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  • 1
    Keywords: SURVIVAL ; tumor ; Germany ; INHIBITION ; MODEL ; MODELS ; DISEASE ; DISEASES ; incidence ; liver ; RISK ; SITE ; SITES ; GENE ; TUMORS ; STORAGE ; TIME ; PATIENT ; NITRIC-OXIDE SYNTHASE ; INJURIES ; DNA ; INFECTION ; RISK-FACTORS ; CARCINOGENESIS ; RAT ; RATS ; PROTEIN-KINASE ; treatment ; virus ; prevention ; STRESS ; risk factors ; metastases ; DAMAGE ; chemoprevention ; COLON CARCINOGENESIS ; copper toxicity ; curcumin ; ETHENO-DNA ADDUCTS ; HEREDITARY HEPATITIS ; LEC rats ; LIPID-PEROXIDATION ; MOUSE FIBROBLAST CELLS ; NIH 3T3 ; ORNITHINE DECARBOXYLASE ; OXIDATIVE STRESS
    Abstract: Long-Evans Cinnamon (LEC) rats, an inbred mutant strain which accumulates copper due to an aberrant copper-transporting ATPase gene, develop acute hepatitis, chronic liver injury and liver tumors as a result of copper-induced oxidative stress, lipid peroxidation and DNA damage. Curcumin, an antioxidant and anti-inflammatory agent, has shown anticancer properties in many rodent models. We investigated the modulating role of curcumin in liver and kidney carcinogenesis in LEC rats. Two groups of 4-week-old LEC rats (n = 60 each) were fed either a standard diet (control) or received 0.5% curcumin in the diet for life. In untreated LEC rats, the rate of acute liver failure, the incidence of liver tumors and of kidney tumors were 32, 100 and 10% respectively, which was not altered by curcumin treatment. However, curcumin reduced tumor incidence at other organ sites (15% versus 0%; P = 0.025) and suppressed formation of metastases (18% versus 0%; P = 0.01). Median survival time was decreased from 88.7 to 78.1 weeks in curcumin-treated rats (P = 0.002). The lack of chemoprevention of liver and kidney tumors in LEC rats by curcumin may be caused by enhanced toxicity and oxidative stress due to excess copper. We conclude that curcumin should be contra-indicated for patients suffering from inherited and acquired metal storage diseases that include patients with hepatitis C virus infection. (C) 2002 Elsevier Science B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 12628510
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  • 2
    Keywords: CANCER ; IN-VITRO ; tumor ; AGENTS ; Germany ; IN-VIVO ; INHIBITION ; screening ; SYSTEM ; SYSTEMS ; RISK ; ENZYMES ; DRUG ; NITRIC-OXIDE ; murine ; RISK-FACTORS ; CARCINOGENESIS ; INDUCTION ; KERATINOCYTES ; mechanisms ; culture ; IDENTIFICATION ; prevention ; risk factors ; MODULATION ; RISK FACTOR ; butyrate ; HEPATOMA ; fatty acids ; FATTY-ACIDS ; NF-kappa B ; ALCOHOL ; SODIUM-BUTYRATE ; curcumin ; ORNITHINE DECARBOXYLASE ; ANTIOXIDANT ; bioassay systems ; cancer chernoprevention ; CONSTITUENTS ; iNOS ; PEITC ; SULFORAPHANE ; SUPEROXIDE
    Abstract: Identification and use of effective cancer chemopreventive agents have become an important issue in public health-related research. For identification of potential cancer chemopreventive constituents we have set up a battery of cell- and enzyme-based in vitro marker systems relevant for prevention of carcinogenesis in vivo. These systems include modulation of drug metabolism (inhibition of Cyp1A activity, induction of NAD(P)H:quinone reductase (QR) activity in Hepalclc7 murine hepatoma cell culture), determination of radical scavenging (DPPH scavenging) and antioxidant effects (scavenging of superoxide anion-, hydroxyl- and peroxyl- radicals), anti-inflammatory mechanisms (inhibition of lipopolysaccharide (LPS)-mediated nitric oxide (NO) generation by inducible NO synthase (iNOS) in Raw 264.7 murine macrophages, cyclooxygenase-1 (Cox-1) inhibition), and anti- tumor promoting activities (inhibition of phorbol ester-induced ornithine decarboxylase (ODC) activity in 308 murine keratinocytes). We have tested a series of known chemopreventive substances belonging to several structural classes as reference compounds for the identification of novel chemopreventive agents or mechanisms. These include organosulfur compounds (phenethylisothiocyanate (PEITC), diallylsulfide, diallyldisulfide), terpenes (limonene, perillyl alcohol, oleanolic acid, 18-beta-glycyrrhetinic acid), short- chain fatty acids (sodium butyrate), indoles (indole-3- carbinol), isoflavonoids (quercetin, silymarin, genistein), catechins ((-)-epigallocatechin gallate (EGCG)), simple phenols (ellagic acid, resveratrol, piceatannol, curcumin), pharmaceutical agents (piroxicam, acetylsalicylic acid, tamoxifen), and vitamins/derivatives (ascorbic acid, Trolox). We confirmed known chemopreventive mechanisms of these compounds. Additionally, we could demonstrate the usefulness of our approach by identification of hitherto unknown mechanisms of selected agents. As an example, we detected anti- inflammatory properties of PEITC, based on NF-kappaB-mediated inhibition of NO production. Further, PEITC inhibited phorbol ester-induced superoxide anion radical production in granulocytes, and ODC induction in the 308 cell line. These mechanisms might contribute to the chemopreventive potential of PEITC. (C) 2002 Elsevier Science B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 12628514
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  • 3
    Keywords: CELLS ; IN-VITRO ; Germany ; IN-VIVO ; VITRO ; TISSUE ; FLAVONOIDS ; HOPS ; HUMULUS-LUPULUS ; bioavailability ; BITTER ACIDS ; C-14-radiolabelling ; HOP ; xanthohumol
    Abstract: Xanthohumol (Xn) has well-established chemopreventive potential in vitro. In order to carry out in vivo bioavailability and tissue distribution studies, C-14-labelled Xn was produced by biolabelling. Supplying hop sprouts with 5 mCi [U-C-14]glucose led to incorporation of C-14 into Xn. Delivering the radioactive precursor at once resulted in Xn with a specific activity of 318 mu Ci (.) mmol(-1); if however the amount was supplied in aliquots over 4 days a specific activity of only 53.1 mu Ci (.) mmol(-1) Xn was obtained
    Type of Publication: Journal article published
    PubMed ID: 16092066
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  • 4
    Keywords: IN-VITRO ; NITRIC-OXIDE ; LIVER-MICROSOMES ; CELL-CYCLE ; BREAST-CANCER ; TRANSGENIC MICE ; FACTOR-KAPPA-B ; PRENYLATED FLAVONOIDS ; HUMULUS-LUPULUS L. ; INHIBITION CONSTANTS
    Abstract: Characterization and use of effective cancer chemopreventive agents have become important issues in public health-related research. Aiming to identify novel potential chemopreventive agents, we have established an interrelated series of bioassay systems targeting molecular mechanisms relevant for the prevention of tumor development. We report anticarcinogenic properties of Xanthohumol (XN), a prenylated chalcone from hop (Humulus Iupulus L.) with an exceptional broad spectrum of inhibitory mechanisms at the initiation, promotion, and progression stage of carcinogenesis. Consistent with anti-initiating potential, XN potently modulates the activity of enzymes involved in carcinogen metabolism and detoxification. Moreover, XN is able to scavenge reactive oxygen species, including hydroxyl- and peroxyl radicals, and to inhibit superoxide anion radical and nitric oxide production. As potential antitumor-promoting mechanisms, it demonstrates anti-inflammatory properties by inhibition of cyclooxygenase-1 and cyclooxygenase-2 activity and is antiestrogenic without possessing intrinsic estrogenic potential. Antiproliferative mechanisms of XN to prevent carcinogenesis in the progression phase include inhibition of DNA synthesis and induction of cell cycle arrest in S phase, apoptosis, and cell differentiation. Importantly, XN at nanomolar concentrations prevents carcinogen-induced preneoplastic lesions in mouse mammary gland organ culture. Because XN is easily cyclized to the flavanone isoxanthohumol, activities of both compounds were compared throughout the study. Together, our data provide evidence for the potential application of XN as a novel, readily available chemopreventive agent, and clinical investigations are warranted once efficacy and safety in animal models have been established.
