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)

Iron chelating agents have been demonstrated to inhibit tumour cell growth. However, in vitro and in vivo results using desferrioxamine a hexadentate iron chelating agent, for anti-cancer treatment are not always in agreement. Therefore, we have studied the response of three human tumour cell lines (HL-60 promyelocytic leukaemia, MCF-7 breast cancer and HepG2 hepatoma), grown in culture medium supplemented with either human pooled (HPS) or fetal bovine serum (FBS), to desferrioxamine. Desferrioxamine, at micromolar concentrations, induced severe cytotoxicity in all tumour cell lines grown in FBS medium. When grown in HPS medium, comparable desferrioxamine cytotoxicity was observed in the millimolar range. The addition of 50% saturated human transferrin to FBS medium resulted in protection against desferrioxamine cytotoxicity. HL-60 cells were further studied for iron metabolism characteristics. HL-60 cells, grown in medium with FBS, were found to have an 8.4 fold increase in surface transferrin receptor (TfR) expression (P < 0.001) as compared with HL-60 cells grown in medium with HPS. However, iron uptake of HPS cultured HL-60 cells, after incubation with saturated human transferrin, was higher, resulting in a higher concentration of iron in HPS cultured HL-60 cells as compared with FBS cultured cells (1.72 +/- 0.02 mumol/g protein v. 1.32 +/- 0.14 mumol/g protein; P < 0.001). Using desferrioxamine it was shown that TfR expression is dependent on the biological availability of iron in the cell. Consistent with the lower iron content in FBS cultured cells, we conclude that the cytotoxicity of desferrioxamine is dependent on the ability of cells to replenish cellular iron stores from the culture medium. Cells grown in FBS medium lack this ability and are therefore more susceptible to desferrioxamine.
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PMID:The in vitro response of human tumour cells to desferrioxamine is growth medium dependent. 843 91

Tamoxifen inhibits the binding of [3H]nitrobenzylthioinosine ([3H]NBMPR) to human MCF-7 breast cancer cells with an IC50 of 8 microM. Tamoxifen at 30 microM changed the apparent Kd for [3H]NBMPR binding from 0.63 +/- 0.12 to 4.75 +/- 0.58 nM, with little effect on the Bmax (311000 +/- 76000 and 263000 +/- 46000 sites per cell for untreated and tamoxifen-treated cells respectively). Corresponding to this decrease in binding of [3H]NBMPR in the presence of tamoxifen was an inhibition of NBMPR-sensitive equilibrative transport of 50 microM [3H]uridine (IC50 7-10 microM). In the presence of 15 microM tamoxifen, the apparent K(m) for [3H]uridine transport was increased from 390 +/- 30 to 1500 +/- 250 microM, with no change in Vmax (12.0 +/- 0.1 and 11.3 +/- 4.3 microM/s for untreated and tamoxifen-treated cells respectively). The inhibitory effect of tamoxifen on NBMPR-sensitive equilibrative uridine transport was specific, as similar results were also observed in HL-60 leukaemia and EL4 lymphoma cells. Furthermore a similar concentration of tamoxifen had no effect on the NBMPR-insensitive equilibrative transport of uridine in MCF-7, HL-60 and Morris 7777 hepatoma cells, and on the Na(+)-dependent transport of uridine in murine splenocytes. In this paper we demonstrate that tamoxifen by itself might have some antiproliferative effects through inhibition of DNA synthesis by blocking the nucleoside salvage pathway.
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PMID:Tamoxifen inhibits nitrobenzylthioinosine-sensitive equilibrative uridine transport in human MCF-7 breast cancer cells. 900 90

We previously demonstrated an enhancer-like positive regulatory element within a 259-bp sequence (-2352 to -2094 bp) of the human CYP1A2 gene in HepG2 cells. Three protein binding sites were identified by DNase I footprinting analyses within the 259-bp sequence: protected region A PRA; -2283 to -2243 bp), PRB (-2218 to -2187 bp), and PRC (-2124 to -2098 bp) (I. Chung and E. Bresnick, Mol. Pharmacol. 47, 677-685, 1995). In the present study, the functional significance of those protected regions was examined. Transfection experiments with deletion and substitution mutants defined the PRB and PRC as containing positive and negative regulatory elements, respectively. Human breast carcinoma MCF-7 cells were cotransfected with a hepatocyte nuclear factor-1 (HNF-1) expression vector and CYP1A2 promoter- or thymidine kinase promoter-luciferase reporter gene constructs. HNF-1, which contributes to the liver specificity of genes, enhanced reporter gene activity in a PRC sequence-dependent manner. These results suggested that PRC could exist bound to a repressor which was displaceable by other transcription factors such as HNF-1. Results obtained by transfection of HepG2 hepatoma cells with various PRB substitution mutant-luciferase gene fusion constructs indicated that the entire sequence of PRB was necessary for promoter activity. Consequently, the regulation of CYP1A2 expression is very complex, requiring a number of both positive and negative regulatory factors.
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PMID:Identification of positive and negative regulatory elements of the human cytochrome P4501A2 (CYP1A2) gene. 902 75

