Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The common dietary constituent quercetin was a potent inhibitor of sulfoconjugation of acetaminophen and minoxidil by human liver cytosol, partially purified P-form phenolsulfotransferase (PST), and recombinant P-form PST, with IC50 values of 0.025-0.095 microM. Quercetin inhibition of acetaminophen was noncompetitive with respect to acceptor substrate, with a Ki value of 0.067 microM. A number of other flavonoids, such as fisetin, galangin, myricetin, kaempferol, chrysin, and apigenin, were also potent inhibitors of P-form PST-mediated sulfation, with IC50 values < 1 microM. Studies of structural analogs indicated the flavonoid 7-hydroxyl group as particularly important for potent inhibition. Potential human metabolites of quercetin were poor inhibitors. Curcumin, genistein, and ellagic acid (other polyphenolic natural products) were also inhibitors of P-form PST, with IC50 values of 0.38-34.8 microM. Quercetin was also shown to inhibit sulfoconjugation by the human hepatoma cell line Hep G2. Although less potent in this intact cell system (IC50 2-5 microM), quercetin was still more potent than 2,6-dichloro-4-nitrophenol, the classical P-form PST inhibitor that has been shown to be an inhibitor also in vivo. These observations suggest the potential for clinically important drug interactions, as well as a possible role for flavonoids as chemopreventive agents in sulfation-induced carcinogenesis.
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PMID:Flavonoids, potent inhibitors of the human P-form phenolsulfotransferase. Potential role in drug metabolism and chemoprevention. 874 36

The ability of flavonoid compounds to induce the activity of the phase II anticarcinogenic marker enzyme, quinone reductase (QR), has been studied in a wild-type murine hepatoma cell line (Hepalclc7) and in an Ah-receptor-defective mutant of the same cell line (Hepalclc7 bp(r)cl). The results showed that 10 (beta-naphthoflavone, kaempferide, tamarixetin, rhamnetin, quercetin, kaempferol, quercetin-4'-glucoside, isorhamnetin, daidzein and genistein) of the 13 flavonoids tested induced QR activity in the wild-type cells. Only the latter six also showed such activity in the bp(r)cl mutant, which indicates that they induce phase II enzymes directly (monofunctional inducers), whereas the others induce phase 11 enzymes only in cells with an operative Ah receptor system (bifunctional inducers). The metabolism of representatives of monofunctional (quercetin) and bifunctional (tamarixetin and rhamnetin) flavonol inducers were studied in both wild-type and bp(r)cl cells. In all cases, the major metabolites were glucuronides. Quercetin produced identical metabolites in both cell types, whereas one glucuronide of tamarixetin and two glucuronides of rhamnetin were not formed in the mutant cells. This shows that flavonoids can be mono- or bifunctional inducers depending on their chemical structure, and that the glucuronidation pattern of bifunctional inducers is altered by the presence of a functional Ah receptor system.
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PMID:Characterization of flavonoids as monofunctional or bifunctional inducers of quinone reductase in murine hepatoma cell lines. 973 12

