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<p>Colorectal cancer (CRC) is the third most prevalent cancer in the United States and estimated to affect 151,030 people and kill 52,580 people in 2022. Although some populations are more susceptible for CRC due to inherited cancer-causing mutations or having family history of CRC, most CRC cases occur sporadically with accumulation of a series of somatic mutation in tumor suppressor genes, oncogenes, and DNA repair system in the colon. Mutations in the adenomatous polyposis coli <em>(APC)</em> and the Kirsten rat sarcoma viral oncogene homologue <em>(KRAS)</em> are known as cancer driving mutations which are most frequently identified genetic lesions at early stages of sporadic CRC development. To evaluate effective drugs for prevention and treatment, preclinical models of CRC that resemble key features of human CRCs are crucial. Genetically modified mouse models (GEMM) of CRC bearing loss of <em>Apc</em> with or without other mutations, such as oncogenic <em>Kras</em> have been valuable tools to study pathobiology, treatment, and prevention of CRC. However, a major limitation of most <em>Apc</em>-mutant GEMMs is the predominant distribution of tumors in the small intestine rather than in the colon. Previously, a murine model bearing colon-specific mutations in <em>Apc</em> and <em>Kras</em> has been reported to develop colon-specific tumorigenesis in the colon, utilizing the <em>carbonic anhydrase 1 promoter/enhancer-Cre recombinase (CAC)</em> in Cre-LoxP system to restrict <em>Apc</em> knockout and a latent expression of oncogenic <em>Kras</em> in the colon tissue. However, only limited features of this model, so called AKC mouse, have been characterized so far. The lack of in depth understanding of this model could potentially hamper its utility for cancer research. Therefore, in Chapter 2 of this dissertation, I first characterized key aspects of disease-related phenotypes including clinical and histopathological features, tumor-elicited inflammation, the transcriptomic profiles, the gut microbial profiles in the AKC mice. Further, comparative analysis has been made on the transcriptomic profiles between AKC mice and human colon cancers with mutations in <em>APC</em> and <em>KRAS</em> at cancer stage II or below to evaluate the utility of the mouse model for studying human CRCs.</p> <p>Chemoprevention is the use of drugs or natural substances to inhibit initiation and delay of the progression of tumorigenesis, which could be a promising approach to reduce the incidence, mortality, and morbidity of CRC. Delta-tocotrienol (𝛿TE) is a natural analogue of vitamin E which has been shown to have antioxidant, anti-inflammatory and anticancer activities. Although its anticancer effects have been studied in different models of CRCs, including carcinogen-induced models, carcinogen-induced colitis-associated models, and colon cancer xenograft models, it has not been tested in a genetic model of sporadic CRC harboring <em>Apc</em> and <em>Kras</em> mutations. Therefore, in Chapter 3, the antitumor effects of 𝛿TE-rich tocotrienols (𝛿TE/gTE) and the potential mechanisms were investigated in AKC mice. 𝛿TE/𝛾TE-supplementation significantly improved the survival of AKC mice and suppressed tumorigenesis in association with inhibition of cell proliferation in the tumors. Further, the anti-tumor effects were correlated with reduction of pro-inflammatory and pro-tumorigenic cytokines, such as interleukin-1b and granulocyte-macrophage colony stimulating factor (GM-CSF), transcriptional enrichment of pathways involved in fatty acid metabolism, and reduction of diacylglycerol (DG) level in the colon tissue.