The environmental contaminant benzo[c]phenanthrene (B[c]Ph) has weak carcinogenic activity in rodent bioassays; however, the fjord region diol epoxides of B[c]Ph, B[c]Ph-3,4-diol 1,2-epoxides (B[c]PhDE), are potent carcinogens. To determine the role of cytochrome P450 isozymes in the activation of B[c]Ph in MCF-7 cells and the low activation of B[c]Ph in mouse skin, cells of the MCF-7 and the human hepatoma HepG2 cell lines were treated with the potent Ah receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) prior to exposure to B[c]Ph for 24 h. Mice were treated topically with 1 microg of TCDD or vehicle (control) for 73 h and then with 2 micromol of B[c]Ph for 24 h. In MCF-7 cells, TCDD exposure increased B[c]PhDE-DNA adduct levels more than 3-fold with a 10-fold increase in the (-)-B[c]PhDE-2-dA(t) adduct. Treatment of HepG2 cells with TCDD prior to B[c]Ph application did not increase B[c]PhDE-DNA binding. Total B[c]PhDE-DNA adducts increased 3-fold in TCDD-treated mouse epidermis: the majority of the increase resulted from (+)-B[c]PhDE-1-dA adducts. Analysis of P450 enzymes by Western blotting detected a large increase of P4501B1 but almost no increase in P4501A1 in MCF-7 cells exposed to 10 microM B[c]Ph for 24 or 48 h. In HepG2 cells, there were no detectable levels of P4501A1 or P4501B1 after treatment with 10 microM B[c]Ph for 24 h. In contrast, topical application of 2 micromol of B[c]Ph to mouse skin for 48 or 72 h increased P4501A1, but no P4501B1 was detected. As a measure of P450 activity, the metabolism of 7,12-dimethylbenz[a]anthracene (DMBA) was analyzed in microsomes prepared from MCF-7 and HepG2 cells exposed to 0.1% DMSO, 10 microM B[c]Ph, or 10 nM TCDD for 24 or 48 h and from mouse epidermis treated with 1 microg of TCDD, or vehicle control for 72 h, or 2 micromol of B[c]Ph for 48 h. The levels of DMBA metabolites were low or undetectable in microsomes from B[c]Ph-treated MCF-7 and HepG2 cells, but a metabolite pattern consistent with P4501A1 metabolism of DMBA was present in B[c]Ph-exposed mouse epidermal microsomes. TCDD-treated MCF-7 cells, HepG2 cells, and mouse epidermis had DMBA metabolism patterns characteristic of P4501A1 activity. Microsomes from TCDD-treated human cells formed a higher proportion of the proximate carcinogenic metabolite DMBA-3,4-dihydrodiol (16% of total identified metabolites) than TCDD-treated mouse epidermis (2%). In mouse epidermis, the weak ability of B[c]Ph to increase hydrocarbon-metabolizing activity and the increase in mainly P4501A1, leading to formation of the less carcinogenic stereoisomer B[c]PhDE-1, may explain the low carcinogenic activity of B[c]Ph. In a human mammary carcinoma cell line, treatment with B[c]Ph increases mainly P4501B1 and results in formation of a higher proportion of the more carcinogenic B[c]PhDE-2. This indicates that cells in which B[c]Ph treatment increases P4501B1 levels effectively activate B[c]Ph to potent carcinogenic metabolites.
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PMID:Role of cytochrome P450 enzyme induction in the metabolic activation of benzo[c]phenanthrene in human cell lines and mouse epidermis. 916 60

