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

Assessing the inducibility of CYP3A4 by various xenobiotics can predict potential drug interactions. In the present investigation, human hepatoma cells were stably integrated with either the CYP3A4 enhancer region and a luciferase reporter gene or the CYP3A4-luciferase construct and the human pregnane X receptor (PXR). Several colonies containing one to three copies of luciferase per cell were identified by Southern blot analysis. Those transformants producing high luciferase activity in response to rifampicin were used to standardize a 96-well plate screening system with minimal inter- and intraplate variability. Standardization also consisted of assessing viability of cells cultured in medium containing various serum concentrations. In cells maintained for 48 h in medium with less than 5% serum, a significant (p < 0.01) decline was observed in viability accompanied by altered induction. A defined serum-free medium also produced less viable cells but did not alter the inductive response. Treatment of transformants with various concentrations of rifampicin produced a dose-response curve with maximal induction at 10 microM (5.6 +/- 0.18- and 2.1 +/- 0.3-fold above dimethyl sulfoxide (DMSO)-treated cells in transformants with and without PXR, respectively). Of additional agents examined for their ability to induce CYP3A4, omeprazole (200 microM) was the most potent inducer (12.8 +/- 1.9- and 2.4 +/- 0.2-fold above DMSO-treated cells in transformants with and without PXR, respectively). Mifepristone and mevastatin produced modest induction (approximately 3-fold) in the cell line containing exogenous PXR, but produced less than 1.2-fold increases in cells lacking PXR. Thus, only potent inducers can be identified in the cell line without PXR. In contrast, cells containing the receptor can be used to rank CYP3A4 induction. Because a high volume of chemicals can be readily and accurately screened for their ability to induce CYP3A4 with this format, such a system could be valuable in the initial stages of preclinical drug development.
 ...
PMID:A cell-based reporter gene assay for determining induction of CYP3A4 in a high-volume system. 1223 78

Microcystins are naturally occurring hepatotoxins produced by strains of Microcystis aeruginosa. They are involved in promoting primary liver tumours and a previous study showed that they might also be tumour initiators. In this study we demonstrate that microcystin-LR (MCLR) at doses that were not cytotoxic (0.01-1 microg/ml), induced dose and time dependent DNA strand breaks in human hepatoma cell line HepG2. These DNA strand breaks were transient, reaching a maximum level after 4h of exposure and declining with further exposure. In the presence of the DNA repair inhibitors cytosine arabinoside (AraC) and hydroxyurea (HU), together with MCLR, DNA strand breaks accumulated after prolonged exposure. These results suggest that DNA strand breaks are intermediates, produced during the cellular repair of MCLR induced DNA damage. Digestion of DNA with purified, oxidative DNA damage specific enyzmes, endonuclease III (Endo III) and formamidopyrimidine-DNA glycosylase (Fpg) markedly increased DNA strand breaks in MCLR treated cells, providing evidence that a substantial portion of the MCLR induced DNA strand breaks originate from excision of oxidative DNA adducts. A hydroxyl radical scavenger (DMSO) significantly reduced MCLR induced DNA damage. From these results we conclude that MCLR induces formation of reactive oxygen species that cause DNA damage, and that MCLR may act as an initiator of liver cancer.
 ...
PMID:Microcystin-LR induces oxidative DNA damage in human hepatoma cell line HepG2. 1246 60

Treatment for 48 h of murine Hepa 1c1c7 cells in culture with the cancer chemopreventive oltipraz (1) followed by addition of CD(3)I and immediate cell lysis yields, by LC/MS analysis, three isotopomers of the methylated pyrrolopyrazine (2), a known human metabolite of oltipraz. The major isotopomer (58%) is the one containing two CD(3)- groups attached to the pendant sulfur atoms of the pyrrolopyrazine ring, the others containing one CD(3)- and one CH(3)- group or two CH(3)- groups. It is concluded from this that the unmethylated pyrrolopyrazine (4) is the major metabolite of oltipraz. Prodrugs 5 and 6, which have been shown to rapidly generate 4 in the presence of GSH at physiological pH, induce the phase 2 enzyme NQO1 in Hepa 1c1c7 cells with potencies on par with oltipraz itself: CD(NQO1) = 14.4 +/- 1.3, 20.1 +/- 4.6, and 23.6 +/- 1.6 microM for oltipraz, 5, and 6, respectively. Pretreatment of oltipraz, 5, and 6 in cell culture media with 1 mM GSH, which is shown to immediately convert 5 and 6 to 4, followed by incubation with Hepa 1c1c7 cells shows similar potencies for oltipraz and the (decomposed) produrgs, with CD(NQO1) = 18.0 +/- 4.4 microM for 5, 17.8 +/- 0.2 microM for 6, and 13.5 +/- 1.4 microM for oltipraz. Treatment with compound 6 of murine hepatoma cells containing a luciferase gene under the control of the antioxidant response element (ARE) from the mouse heme oxygenase (ho-1) gene elicits induction of luciferase activity, CD = 35.8 +/- 2.8 microM, somewhat greater than the potency than oltipraz itself. Western blots of nuclear proteins isolated from Hepa 1c1c7 cells and probed with anti-Nrf2 indicate that as compared to vehicle DMSO, compound 6 stimulates nuclear translocation of Nrf2 from the cytosol. From this study, it is concluded that the major metabolite of the cancer chemopreventive oltipraz is a phase 2 enzyme inducer of comparable potency that activates the ARE and initiates nuclear translocation of transcription factor Nrf 2.
 ...
PMID:Phase 2 enzyme induction by the major metabolite of oltipraz. 1461 73