    Type of Publication: Journal article published
    PubMed ID: 12481418
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  • 5
    Keywords: AGENTS ; Germany ; INHIBITION ; TIME ; ACID ; BIOSYNTHESIS ; DERIVATIVES ; LENGTH ; CHEMISTRY ; FRACTION ; HOPS ; HUMULUS-LUPULUS ; IC50 ; BITTER ACIDS ; HOP ; xanthohumol ; EXTRACT ; COX-1 ; PRENYLFLAVONOIDS ; PROANTHOCYANIDINS
    Abstract: The polyphenol-enriched fraction of an ethanolic hops extract (Humulus lupulus) was separated to provide four acylphloroglucinol-glucopyranosides (1-4). 1-(2-Methylpropanoyl)phloroglucinol-glucopyranoside 1 has been isolated from hops before, whereas 1-(2-methylbutyryl)phloroglucinol-glucopyranoside 2, known as multifidol glucoside, and 1-(3-methylbutyryl)phloroglucinol-glucopyranoside 3 were found in hops for the first time. 5-(2-Methylpropanoyl)phloroglucinol-glueopyranoside 4 was identified as a new natural product. The compounds were tested for inhibition of COX-1 activity. The aglycon 5, obtained by acid hydrolysis of 1, was equally effective as phloroglucinol, with an IC50 of 3.8 mu M. The inhibitory potential of the glucosides was 1 〉 2 〉 3 and decreased with increasing length of the acyl side chain. Compound 4 was about 2.5-fold less active than 1 (IC50: 23.7 and 58.7 mu M, respectively)
    Type of Publication: Journal article published
    PubMed ID: 16252923
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  • 6
    Keywords: CANCER ; IN-VITRO ; Germany ; LUNG ; TOXICITY ; liver ; RISK ; HEART ; kidney ; RISK-FACTORS ; RAT ; RATS ; risk factors ; DIET ; SAFETY ; HUMAN LIVER-MICROSOMES ; APPEARANCE ; INHIBITORS ; chalcones ; MAMMARY-GLAND ; WEIGHT ; GLAND ; development ; FLAVANONES ; xanthohumol ; BEER ; BIOLOGICAL-ACTIVITY ; chalcone ; HOPS HUMULUS-LUPULUS ; PRENYLATED FLAVONOIDS ; Sprague Dawley rats ; BIRTH ; fertility study ; hepatotoxicity ; mammary gland ; sex ratio ; subchronic toxicity
    Abstract: Xanthohumol (XN) is a prenylated chalcone, which has been shown to possess a broad range of potential cancer preventive and additional biological activities. In the present study, we have determined the subchronic 4-wk toxicity of XN and monitored its influence on fertility and development of offspring in two fertility studies. Four-week-old female Sprague Dawley (SD) rats were treated with 0.5% XN in the diet or with 1000 mg XN/kg body weight (b.w.) per day by gavage for 28 days. No remarkable treatment-related changes in general appearance and b.w. occurred during the study. After autopsy, liver, kidney, lung, heart, stomach, and spleen were examined macroscopically and histopathologically. Relative liver weights of animals in both treatment groups were significantly reduced by 30-40% in comparison with the control group, indicating weak hepatotoxicity. Also, mammary glands of treated rats appeared less developed compared to the controls. Consequently, we investigated the influence of XN on rat reproduction. In two fertility studies, XN (100 mg/kg b.w. per day), given either for 4 wk prior to or during mating, gestation, and nursing, did not cause any adverse effects on female reproduction and the development of offspring. Noteworthy, treatment of male rats prior to mating significantly (p = 0.027) increased the sex ratio of male to female offspring. Overall, lifelong treatment at a daily dose of 100 mg/kg b.w. in a two-generation study did not affect the development of SD rats
    Type of Publication: Journal article published
    PubMed ID: 16092070
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  • 7
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  • 9
    Keywords: CANCER ; CELLS ; IN-VITRO ; INHIBITOR ; Germany ; CARCINOGENESIS ; mechanisms ; MOUSE ; SULFORAPHANE ; cancer chemoprevention ; carcinogen metabolism ; Iridaceae ; Iris germanica ; isoflavones