The estrogen receptor and aryl hydrocarbon receptor (AhR) are coexpressed in several Ah and estrogen-responsive human breast cancer cell lines. However, a recent study reported that 17beta-estradiol (E2) inhibited Ah responsiveness in mouse Hepa 1c1c7 hepatoma cells (Kharat, I., and Saatcioglu, F. (1996) J. Biol. Chem. 271, 10533-10537), and therefore, estrogen receptor-AhR cross-talk was reinvestigated in MCF-7 and mouse Hepa 1c1c7 cells. Treatment of MCF-7 or Hepa 1c1c7 cells with 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in induction of CYP1A1-dependent activity and mRNA levels. Treatment of both cell lines with E2 had no effect on basal or TCDD-inducible CYP1A1-dependent activity or mRNA levels. In MCF-7 and Hepa 1c1c7 cells transiently transfected with an Ah-responsive plasmid containing the 5'-regulatory region of the human CYP1A1 gene fused to the chloramphenicol acetyltransferase reporter gene 10 nM TCDD significantly induced chloramphenicol acetyltransferase activity; in cells cotreated with TCDD plus E2 the induced response was not affected by the hormone. Nuclear extracts from cells treated with dimethyl sulfoxide, E2, TCDD, and TCDD plus E2 were incubated with the [32P]dioxin-responsive element and analyzed by gel electrophoretic mobility shift assays. A retarded band associated with formation of a [32P]dioxin-responsive element-AhR complex was observed in nuclear extracts from cells treated with TCDD or TCDD plus E2 (cotreated). Collectively these studies suggest that E2 does not modulate AhR-mediated CYP1A1 gene expression in MCF-7 or Hepa 1c1c7 cells.
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PMID:Estrogen does not inhibit 2,3,7, 8-tetrachlorodibenzo-p-dioxin-mediated effects in MCF-7 and Hepa 1c1c7 cells. 937 12

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces both phase I and phase II drug-metabolizing enzymes in rodent liver and hepatoma cell lines and this induction is mediated by the aryl hydrocarbon (Ah) receptor. Induction of CYP1A1 by TCDD in human breast cancer cells has been reported and results of several studies suggest that the estrogen receptor (ER) may be required for Ah responsiveness. This study investigates the induction of GST pi by TCDD in human breast cancer cells and the role of the ER in mediating this response. TCDD did not induce chloramphenicol acetyl transferase (CAT) activity in ER positive (ER+) MCF-7 and ER- MDA-MB-468 and MDA-MB-231 human breast cancer cell lines transiently transfected with GST pi (human) or GSTP (rat) promoter-reporter constructs containing the -291/+36 and -2.9/+59 region, respectively, of the GST pi and GSTP gene promoters. Furthermore, TCDD did not induce GST pi or GSTP in MDA-MB-468 and MDA-MB-231 human breast cancer cells stably transfected with the ER. RT-PCR confirmed that GST pi mRNA levels were low in ER+ MCF-7 cells and high in ER- MDA-MB-468 and MDA-MB-231 cells; however, in MDA-MB-468 and MDA-MB-231 cells stably transfected with the ER GST pi mRNA levels remained elevated and were not inducible. MDA-MB-468 and MDA-MB-231 cells stably transfected with the ER exhibited increased GST activity and decreased GSH content compared to wild-type cells; however, in MDA-MB-468 cells stably transfected with ER, the susceptibility to doxorubicin, ellipticine, chlorambucil, malphalan, or cisplatin was similar to that observed in wild-type cells. Adriamycin accumulation was similar in wild-type and ER stably transfected cells and verapamil did not affect this response, suggesting that ER expression did not influence p-glycoprotein activity. Taken together these data suggest that not all GST isoforms are responsive to TCDD and stable transfection of ER- cells with ER is not sufficient to restore the ER+ phenotype in some breast cancer cell lines.
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PMID:Studies on the relationship between estrogen receptor content, glutathione S-transferase pi expression, and induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin and drug resistance in human breast cancer cells. 939 Jan 89

The dose-dependent alpha-fetoprotein (AFP) reactivity of different types of tumor cells and normal embryonal fibroblasts, which are capable of taking up AFP, was investigated. High doses (more than 100 micrograms/ml) of purified human AFP were shown to induce strongly dose-dependent growth inhibition of human hepatoma HepG2 cells, human lymphoblastoma MT4 cells, lymphoma Jurkat cells and murine fibroblastoma L929 cells. Human mammary carcinoma MCF-7 cells also revealed a growth inhibitory response to AFP, although to a lesser extent. Equivalent doses of human serum albumin (HSA) demonstrated no effect on these cells. On the contrary, normal embryonal fibroblasts of different organ origin showed dose-dependent stimulation (50-90%) of proliferation in response to AFP. A similar stimulative effect was obtained when embryonal fibroblasts were treated with the same doses of HSA. The myeloblastoma cell line U-937 and the normal epidermal fibroblast cell line M19 were shown to be resistant to the AFP action over a wide range of protein concentrations. It was demonstrated that growth factor deprivation (i.e. low serum concentration) could stimulate U-937 cell proliferation in response to high doses of AFP. It was also shown that intensive washing of U-937 and MCF-7 cells with fresh medium to remove secreted cytokines and growth factors distinctly increased cell sensitivity to high-dose-AFP-induced growth-inhibitory activity. Low AFP concentrations (less than 100 micrograms/ml) failed to induce growth inhibition in all studied cells and rather showed a slight stimulative effect. These findings demonstrate that physiological levels of AFP can exhibit a dose-dependent growth-regulatory activity toward sensitive tumor or developing cells. Our data demonstrated that AFP could reveal either stimulative or inhibitory growth activity, depending on the relative concentration of AFP and on exogenous or endogenous cytokines and growth factors in the cell culture medium. A growth-stimulative activity in normal embryonal fibroblasts and certain tumor cell lines exhibited by low AFP concentrations is supposed to result from the synergistic effects of AFP and various other secreted growth factors.
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PMID:Growth-regulative activity of human alpha-fetoprotein for different types of tumor and normal cells. 942 80