The objective of this study was to investigate the effects of Gelidium amansii, an edible red agar cultivated off the northeast coast of Taiwan, on the growth of two lines of cancer cells, murine hepatoma (Hepa-1) and human leukemia (HL-60) cells, as well as a normal cell line, murine embryo fibroblast cells (NIH-3T3). The potential role of G. amansii on the induction of apoptosis was also examined. The results indicated that all extracts from G. amansii, including phosphate-buffered saline (PBS) and methanol extracts from dried algae as well as the dimethyl sulfoxide (DMSO) extract from freeze-dried G. amansii agar, inhibited the growth of Hepa-1 and NIH-3T3 cells, but not the growth of HL-60 cells. Annexin V-positive cells were observed in methanol and DMSO extract-treated, but not PBS extract-treated Hepa-1 and NIH-3T3 cells, suggesting that the lipid-soluble extracts of G. amansii induced apoptosis. In summary, extracts of G. amansii from various preparations exhibited antiproliferative effects on Hepa-1 and NIH-3T3 cells, and apoptosis may play a role in the methanol and DMSO extract-induced inhibitory effects. However, the antiproliferative effects of PBS extracts was not through apoptosis. Moreover, the growth-inhibitory effects of G. amansii were not specific to cancer cells.
 ...
PMID:Growth-inhibitory effects of the red alga Gelidium amansii on cultured cells. 1475 29

A variant of the serpin squamous cell carcinoma antigen (SCCA) has been identified as a hepatitis B virus binding protein and high expression of SCCA has recently been found in hepatocarcinoma. Since HBV is involved in liver carcinogenesis, experiments were carried out to examine the effect of HBV preS1 envelope protein on SCCA expression. Surface and intracellular staining for SCCA was assessed by FACS analysis. Preincubation of HepG2 cells and primary human hepatocytes with preS1 protein or with preS1(21-47) tetrameric peptide significantly increased the surface expression of SCCA, without modification of its overall cellular burden, suggesting a surface redistribution of the serpin. An increase in HBV binding and internalization was observed after pre-incubation of the cells with preS1 preparations, compared to cells preincubated with medium alone. Pretreatment of cells with DMSO, while not influencing SCCA basal expression, was responsible for an increase in the efficiency of HBV internalization and this effect was additive to that obtained after incubation with preS1 preparations. In conclusion, the HBV preS1(21-47) sequence is able to induce overexpression of SCCA at the cell surface facilitating virus internalization, while the increased efficiency of HBV entry following DMSO addition is not mediated by SCCA.
 ...
PMID:Surface expression of squamous cell carcinoma antigen (SCCA) can be increased by the preS1(21-47) sequence of hepatitis B virus. 1499 46

Microcystins are cyclic heptapeptides produced by different freshwater cyanobacterial species such as Microcystis aeruginosa. They have been shown to induce DNA damage in vitro and in vivo, however, the mechanisms of their genotoxic activity remain unclear. With the comet assay we demonstrate that, in human hepatoma HepG2 cells, microcystin-LR (MCLR) induced DNA strand breaks which were transiently present and probably produced during the cellular repair of MCLR-induced DNA damage. Digestion of DNA from MCLR-treated HepG2 cells with purified formamidopyrimidine-DNA glycosylase (Fpg), which recognizes specific oxidized purines, displayed a greater extent of DNA strand breaks than non-digested DNA, providing evidence that MCLR induced oxidation of purines. The number of DNA strand breaks detected after digestion with Fpg increased with time of exposure of the cells to MCLR, indicating that oxidized purines were not repaired. Using the 2',7'-dichlorofluorescin diacetate (DCFH-DA) fluoroprobe we showed that MCLR, at non-cytotoxic concentrations, induced a time and dose dependent increase of intracellular reactive oxygen species (ROS) formation in HepG2 cells. The role of ROS in MCLR-induced DNA damage was further confirmed by exposing the cells to MCLR in the presence of different ROS scavengers. The formation of DNA strand breaks and oxidized purines was completely prevented by a superoxide dismutase mimic, 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPOL), an iron chelator, deferoxamine (DFO), a precursor of glutathione (GSH) and intracellular ROS scavenger, N-acetyl-L-cysteine (NAC), and partly by hydroxyl radical scavengers dimethylsulphoxide (DMSO) and 1,3-dimethyl-2-thiourea (DMTU). The results provide evidence that the genotoxicity of MCLR is mediated by ROS.
 ...
PMID:The role of reactive oxygen species in microcystin-LR-induced DNA damage. 1515 64

