Browsing by Subject "Chemoprevention"

Now showing 1 - 4 of 4
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    Aspirin intervention, inflammation and the oral microbiome
    (2020-10) Onyeaghala, Guillaume
    Specific pro-inflammatory oral taxa have been shown to be increased in the gut microbiome of individuals with colorectal cancer (CRC). Aspirin is associated with decreased risk of colorectal cancer, potentially by modulating the gut and the oral microbiome. However, it remains unclear how pro-inflammatory oral taxa would respond to anti-inflammatory agents such as aspirin. In this dissertation, we aimed to evaluate the effect of aspirin intervention on specific pro-inflammatory oral taxa and inferred functional traits linked to inflammation in a 6-week double-blind placebo-controlled trial.In the first manuscript, we evaluated the effect of aspirin intervention on the relative abundance of pro-inflammatory oral taxa. We found that the change over-time in the relative abundance of 9 out of the 12 pre-specified taxa at the genus level, and 1 out of 2 pre-specified taxa at the family level differed between the aspirin and placebo groups. These preliminary findings suggest that aspirin may change the relative abundance of oral taxa associated with inflammation. In manuscript 2, we evaluated the effect of aspirin intervention on the relative abundance of inferred functional traits linked to the pro-inflammatory bacterial metabolite, lipopolysaccharide (LPS). We did not find an association between aspirin intervention and the change in relative abundance of inferred functional traits for LPS. However, we observed a positive correlation between the relative abundance of pro-inflammatory oral taxa and the relative abundance of inferred functional traits for LPS. These findings are in line with the current literature on bacterial virulence factors. Lastly, we investigated whether inflammation-related oral taxa and inflammation-related gut taxa are correlated and whether oral and gut microbiome communities respond similarly to aspirin. Our results show that aspirin may induce changes in oral and gut alpha diversity in a similar fashion. In addition, our findings of an inverse correlation between SCFA-producing gut taxa and pro-inflammatory oral taxa suggest that studying oral taxa may be important to understanding the link between inflammation and the gut microbiome. Overall, these findings are in line with a growing body of evidence highlighting the role of the oral microbiome in chronic inflammatory disorders of the intestine, including CRC.
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    Examining and improving the chemopreventive efficacy of curcumin
    (2012-09) Grill, Alexander E.
    Curcumin, a polyphenol extracted from turmeric, has shown chemopreventive and chemotherapeutic effects against cancer. However, curcumin suffers from poor bioavailability, which limits its clinical use. We hypothesized that using novel microparticle and SMEDDS formulations will improve the pharmacokinetics and therapeutic efficacy of curcumin. Initial studies examined the anticancer efficacy of curcumin loaded poly(lactide-co-glycolic acid) (PLGA) microparticles in a transgenic mouse model of human epidermal growth factor receptor-2 (HER-2) cancer, Balb-neuT. HER-2 is overexpressed in 30% of breast cancer cases and is associated with poor prognosis and high incidence of metastasis. Curcumin microparticles delayed tumor appearance by 2-3 weeks and were associated with a decrease in VEGF protein levels and CD-31+ microvasculature compared to empty microparticles. However, when compared to saline controls, blank microparticles appeared to accelerate tumorigenesis. Blank PLGA microparticles were shown to activate NF-kB signaling, indicating systemic inflammation after injection. The delay in tumorigenesis with curcumin-loaded microparticles was likely attributed to the anti-inflammatory effects of curcumin. Future studies will examine the systemic effects of blank PLGA microparticles as well as explore other polymers for curcumin microparticle delivery. A self microemulsifying drug delivery system (SMEDDS) was examined for oral delivery of curcumin. The SMEDDS formulation solubilized curcumin at high concentrations (~45 mg/mL). However, administering curcumin in the SMEDDS formulation did not increase curcumin bioavailability but increased gut absorption, evident by increased plasma curcumin glucuronide levels. We hypothesized that oral bioavailability of curcumin could be enhanced by increasing its absorption and decreasing metabolic clearance simultaneously. Microsomal studies showed that silibinin and quercetin inhibited curcumin glucuronidation in vitro. Piperine, which was shown to improve curcumin bioavailability previously, silibinin and quercetin were administered with curcumin in vivo. Coadministration of curcumin and piperine showed high variability after dosing. Addition of silibinin significantly improved curcumin bioavailability (3.5 fold) compared to curcumin alone. Future studies should examine the chemopreventive potential of curcumin and silibinin for HER-2+ breast cancer.