    Abstract: Six known isoflavones were isolated from the rhizomes of Iris germanica, and were established by UV, MS and NMR techniques as irisolidone (1), irisolidone 7-0-alpha-D-glucoside (1a), irigenin (2), irilone (3), iriflogenin (4), and iriskashmirianin (5). These compounds were examined for their cancer chemopreventive potential. They were shown to be potent inhibitors of cytochrome P450 1A activity with IC50 values in the range 0.25 - 4.9 muM. The isoflavones 2, 3 and 5 displayed moderate activity as inducers of NAD(P)H:quinone reductase (QR) in cultured mouse Hepa 1c1c7 cells, with CD values (concentration required to double the specific activity of QR) of 3.5-16.7 muM, whereas weak activity was observed with compounds 4 and 5 in the radical (DPPH) scavenging bioassay (IC50 values 89.6 and 120.3 muM, respectively). With respect to anti-tumor promoting potential based on anti-inflammatory mechanisms, none of the compounds demonstrated significant activity in the concentration range tested
    Type of Publication: Journal article published
    PubMed ID: 12567273
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  • 10
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; Germany ; MODEL ; VITRO ; DISEASE ; HEPATOCELLULAR-CARCINOMA ; liver ; RISK ; HYBRIDIZATION ; RNA ; TUMORS ; DNA ; RISK-FACTORS ; CARCINOGENESIS ; INDUCTION ; RAT ; RATS ; IN-SITU ; LESIONS ; RAT-LIVER ; PROGRESSION ; ESCHERICHIA-COLI ; GLUTATHIONE ; CD95 ligand ; STRESS ; AGE ; risk factors ; DAMAGE ; DNA-DAMAGE ; ADDUCTS ; DIET ; DIETARY ; rat liver ; LIPID-PEROXIDATION ; OXIDATIVE STRESS ; PERFORMANCE LIQUID-CHROMATOGRAPHY ; in situ hybridization ; lipid peroxidation ; WILSONS-DISEASE ; RE ; LIVER-CANCER ; OXIDATIVE-STRESS ; ADDUCT ; DNA damage ; DNA ADDUCT ; ANIMAL-MODEL ; EVENTS ; HEPATITIS-C ; etheno-DNA-adducts
    Abstract: Long-Evans Cinnamon (LEC) rats, a model for human Wilson's disease, develop chronic hepatitis and liver tumors owing to accumulation of copper and induced oxidative stress. Lipid peroxidation (LPO)-induced etheno-DNA adducts in nuclear- and mitochondrial-DNA along with apoptosis was measured in LEC rat liver. Levels of etheno-DNA adducts (1,N-6-ethenodeoxyadenosine and 3,N-4-ethenodeoxycytidine) increased with age reaching a peak at 8 and 12 weeks in nuclear and mitochondrial DNA, respectively. This is the first demonstration that etheno-DNA adducts are also formed in mitochondrial DNA. Apoptosis was assessed by TUNEL+ cells in liver sections. CD95L RNA expression was also measured by in situ hybridization in the same sections. The highest nuclear DNA adduct levels coincided with a reduced apoptotic rate at 8 weeks. Mitochondrial-DNA adducts peaked at 12 weeks that coincided with the highest apoptotic rate, suggesting a link of etheno-DNA adducts in mitochondrial DNA to apoptosis. The DNA damage in liver was further enhanced and sustained by 0.5% curcumin in the diet. Treatment for 2 weeks elevated etheno-DNA adducts 9- to 25-fold in nuclear DNA and 3- to 4-fold in mitochondrial-DNA, providing a plausible explanation as to why in our earlier study [Frank et al. (2003) Mutat. Res., 523-524, 127-135], curcumin failed to prevent liver tumors in LEC rats. Our results also confirm the reported in vitro DNA damaging potential of curcumin in the presence of copper ions by reactive oxygen species. LPO-induced adduct formation in nuclear and mitochondrial DNA appear as early lesions in LEC rat liver carcinogenesis and are discussed in relation to apoptotic events in the progression of malignant disease
    Type of Publication: Journal article published
    PubMed ID: 15790590
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