Antiangiogenic activity of curcumin on the tumor neogenesis was investigated by evaluating the density of neocapillaries induced by Hepatocellular carcinoma cells (HepG2) in mice, using intravital fluorescence videomicroscopy. Male BALB/c nude mice (20-25 g) were used, and a dorsal skin-fold chamber was implanted. HepG2 (30 microl of 2 x 10(6) cells) were inoculated on the upper surface of the skin within the chamber. The mice were divided into two groups as follows. Dimethyl sulfoxide solution (0.1%) was fed (HepG2 group, n=5) or curcumin solution (3000 mg/kg bw) was fed oral daily (HepG2-Cur group, n=5), one day after the inoculation of HepG. On days 7 and 14 post-tumor-inoculation, the tumor microvasculature was visualized by injecting 0.1 ml of 0.5% rhodamine B isothiocyanate-labeled dextran intravenously, and observed under an intravital fluorescence videomicroscope. Based on the recorded videoimage, the tumor neocapillary density and microvasculature were evaluated using a digital image analysis and correlated with the tumor area. The image analysis demonstrated that in the HepG2-group the neocapillary densities were significantly increased on day 7, and day 14, compared to the aged-matched Sham-group (P<0.05). In the HepG2-Cur group, the increase of tumor neocapillary density was attenuated significantly. It was suggested that high dose of curcumin might be an effective anti-angiogenic drug in the treatment against tumor.
 ...
PMID:Antiangiogenic activity of curcumin in hepatocellular carcinoma cells implanted nude mice. 1615 Dec 60

HepG2 cells, a human hepatoma cell line, stably expressing NADPH-cytochrome P450 reductase (OR) and/or cytochrome P450 2D6 wild-type (CYP2D6-WT) or its variants (Pro34Ser, Gly42Arg, Arg296Cys and Ser486Thr) were established in the present study. The cultivation of HepG2 cells expressing CYP2D6-WT in the culture medium containing dimethyl sulfoxide (DMSO, 0.1% of final concentration) markedly increased the bufuralol (BF) 1''-hydroxylase activity compared with that of control cells when cultivated without DMSO. A similar effect was also observed in HepG2 cells stably expressing CYP2D6 and OR. The addition of hemin in place of DMSO to the culture medium resulted in no increase in the enzyme activity. Western blot analysis revealed that the levels of CYP2D6 protein were similar between DMSO-treated and non-treated HepG2 cells regardless of OR expression. Spectrophotometric analysis of reduced carbon monoxide-difference spectra of HepG2 cells expressing CYP2D6-WT and/or OR demonstrated that the addition of DMSO increased the peak height of functional CYP2D6 at 450 nm. These results suggest that the increase in CYP2D6 activity is attributable to the radical-scavenging effect of DMSO. The HepG2 cell lines stably expressing OR and CYP2D6 or its variants in combination with DMSO treatment may be useful for screening the cytotoxicity of chemical compounds which undergo oxidation by CYP2D6.
 ...
PMID:The effect of dimethyl sulfoxide on the function of cytochrome P450 2D6 in HepG2 cells upon the co-expression with NADPH-cytochrome P450 reductase. 1621 21

The influence of cytoskeleton integrity on the metabolism of saturated and unsaturated FA was studied in surface cultures and cell suspensions of human Hep G2 hepatoma cells. We found that colchicine (COL), nocodazol, and vinblastin produced a significant inhibition in the incorporation of labeled saturated FA, whereas incorporation of the unsaturated FA remained unaltered. These microtubule-disrupting drugs also diminished Delta9-, Delta5-, and Delta6-desaturase capacities. The effects produced by COL were dose (0-50 microM) and time (0-300 min) dependent, and were antagonized by stabilizing agents (phalloidin and DMSO). Dihydrocytochalasin B (20 microM) was tested as a microfilament-disrupting drug and produced no changes in either the incorporation of [14C] FA or the desaturase conversion of the substrates. We hypothesized that the interactions between cytoskeleton and membrane proteins such as FA desaturases may explain the functional organization, facilitating both substrate channeling and regulation of unsaturated FA biosynthesis.
 ...
PMID:Microtubular integrity differentially modifies the saturated and unsaturated fatty acid metabolism in cultured Hep G2 human hepatoma cells. 1638 71

Dimethyl sulfoxide (DMSO) has been shown to induce the differentiation of primary hepatocytes in vitro. When actively dividing poorly differentiated human hepatoma-derived (Huh7) cells were cultured in the presence of 1% DMSO, cells became cytologically differentiated and transitioned into a nondividing state, characterized by the induction of hepatocyte-specific genes. Moreover, these cells were highly permissive for acute hepatitis C virus (HCV) infection, and persistent long term infection of these cultures could also be achieved. As HCV naturally replicates in highly differentiated nondividing human hepatocytes, this system may more accurately mimic the conditions under which HCV replicates in vivo than previous models using poorly differentiated rapidly dividing hepatoma cells.
 ...
PMID:Production of infectious hepatitis C virus by well-differentiated, growth-arrested human hepatoma-derived cells. 1700 3


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>