Phytochemical investigation of plants used in traditional Indonesian medicine (Jamu) yielded lignans (pinoresinol, 9 alpha-hydroxypinoresinol and salicifoliol), flavonoids (3-O-beta-(D)-glucopyranosyl-(1-->6)-beta-(D)-glucopyranosylkaempferol, luteolin and apigenin) and coumarins (coumarin, 8-hydroxycoumarin and 5-hydroxycoumarin). The beneficial effects of the respective plants for human health are thought to be associated with antioxidative activity. In the present study, the antioxidative capacity of the isolated compounds was determined in an in-vitro assay. Luteolin and kaempferol (cleavage product of 3-O-beta-(D)-glucopyranosyl-(1-->6)-beta-(D)-glucopyranosylkaempferol, which is thought to be formed in the intestine) showed strong antioxidant activity; pinoresinol and 9 alpha-hydroxypinoresinol showed only minor antioxidative effects. The coumarins, as well as apigenin and 3-O-beta-(D)-glucopyranosyl-(1-->6)-beta-(D)-glucopyranosylkaempferol were inactive. The antioxidative effects of luteolin, kaempferol and pinoresinol were further investigated in H4IIE rat hepatoma cells. A strong protective effect of kaempferol and luteolin was found against H2O2-mediated intracellular reactive oxygen species formation measured using the dichlorofluorescein assay and H2O2-mediated DNA strand breaks. Pinoresinol did not have a protective effect against H2O2-mediated DNA-damage, but in the dichlorofluorescein assay, an antioxidative effect was detectable. During studies with H4IIE cells, kaempferol, luteolin and pinoresinol were taken up by the cells within 60 min. The flavonoids were found to be relatively toxic at higher concentrations, while pinoresinol was less cytotoxic. In conclusion, kaempferol and luteolin, at low concentrations (< or = 50 microM), protect H4IIE cells against oxidative stress but are cytotoxic at higher concentrations; the biological effects of pinoresinol are less prominent in comparison. These results are important for the identification of pharmacologically active substances from traditional Indonesian medicinal plants.
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PMID:Polyphenols from plants used in traditional Indonesian medicine (Jamu): uptake and antioxidative effects in rat H4IIE hepatoma cells. 1572 Jul 88

Flavonoids are ubiquitous substances in fruits and vegetables. Among them, the flavonol kaempferol contributes up to 30% of total dietary flavonoid intake. Flavonoids are assumed to exert beneficial effects on human health, e.g., anticancer properties. For this reason, they are used in food supplements at high doses. The aim of this project was to determine the effects of kaempferol on oxidative stress and apoptosis in H4IIE rat hepatoma cells over a broad concentration range. Kaempferol is rapidly taken up and glucuronidated by H4IIE cells. The results demonstrate that kaempferol protects against H2O2-induced cellular damage at concentrations which lead to cell death and DNA strand breaks in the absence of H2O2-mediated oxidative stress. Preincubation with 50 microM kaempferol exerts protection against the loss of cell viability induced by 500 microM H2O2 (2 h) while the same concentration of kaempferol reduces cell viability by 50% in the absence of H2O2 (24 h). Preincubation with 50 microM kaempferol ameliorates the strong DNA damage induced by 500 microM H2O2 while 50 microM kaempferol leads to a significant increase of DNA breakage in the absence of H2O2. Preincubation with 50 microM kaempferol reduces H2O2-mediated caspase-3 activity by 40% (4 h) while the same concentration of kaempferol leads to the formation of a DNA ladder in the absence of H2O2 (24 h). It is concluded that the intake of high dose kaempferol in food supplements may not be advisable because in our cellular model protective kaempferol concentrations can also induce DNA damage and apoptosis by themselves.
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PMID:Protective and detrimental effects of kaempferol in rat H4IIE cells: implication of oxidative stress and apoptosis. 1611 56

Naturally occurring compounds have protective effects towards mutagens and carcinogens. The leaf extract of Monimiastrum globosum (Bois de Clous), a Mauritian endemic plant from the Myrtaceae family, was studied for its potency to induce DNA damage in human HepG2 hepatoma cells using DNA migration as a biological endpoint in the alkaline single cell gel electrophoresis (SCGE) assay. This was contrasted with the ability to modulate the benzo[a]pyrene (BaP)-dependent DNA damage in human hepatoma cells. M. globosum caused genotoxicity in HepG2 cells at concentrations exceeding 3mg fresh weight (FW) per ml cell culture in the absence of cytotoxicity. Pre-treatment of the cells with 12.2 microg FW/ml to 1.56 mg FW/ml led to a pronounced antigenotoxic effect towards BaP-induced DNA damage. DNA migration (OTM) was reduced by 66%, 81.5% and 74% for 49, 98 and 195 microg FW/ml, respectively. A U-shaped dose-response curve was derived for M. globosum indicating genotoxic effects in high doses and antigenotoxic effects in low doses. M. globosum extract had total phenolics (15 mg/g FW) with flavonoids (aglycones and conjugates: 8 mg/g FW) and proanthocyanidins (3mg/g FW) as major phenolic subclasses. The hydrolysis of conjugated flavonoids yielded the aglycones quercetin (606 microg/g FW) and kaempferol (117.8 microg/g FW) while HPLC-MS/MS analysis of the total extract revealed free flavonoids such as quercetin (19.2 microg/g FW) and myricetin (2.5 microg/g FW). The antioxidant activity of the extract of M. globosum, assessed by the FRAP and TEAC assays yielded values of 275+/-3.82 micromol/g FW and 346+/-4.2 micromol/g FW, respectively.
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PMID:Assessment of the DNA damaging potency and chemopreventive effects towards BaP-induced genotoxicity in human derived cells by Monimiastrum globosum, an endemic Mauritian plant. 1693 55

