Browsing by Subject "Chemoprevention"
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Item Anti-inflammatory Properties of Citrus Limonoids and Their Isolation and Characterization(2012-02-14) Kim, Jin HeeThis dissertation investigates the role of limonoids in inflammation to reduce risk of breast cancer and cardiovascular disease. Radical scavenging activity and apoptotic effects of extracts from lemon seeds were investigated in human breast adenocarcinoma (MCF-7) cells and non-malignant breast (MCF-12F) cells. The MeOH:water (80:20) extract showed the highest (29.1%, P < 0.01) inhibition of MCF-7 cells without affecting the non-malignant breast cells. Further, the purified and modified limonoids were screened for their cytotoxicity on estrogen receptor (ER)-positive (MCF-7) or ER-negative (MDA-MB-231) human breast cancer cells. The MCF-7 cell was more susceptible to tested limonoids. Although most of limonoids induced anti-aromatase activity, the inhibition of proliferation was not related to the anti-aromatase activity. On the other hand, the anti-proliferative activity was significantly correlated with the level of caspase-7 activation by limonoids. The next study investigated the mechanism of anti-breast cancer and anti-aromatase activities of obacunone through inhibition of MCF-7 cell proliferation without affecting non-malignant breast cells. Treatment with obacunone resulted in an increased G1 cell cycle arrest and induction of apoptosis. Exposure of MCF-7 breast cancer cells to obacunone down-regulated expression of inflammatory molecules including nuclear factor-kappa B (NF--2 (COX-2). Furthermore, potential of obacunone on inhibition of COX-2 and NF-the p38 mitogen-activated protein (MAP) kinase was also investigated. In the final study, nomilin was the most potent natural inhibitor for p38 MAP kinase activity in human aortic smooth muscle cells indicating that a seven-membered A ring with acetoxy group, present in nomilin, seems to be essential for its inhibitory activity on p38 MAP kinase. The possible mechanism of nomilin for prevention of cardiovascular disease was determined. Pre-treatment with nomilin resulted in significant inhibition of TNF- induced HASMCs proliferation. The anti-proliferative activity of nomilin is due to apoptosis through mitochondrial dependent pathway.Item Chemopreventive effects of curcumin and green tea on B[a]P-induced carcinogenesis in the hamster cheek pouch(Texas A&M University, 2005-08-29) Brandon, Jimi LynnThe present study was carried out to examine the chemopreventive effects of curcumin and green tea polyphenols on the hamster cheek pouch carcinogenesis model. This model of oral carcinogenesis has been widely used in chemoprevention studies, however, these studies have been limited to the use of DMBA as the carcinogenic agent. We have developed a protocol of carcinogenesis in the hamster cheek pouch using B[a]P, a broadly distributed environmental carcinogen, formed as a by-product of the combustion of organic materials including cigarette smoke. B[a]P- induced tumors in the hamster cheek pouch are primarily endophytic squamous cell carcinomas that closely resemble squamous cell carcinomas of the human oral mucosa. The cheek pouch of male Syrian hamsters were treated topically for eight weeks with 0.6% curcumin, 6.0% curcumin, 2.5% green tea polyphenols, or 5.0% green tea polyphenols, 3 times per week 30 minutes prior to the application of 2.0% B[a]P. The animals were sacrificed 24 hours and 72 hours after the last treatments. Short-term mechanistic markers of malignant progression were used to determine effects of each compound. Cellular proliferation, assessed by bromodeoxyuridine (Brdu) incorporation, p53 protein accumulation, and apoptotic activity were evaluated. The results of the present study demonstrated that 0.6% curcumin and 2.5% green tea polyphenols had strong inhibitory effects on cellular proliferation and p53 protein accumulation. And 6.0% curcumin and 5.0% green tea polyphenols appeared to induce apoptosis. Our data suggest that curcumin and green tea polyphenols may have a plausible chemopreventive effect on oral carcinogenesis in the hamster cheek pouch model.Item Chemopreventive Potential of Sorghum with Different Phenolic Profiles(2010-07-14) Yang, LiyiEpidemiological evidence has correlated consumption of sorghum with reduced incidences of gastrointestinal (GI) tract cancer, especially esophageal cancer. There is little evidence on how phenols of sorghum may affect chemoprevention. Seventeen sorghum varieties were screened for phenolic profiles and antioxidant capacity. The ability of crude sorghum extracts to induce NAD(P)H:quinone oxidoreductase (QR, a phase II protective enzyme), and inhibit proliferation of colon (HT-29) and esophageal (OE33) carcinoma cells using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) and PicoGreen assays, were determined in vitro. 