</p> <p>Finally, AKC mice were used for screening the efficacies of other potential chemoprevention candidates, including aspirin, sulindac, and resveratrol in Chapter 4. Aspirin and sulindac are nonsteroidal anti-inflammatory drugs (NSAIDs) and they are among the most studied chemoprevention agents for CRC. However, the long-term regular use of NSAIDs may cause bleedings in the gastrointestinal organ system or hemorrhagic stroke. For aspirin, although extensive studies have shown its beneficial role in the prevention of primary CRC, there are mixed results for its benefit and harms, which may require further identification of populations who will benefit from the regular use of aspirin for prevention of CRC. Resveratrol is a naturally derived polyphenol, which is known for its antioxidant, anti-inflammatory, and antimicrobial activities with generally good safety profile. In our study, when the dietary supplementation of three compounds alone or in combination with 𝛿TE/gTE were examined for its antineoplastic effects in the AKC mice, only aspirin significantly suppressed tumorigenesis with decreased pro-inflammatory and pro-tumorigenic cytokines in the colon without overt toxicity. We found that sulindac induced serious gastric lesions and potential liver toxicity with some animals died earlier than the rest over the study period. Additionally, in this model, resveratrol was not effective in reducing tumorigenesis, in contrast to a previous study where the workgroup used similar genetic model of CRC but different modality to induce the mutations. Our findings add lines of evidence that depending on the use of different models the test compounds, aspirin, sulindac, and resveratrol may exhibit varying cancer prevention effects. Further research is warranted to identify underlying mechanisms that could explain the heterogenous responses to the test compounds and to optimize the interventions. </p>

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The purported chemopreventive and chemotherapeutic properties of the dietary phytochemical resveratrol continue to undergo active investigations. Systemic pharmacokinetics of this compound revealed that it was rapidly and extensively metabolized into its sulfate and glucuronide conjugates. This extensive metabolism leads to high plasma levels of resveratrol sulfates and glucuronides and very low levels of the parent compound (low bioavailability). These observations raised many questions, some of which this body of work examined and has helped to explain. Chapter 1 presents a detailed introduction to resveratrol and its role in colorectal cancer chemoprevention. It also lays the foundation for the hypotheses generated and the studies presented in succeeding chapters. In chapter 2, we explored the possibility that resveratrol metabolites possess intrinsic activity and thus contribute to the observed effects of the parent. The mono-sulfated and glucuronidated conjugates of trans-resveratrol were synthesized and tested for antiproliferative activity in a panel of mammalian cell lines. Their activity was then compared with the parent compound. Resveratrol was shown to be antiproliferative in all cell lines studied while no discernible antiproliferative activity was observed for the metabolites. Chapter 3 details the results of the glucuronidation kinetics of cis and trans-resveratrol isomers across a wide concentration range chosen to mimic blood levels following high dose consumption. Human tissue microsomes and recombinant supersomes over-expressing the enzymes (UGTs) of interest were used for these studies. Our results show the presence of atypical kinetics for the formation of resveratrol glucuronides across most of the protein sources used. Prior to this study, the full glucuronidation kinetics of total resveratrol had not been conducted. In chapter 4, we examined the association between genetic polymorphisms in the major enzymes (UGT1A1 and UGT1A6) and rates of glucuronidation of trans and cis-resveratrol. We set out to correlate functional genetic variations in these UGTs with their catalytic rates and a positive association was made for cis-resveratrol and UGT1A6 where the UGT1A6 variants mediated higher glucuronidation rates compared to the reference genotype. Chapter 5 explored the inherent ability of resveratrol to induce its own glucuronidation upon chronic dosing. Enzyme induction has been proposed as a mechanism that may contribute to the low bioavailability of resveratrol. Since dietary polyphenols like resveratrol are not consumed in isolation, we also studied the effects