A cellular antioxidant activity (CAA) assay for quantifying the antioxidant activity of phytochemicals, food extracts, and dietary supplements has been developed. Dichlorofluorescin is a probe that is trapped within cells and is easily oxidized to fluorescent dichlorofluorescein (DCF). The method measures the ability of compounds to prevent the formation of DCF by 2,2'-azobis(2-amidinopropane) dihydrochloride (ABAP)-generated peroxyl radicals in human hepatocarcinoma HepG2 cells. The decrease in cellular fluorescence when compared to the control cells indicates the antioxidant capacity of the compounds. The antioxidant activities of selected phytochemicals and fruit extracts were evaluated using the CAA assay, and the results were expressed in micromoles of quercetin equivalents per 100 micromol of phytochemical or micromoles of quercetin equivalents per 100 g of fresh fruit. Quercetin had the highest CAA value, followed by kaempferol, epigallocatechin gallate (EGCG), myricetin, and luteolin among the pure compounds tested. Among the selected fruits tested, blueberry had the highest CAA value, followed by cranberry > apple = red grape > green grape. The CAA assay is a more biologically relevant method than the popular chemistry antioxidant activity assays because it accounts for some aspects of uptake, metabolism, and location of antioxidant compounds within cells.
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PMID:Cellular antioxidant activity (CAA) assay for assessing antioxidants, foods, and dietary supplements. 1790 27

Hepatocyte growth factor (HGF) and its receptor, Met, known to control invasive growth program have recently been shown to play crucial roles in the survival of breast cancer patients. The diet-derived flavonoids have been reported to possess anti-invasion properties; however, knowledge on the pharmacological and molecular mechanisms in suppressing HGF/Met-mediated tumor invasion and metastasis is poorly understood. In our preliminary study, we use HGF as an invasive inducer to investigate the effect of flavonoids including apigenin, naringenin, genistein and kaempferol on HGF-dependent invasive growth of MDA-MB-231 human breast cancer cells. Results show that apigenin presents the most potent anti-migration and anti-invasion properties by Boyden chamber assay. Furthermore, apigenin represses the HGF-induced cell motility and scattering and inhibits the HGF-promoted cell migration and invasion in a dose-dependent manner. The effect of apigenin on HGF-induced signaling activation involving invasive growth was evaluated by immunoblotting analysis, it shows that apigenin blocks the HGF-induced Akt phosphorylation but not Met, ERK, and JNK phosphorylation. In addition to MDA-MB-231 cells, apigenin exhibits inhibitory effect on HGF-induced Akt phosphorylation in hepatoma SK-Hep1 cells and lung carcinoma A549 cells. By indirect immunofluorescence microscopy assay, apigenin inhibits the HGF-induced clustering of beta 4 integrin at actin-rich adhesive site and lamellipodia through PI3K-dependent manner. Treatment of apigenin inhibited HGF-stimulated integrin beta 4 function including cell-matrix adhesion and cell-endothelial cells adhesion in MDA-MB-231 cells. By Akt-siRNA transfection analysis, it confirmed that apigenin inhibited HGF-promoted invasive growth involving blocking PI3K/Akt pathway. Finally, we evaluated the effect of apigenin on HGF-promoted metastasis by lung colonization of tumor cells in nude mice and organ metastasis of tumor cells in chick embryo. By histological and gross examination of mouse lung and real-time PCR analysis of human alu in host tissues, it showed that apigenin, wortmannin, as well as anti-beta 4 antibody all inhibit HGF-promoted metastasis. These data support the inhibitory effect of apigenin on HGF-promoted invasive growth and metastasis involving blocking PI3K/Akt pathway and integrin beta 4 function.
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PMID:Apigenin inhibits HGF-promoted invasive growth and metastasis involving blocking PI3K/Akt pathway and beta 4 integrin function in MDA-MB-231 breast cancer cells. 1796 21