3- Deoxyanthocyanidins, apigeninidin, luteolinidin and their methoxylated derivatives were also investigated for antioxidant capacity, QR inducing and antiproliferative potential. Tannin sorghum generally showed higher antioxidant capacity than non-tannin sorghum varieties. Sorghum varieties containing extractable condensed tannins did not show any significant QR inducing potential; on the other hand, non-tannin sorghums increased QR activity by 1.5-2.7 times; black sorghum (Tx430) was most potent (doubled QR activity at 25 mg/mL, 2.7-fold increase at 100 mg/mL). All sorghum extracts showed relatively strong antiproliferation activity with IC50s (the concentration needed to inhibit cancer cell growth by 50%) of 49.7-883 mg/mL. Tannin-containing sorghums had stronger cancer cell proliferation inhibitory potential (IC50s 49.7-131 mg/mL) than non-tannin sorghums (IC50s 141-883 mg/mL). Total phenol content and antioxidant capacity of crude sorghum extracts positively correlated with their antiproliferative potential (r2 0.71-0.97). Among tested 3-deoxyanthocyanidins, methoxylation on A-ring improved QR inducing potency. 5,7-Dimethoxyluteolinidin had the greatest QR inducing potency (4.3- fold at 100 mM). Methoxylation also improved their antiproliferation potential; the IC50s trend was di-methoxylated (8.3-105 mM) > mono-methoxylated (40.1-192 mM) > apigeninidin and luteolinidin (81.5-284 mM). This study provides information for how phenolic compositions of sorghum and 3-deoxyanthocyanidin structure affect their capacity to induce QR activity and inhibit GI tract cancer cell proliferation. The information is useful to promote the utilization of sorghum in functional foods, beverages, dietary supplements, and other health-related industries. Further study will focus on, fractioned and isolated sorghum phenols, the effect of food processing on their chemopreventive potential, as well as cellular mechanisms involved.Item Effect of pentacyclic triterpenes found in Perilla frutescens alone or in combination with resveratrol on skin tumor promotion by 12-o-tetra-decanoylphorbol-13-acetate(2015-08) Cho, Jiyoon; DiGiovanni, John; Vasquez, Karen M; Mills, Edward M; Slaga, Thomas J; Siegel, Dionicio RA series of pentacyclic triterpenes found in P. frutescens, including ursolic acid (UA), oleanolic acid (OA), augustic acid (AA), corosolic acid (CA), 3-epi-corosolic acid (3-epiCA), maslinic acid (MA), and 3-epi-maslinic acid (3-epiMA) were evaluated for their effects on skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA). UA was also evaluated in a combination with resveratrol (Res) for possible combinatorial chemopreventive activity. All triterpene compounds significantly inhibited skin tumor promotion by TPA. MA and 3-epiCA, were significantly more effective than UA at inhibiting tumor development. Topical pretreatment with all of these compounds significantly inhibited epidermal proliferation induced by TPA, however, CA, 3-epiCA and MA were more effective than UA. All compounds reduced skin inflammation and inflammatory gene expression induced by TPA, however, 3-epiCA and MA were identified to be more effective than UA. Finally, the ability of these compounds to alter epidermal signaling pathways associated with skin tumor promotion by TPA was also evaluated. The greater ability of 3-epiCA and MA to inhibit skin tumor promotion was associated with greater reduction of Cox-2 and Twist1 proteins and inhibition of activation of IGF-1R, Stat3 and Src. The effect of combining UA + Res for combinatorial inhibitory effects on skin tumor promotion were also examined. The combination of UA + Res produced a greater inhibition of TPA-induced epidermal hyperproliferation, epidermal inflammatory signaling, and inflammatory gene expression when compared to UA or Res alone. Furthermore, NF-kB, Egr-1, and AP-1 DNA binding activities following TPA treatment were dramatically decreased by the combination of UA + Res. Treatment with UA + Res during skin tumor promotion by TPA produced greater inhibition of tumor multiplicity and tumor size than with either agent alone. Collectively, the current data demonstrate that UA and related triterpenes as well as the combination of UA + Res inhibited skin tumor promotion by TPA via effects on multiple cellular and biochemical/molecular mechanisms associated with this process similar to calorie restriction. Of the tritperpenes tested, 3-epiCA and MA were the most active. Furthermore, the favorable anti-tumor promoting effects of combining UA + Res suggest that phytochemical combination therapy may be a more efficacious strategy for cancer chemoprevention.Item PHASE IIa chemoprevention trial with green tea polyphenols in high-risk population of liver cancer(2005-08) Luo, Haitao; Wang, Jia-Sheng; Theodorakis, Christopher W.; Shen, Leslie; Pence, Barbara; Anderson, ToddHepatocellular carcinoma (HCC) is the third leading cause of cancer