of combining resveratrol with two dietary polyphenols (curcumin and chrysin) on two chemoprevention endpoints - i) antiproliferation and ii) UGT enzyme induction. Our results indicate that resveratrol is capable of inducing UGT1A1 expression and activity in a non-concentration dependent manner and this induction as well as its antiproliferative effects are enhanced by both curcumin and chrysin. In summary, en route to probing the activity of resveratrol metabolites, we optimized two synthetic routes and generated measurable quantities of these compounds for future use. While the in vitro kinetics of resveratrol did not allow for any in vivo predictions, we were able to show alterations in resveratrol metabolism with respect to genotypic differences and enzyme induction that may contribute to the observed low bioavailability profile. / Pharmaceutical Sciences

Chu Wai Kit. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (leaves 87-96). / Abstracts in English and Chinese. / Acknowledgments --- p.ii / Publication --- p.iii / List of Abbreviations --- p.iv / List of Tables --- p.v / List of Figures --- p.vi / Abstract --- p.vii / 摘要 --- p.x / Table of Contents --- p.xii / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Epidemiology of gastric cancer --- p.1 / Chapter 1.2 --- Risk factors associated with gastric cancer --- p.7 / Chapter 1.3 --- Prevention of Gastric Cancer --- p.9 / Chapter 1.4 --- H. pylori eradication and gastric cancer development --- p.11 / Chapter 1.5 --- Non-steroidal anti-inflammatory drugs and gastric cancer prevention --- p.13 / Chapter 1.6 --- COX-2 independent pathway --- p.14 / Chapter 1.7 --- Animal model of gastric cancer --- p.15 / Chapter 1.8 --- Microarray system --- p.16 / Chapter 1.9 --- Hypothesis --- p.18 / Chapter 1.10 --- Aim of study --- p.19 / Chapter Chapter 2 --- Chemoprevention of gastric cancer by celecoxib --- p.20 / Chapter 2.1 --- Introduction --- p.20 / Chapter 2.2 --- Material and Methods --- p.22 / Chapter 2.2.1 --- Animals --- p.22 / Chapter 2.2.2 --- Chemicals --- p.22 / Chapter 2.2.3 --- Study design --- p.23 / Chapter 2.2.4 --- Cell Culture --- p.24 / Chapter 2.2.5 --- Celecoxib treatment --- p.24 / Chapter 2.2.6 --- Cell proliferation assay --- p.25 / Chapter 2.3 --- Results --- p.26 / Chapter 2.3.1 --- Chemoprevention of gastric cancer by celecoxib in rats --- p.26 / Chapter 2.3.2 --- Effects of celecoxib on growth of human gastric cancer cells --- p.29 / Chapter 2.4 --- Discussion --- p.30 / Chapter 2.4.1 --- MNNG induced gastric cancer effectively --- p.30 / Chapter 2.4.2 --- Celecoxib significantly suppressed gastric carcinogenesis in rats --- p.31 / Chapter 2.4.3 --- Celecoxib inhibited the growth of MKN 45 in a concentration-dependent manner --- p.31 / Chapter 2.4.4 --- Celecoxib may exert its anti-tumor property through COX independent pathway --- p.32 / Chapter Chapter 3 --- Gene expression profiles of celecoxib treated rat gastric tumor and human gastric cells --- p.34 / Chapter 3.1 --- Introduction --- p.34 / Chapter 3.2 --- Material and Methods --- p.34 / Chapter 3.2.1 --- RNA extraction --- p.34 / Chapter 3.2.2 --- Target preparation and Array hybridization --- p.35 / Chapter 3.2.3 --- Post-hybridization processing and Scanning --- p.36 / Chapter 3.2.4 --- Microarray data analysis --- p.36 / Chapter 3.2.5 --- Quantitative RT-PCR --- p.37 / Chapter 3.3 --- Results --- p.39 / Chapter 3.3.1 --- Gene expression profiles of rat gastric tumors --- p.39 / Chapter 3.3.1.1 --- Genes differentially expressed in MNNG induced gastric tumors --- p.39 / Chapter 3.3.1.2 --- Genes differentially expressed in celecoxib treated group --- p.42 / Chapter 3.3.1.3 --- Mechanisms underlying chemoprevention of celecoxib --- p.43 / Chapter 3.3.2 --- Verification of gene expression by quantitative RT-PCR --- p.55 / Chapter 3.3.3 --- Confirmation of the gene expression profiles in human by quantitative RT-PCR --- p.59 / Chapter 3.4 --- Discussions --- p.63 / Chapter Chapter 4 --- Effects of celecoxib on Akt pathway in gastric cancer cells --- p.68 / Chapter 4.1 --- Introduction --- p.68 / Chapter 4.2 --- Material and methods --- p.72 / Chapter 4.2.1 --- Protein extraction --- p.72 / Chapter 4.2.2 --- Western blotting --- p.72 / Chapter 4.3 --- Results --- p.74 / Chapter 4.3.1 --- Expression of the Akt pathway after treatment with celecoxib --- p.74 / Chapter 4.4 --- Discussions --- p.78 / Chapter Chapter 5 --- Conclusion --- p.82 / References --- p.87