Flavonoids are widely distributed in the plant kingdom and show various biological activities. The bioavailability of flavonoids in biological samples has conventionally been quantified by high-performance liquid chromatography and mass spectrometry, but with these analytical techniques it is difficult to estimate the subcellular localization of flavonoids in intact cells. In this study, we attempted to examine the localization of flavonoids in cultured cells using a confocal laser scanning fluorescence microscope and mouse hepatoma Hepa-1c1c7 cells. Five flavonol aglycones showed autofluorescence in the cells under the conditions (Ex. 488 nm to Em. 515-535 nm), whereas three flavonol glycosides and eight compounds belonging to other flavonoid subclasses, i.e., flavones, flavanones, and catechins, did not. The autofluorescence of galangin and kaempferol appeared stronger in the nucleus than cytoplasm, suggesting that they are incorporated into the cells and accumulated in the nucleus. The proposed method provided evidence that flavonol aglycones are incorporated into, and accumulated in the nucleus of, hepatocytes.
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PMID:Subcellular localization of flavonol aglycone in hepatocytes visualized by confocal laser scanning fluorescence microscope. 1956 44

Dioxins enter the body mainly through the diet, bind to the aryl hydrocarbon receptor (AhR), and cause various toxicological effects. In this study, we found that oral administration of kaempferol or ginkgo biloba extract (EGb) containing 24% flavonol at 100 mg/kg body weight suppressed AhR transformation induced by 3-methylcholanthrene at 10 mg/kg body weight in the liver of mice. The suppressive effect of kaempferol was enhanced by verapamil, an inhibitor of P-glycoprotein (P-gp), in ex vivo experiments using a hepatic cytosolic fraction and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Enhancement of the suppressive effect by verapamil was also observed in mouse hepatoma Hepa-1c1c7 cells, accompanied by an increase in the uptake of kaempferol into the cells. In conclusion, inhibition of P-gp enhanced the suppressive effect of kaempferol on AhR transformation through an increase in the intracellular kaempferol concentration.
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PMID:Inhibition of P-glycoprotein enhances the suppressive effect of kaempferol on transformation of the aryl hydrocarbon receptor. 1958 40

Hepatocellular carcinoma (HCC) is characterized by high mortality rates and resistance to conventional treatment. HCC tumors usually develop local hypoxia, which stimulates proliferation of cancer cells and renders them resilient to chemotherapy. Adaptation of tumor cells to the hypoxic conditions depends on the hypoxia-inducible factor 1 (HIF-1). Over-expression of its regulated HIF-1alpha subunit, an important target of anti-cancer therapy, is observed in many cancers including HCC and is associated with severity of tumor growth and poor patient prognosis. In this report we investigate the effect of the dietary flavonoid kaempferol on activity, expression levels and localization of HIF-1alpha as well as viability of human hepatoma (Huh7) cancer cells. Treatment of Huh7 cells with kaempferol under hypoxic conditions (1% oxygen) effectively inhibited HIF-1 activity in a dose-dependent manner (IC(50)=5.16microM). The mechanism of this inhibition did not involve suppression of HIF-1alpha protein levels but rather its mislocalization into the cytoplasm due to inactivation of p44/42 MAPK by kaempferol (IC(50)=4.75microM). Exposure of Huh7 cells to 10microM kaempferol caused significant reduction of their viability, which was remarkably more evident under hypoxic conditions. In conclusion, kaempferol, a non-toxic natural food component, inhibits both MAPK and HIF-1 activity at physiologically relevant concentrations (5-10microM) and suppresses hepatocarcinoma cell survival more efficiently under hypoxia. It has, therefore, potential as a therapeutic or chemopreventive anti-HCC agent.
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PMID:The dietary flavonoid kaempferol effectively inhibits HIF-1 activity and hepatoma cancer cell viability under hypoxic conditions. 2055 39


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