deaths in the developing world, and major risk factors have been identified as chronic infection with hepatitis B virus (HBV) and dietary exposure to aflatoxin B1 (AFB1). One of the current challenges in this field is how to manage high-risk individuals who have been exposed to these risk factors for many years. Chemoprevention was proposed as a good tool to target these individuals. Among various chemopreventive agents, green tea polyphenols (GTP) have been shown to be safe and effective in most in vitro and in vivo studies. To further investigate GTP¡¯s safety and efficacy in humans, a randomized, double-blind, and placebo-controlled phase IIa chemoprevention trial with GTP was carried out in a highrisk population of HCC in Fusui, Guangxi, China. After screening 1200 sera samples from local residents, a total of 124 healthy adults who were sero-positive for HBV and AFB1 was voluntarily recruited, randomized into 3 groups, and received either placebo, 500-mg GTP, or 1,000-mg GTP daily for 3 months. Urine and blood samples at baseline, 1 month, and 3 months of the intervention were collected from these participants and were analyzed for various GTP biomarkers and carcinogen specific biomarkers to assess the efficacy of the trial. An overall compliance of 99% with mild and insignificant sideeffects was observed. Baseline data for all biomarkers analyzed showed homogeneity among the 3 study groups. The placebo group had slight fluctuations in biomarker levels during the course of intervention, whereas urinary excretion of (-)-epigallocatechin (EGC) and (-)-epicatechin (EC) and plasma concentration of (-)-epigallocatechin gallate (EGCG) and (-)-epicatechin gallate (ECG) were dose-dependently elevated in the GTP-treated groups. Urinary excretion of AFB1-mercapturic acid, a detoxified metabolite of AFB1, was significantly increased, while the serum levels of AFB1-albumin adduct, a macromolecule damaged by AFB1, was significantly diminished after GTP intervention. The oxidative DNA damage biomarker, urinary 8-hydroxy-2¡¯-deoxyguanosine, was also significantly decreased by GTP intervention. This study validated GTP biomarkers and proved the relative safety of GTP in humans. GTP intervention significantly inhibited carcinogen biomarkers and enhanced activities of detoxifying enzymes.Item PHASE IIa chemoprevention trial with green tea polyphenols in high-risk population of liver cancer(Texas Tech University, 2005-08) Luo, Haitao; Wang, Jia-Sheng; Theodorakis, Christopher W.; Shen, Leslie; Pence, Barbara; Anderson, ToddHepatocellular carcinoma (HCC) is the third leading cause of cancer deaths in the developing world, and major risk factors have been identified as chronic infection with hepatitis B virus (HBV) and dietary exposure to aflatoxin B1 (AFB1). One of the current challenges in this field is how to manage high-risk individuals who have been exposed to these risk factors for many years. Chemoprevention was proposed as a good tool to target these individuals. Among various chemopreventive agents, green tea polyphenols (GTP) have been shown to be safe and effective in most in vitro and in vivo studies. To further investigate GTP¡¯s safety and efficacy in humans, a randomized, double-blind, and placebo-controlled phase IIa chemoprevention trial with GTP was carried out in a highrisk population of HCC in Fusui, Guangxi, China. After screening 1200 sera samples from local residents, a total of 124 healthy adults who were sero-positive for HBV and AFB1 was voluntarily recruited, randomized into 3 groups, and received either placebo, 500-mg GTP, or 1,000-mg GTP daily for 3 months. Urine and blood samples at baseline, 1 month, and 3 months of the intervention were collected from these participants and were analyzed for various GTP biomarkers and carcinogen specific biomarkers to assess the efficacy of the trial. An overall compliance of 99% with mild and insignificant sideeffects was observed. Baseline data for all biomarkers analyzed showed homogeneity among the 3 study groups. The placebo group had slight fluctuations in biomarker levels during the course of intervention, whereas urinary excretion of (-)-epigallocatechin (EGC) and (-)-epicatechin (EC) and plasma concentration of (-)-epigallocatechin gallate (EGCG) and (-)- picatechin gallate (ECG) were dose- dependently elevated in the GTP-treated groups. Urinary excretion of AFB1-mercapturic acid, a detoxified metabolite of AFB1, was significantly increased, while the serum levels of AFB1-albumin adduct, a macromolecule damaged by AFB1, was significantly diminished after GTP intervention. The oxidative DNA damage biomarker, urinary 8-hydroxy-2¡¯-deoxyguanosine, was also significantly decreased by GTP intervention. This study validated GTP biomarkers and proved the relative safety of GTP in humans. GTP intervention significantly inhibited carcinogen biomarkers and enhanced activities of detoxifying enzymes.