Absorption study showed that gossypetin was methoxylated and conjugated to form glucuronide during the first-pass metabolism after oral administration. Glucuronide conjugate was the major circulating form in the plasma. As determined by HPLC analysis, the total gossypetin concentration in the plasma was higher than the unchanged gossypetin indicating that most of gossypetin underwent first-pass metabolism. Moreover, urinary excretion was not a main elimination route. / Uses of foods and dietary supplements present a safe chemopreventive strategy. The application of phytochemicals for cancer prevention currently receives a great deal of attention. Flavonoids are known to be antiproliferative and may play an important role in the prevention of carcinogenesis. In addition to epidemiologic studies, basic science research to elucidate mechanisms and evaluate chemopreventive potential of phytochemicals is also necessary. In this study, gossypetin was found to have stronger antiproliferative activity when compared with quercetin, a well studied flavonoid, in human hepatocellular carcinoma (HepG2) cells and human breast carcinoma (MCF-7) cells. The results demonstrated that gossypetin induced growth inhibition in MCF-7 cell line by arresting cell cycle at G0/G1 phase. The inhibition of cell cycle progression was associated with the decrement of cyclin D1 expression, cdk6 kinase activity and phosphorylation of retinoblastoma protein (pRb). Although the cdk inhibitor p21 could not be detected, its upstream protein, p53 tumor suppressor protein, was activated by gossypetin in the MCF-7 cell line. Also, the proliferation of MCF-7 cells was suppressed through down-regulating the Erk1/2 pathway. / Ngai Lei-ka. / "August 2005." / Source: Dissertation Abstracts International, Volume: 67-11, Section: B, page: 6156. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 222-250). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Dietary components potentially influence breast cancer risk factors, including breast density (BD) and estrogen metabolism (EM). Tamoxifen (TAM) is a commonly prescribed anti-estrogen adjuvant cancer treatment to reduce breast cancer risk, partially through modulation of BD and EM. Epidemiological evidence has suggested a potential protective effect from dietary intakes of fiber and vegetables in breast cancer recurrence in women on TAM as well as an independent influence on BD and EM. The relationship between dietary intake BD and EM in women prescribed TAM is not fully understood. A cross-sectional analysis using baseline data collected from 130 pre- and post-menopausal women taking TAM and enrolled in the Diindolylmethane Efficacy (DIME) Study was conducted. Participants completed the Arizona Food Frequency Questionnaire to assess dietary intake. TAM metabolites were analyzed through HPLC. BD was measured from digital mammograms and urinary EM was analyzed using LC/MS. Unadjusted linear regression between diet and four TAM metabolites indicated significant association between endoxifen and caffeine. 4-hydroxyTAM had significant inverse associations with fat intake, including monounsaturated, polyunsaturated and saturated fats. Linear regression adjusted for BMI revealed a statistically significant positive association with caffeine intake and BD, with no other dietary associations observed. The highest amount of correlations was observed between 2OHE and energy, total fat, MUFA, PUFA, protein and carbohydrate intake, though weak. Correlations were seen between 4OHE, 16αOHE and total isoflavones. Cholesterol was weakly positively correlated with 2mOHE, E1 and approached significance with E2. Dietary intake shows little association with BD or EM in women taking TAM therapy. Alternate preventive mechanisms for diet in women on TAM therapy should be investigated.