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    Novel studies of fat and nutrient intakes and the risk of human cancers
    (2014-05) Ainslie-Waldman, Cheryl Elaine
    Three unique human studies were conducted to explore the relationship between nutritional factors and cancer. In vivo lipid peroxidation was compared in post-menopausal women following a low-fat diet or a low-fat diet supplemented with 3% of energy from omega-3 fatty acids; the latter diet significantly increased in vivo lipid peroxidation. In the second study, a urinary biomarker of indole-3-carbinol exposure from cruciferous vegetable intake was validated in a crossover feeding study. Finally, the associations between dietary fish, fat, and antioxidant intakes and the risk of gastric cancer were evaluated in the large prospective cohort of the Singapore Chinese Health Study. Although, there were no significant associations with fish or fat, coffee intake significantly decreased the risk of gastric cancer among Singapore Chinese women.
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    Role of ß-Glucuronidase in the Chemopreventive Efficacy of Oral Curcumin: A Prodrug Hypothesis
    (2015-11) Liu, Garvey
    Curcumin, a dietary polyphenol, has been shown to have several preventive and therapeutic benefits in epidemiological studies. The chemopreventive potential of curcumin is related to its anti-inflammatory activity and is largely mediated through inhibition of the transcription factor NF-kB. However, curcumin has rather poor oral bioavailability (<1%). Much of orally dosed curcumin undergoes glucuronidation, resulting in the formation of inactive glucuronides. Thus, it is not clear how dietary curcumin exhibits chemopreventive activity despite not being absorbed into the systemic circulation in its active form. We proposed a prodrug hypothesis to explain this ‘bioavailability paradox’ of curcumin. β-glucuronidase is an enzyme that hydrolyzes the glycosidic bond of glucuronides. Previous studies have shown that the expression of this enzyme is elevated under inflammatory conditions and overexpressed in necrotic regions of tumors. Increased β-glucuronidase activity in the tumor tissue in comparison to its relatively minimal activity in normal cells potentially explains the bioavailability paradox with curcumin. We hypothesized that curcumin glucuronide is an inflammation-responsive natural prodrug that gets converted back to curcumin ‘on-demand’ at the site of action. Our studies were aimed at determining specific activity of β-glucuronidase based on mammary tumor type, stage, and model. β-glucuronidase activity was determined in mammary tumor tissues with HER-2+ (BALB-neuT, TuBo) and triple negative (4T1, JC, MDA-MB-231) phenotypes. Activity assay results showed that the highest rate of conversion was in 4T1 tumors as compared to the other tumor types. Immunohistochemistry (IHC) studies on primary human breast tumor tissue samples showed β-glucuronidase expression levels to be highest in HER-2+ type breast cancer compared to triple negative and ER/PR+ types. Also determined from the microarray of human tissue samples, as well as from Western blotting and fluorescence imaging studies, was the strong correlation between enzyme expression levels and stage of cancer: normal and benign stages showed the lowest levels of β-glucuronidase while the invasive/metastatic stage showed the highest expression levels. Using a self-microemulsifying drug delivery system (SMEDDS) formulation that was developed to improve the oral absorption, we aimed next to investigate the chemopreventive efficacy of curcumin following oral administration. Daily oral dosing of curcumin for one month in the orthotopic models described above showed that those with higher β-glucuronidase specific activities (JC, MDA-MB-231, and 4T1) benefitted the most from curcumin in limiting tumor growth rate. Pharmacokinetic studies with oral dosing of curcumin SMEDDS showed elevated levels of the glucuronide metabolite in plasma as compared to negligible levels of curcumin while the trend was reversed in the tumor tissue, providing further support to the prodrug activation hypothesis. The pharmacokinetics of curcumin glucuronide following intravenous dosing also confirmed conversion of the glucuronide to the parent compound in the tumor tissue. Overall, the work presented in this thesis demonstrated the potential of oral curcumin for breast cancer chemoprevention based on the enzymatic prodrug activation hypothesis.