone (control) group. The specific proteins are outlined in Chapter IV, but overall, these results suggest AG keeps the colon environment in metabolic equilibrium when mice are treated with DSS.

Because of the complicated nature of AG, it is difficult to pin down the specific ingredients within the extract capable of interacting with anti-inflammation and anti-carcinogenesis through a p53 pathway. Future studies will be carried out to delineate the molecular ingredients in AG that target p53 as a molecule at the crossroads of the anti-inflammatory nature of AG against colitis and colon cancer associated with colitis.

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