Foci of altered hepatocytes (FAH) represent preneoplastic lesions, as shown in various animal models of hepatocarcinogenesis, but their significance in the human liver has not been established. The cellular composition, size distribution and proliferation kinetics of FAH in 163 explanted and resected human livers with or without hepatocellular carcinoma (HCC) and their possible association with small-cell change of hepatocytes (SCC) were therefore studied. FAH, including glycogen-storing foci, were found in 84 of 111 cirrhotic livers, demonstrating higher incidences in cases with (29/32) than in those without HCC (55/79). FAH were observed more frequently in HCC-free cirrhosis associated with hepatitis B or C virus or chronic alcoholic abuse (high-risk group) (37/47) than in that due to other causes (low-risk group) (12/21). MCF, predominant in cirrhotic livers of the high-risk group, were more proliferative, larger and more often involved in formation of nodules of altered hepatocytes (39.3%) than were GSF (8.5%). The results suggest that the FAH are preneoplastic lesions, MCF being more advanced than GSF. Oncocytic and amphophilic cell foci were also observed, but their significance remains to be clarified. Two types of SCC, namely diffuse and intrafocal SCC, were identified, but only intrafocal SCC was found to be related to increased proliferative activity and more frequent nodular transformation of the FAH involved, suggesting a close association with progression from FAH to HCC.
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PMID:Human hepatic preneoplasia: phenotypes and proliferation kinetics of foci and nodules of altered hepatocytes and their relationship to liver cell dysplasia. 942 27

It has been difficult to study the regulation of cytochrome P4501A2 (CYP1A2) because expression of this enzyme is reported to be limited or absent in cell culture. We found that CYP1A2 can be induced significantly by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3-methylcholanthrene (MC), or benz[a]anthracene in the human colon carcinoma cell line LS180. TCDD and MC each caused a dramatic elevation of CYP1A2 mRNA, as assessed by reverse transcription-polymerase chain reaction or by northern blot analysis. TCDD also increased immunoreactive CYP1A2 protein and the activity of phenacetin-O-deethylase, a diagnostic catalytic marker for CYP1A2. The induction of CYP1A2 at all levels (mRNA, protein, catalytic activity) was concentration- and time-dependent: the EC50 for mRNA induction by TCDD = 0.5 nM, and by MC = 1.4 microM. Inducible CYP1A2 mRNA also was detected at lower levels in two other human cell lines, the hepatoma cell line HepG2 and the breast carcinoma cell line MCF-7. CYP1A1 and CYP1B1, additional CYP1 enzymes regulated by the aryl hydrocarbon receptor (AHR), also were inducible by TCDD and MC in LS180 cells; their concentration-dependent induction was highly correlated with induction of CYP1A2 at mRNA, protein, and catalytic levels. CYP1B1 was constitutively expressed and inducible in the LS180, MCF-7, and HepG2 cell lines as well as in the human choriocarcinoma cell line JEG-3 and the squamous cell carcinoma line A431. CYP1A2 was neither constitutively expressed nor inducible in A431 or JEG-3 cells. The expression of mRNAs encoding the regulators of CYP1 enzymes-the AHR and its heterodimerization partner, the ARNT (AH receptor nuclear translocator) protein-was not altered by treatment with TCDD or MC. However, the cytosolic content of AHR protein and ARNT protein was depleted substantially following treatment with TCDD. The LS180 cell line should constitute a good model for further mechanistic studies on AHR-regulated CYP1A2 expression.
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PMID:Regulation of cytochrome P450 enzymes by aryl hydrocarbon receptor in human cells: CYP1A2 expression in the LS180 colon carcinoma cell line after treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin or 3-methylcholanthrene. 978 29

Alpha-fetoprotein (AFP) is a transport protein that has growth-regulatory properties in many different tissues. It is known to interfere with responses stimulated by estrogen. The purpose of this study was to determine whether human AFP would inhibit the growth of human breast cancer. AFP was isolated from the culture supernatant of human hepatoma cells (HepG2) grown in serum-free medium and was purified by immunoaffinity chromatography. Human breast cancers were grown as xenografts under the kidney capsule of severe combined immunodeficient mice. The minimum inhibitory dose of AFP against estradiol (E2)-stimulated growth of human MCF-7 breast cancer xenografts was 10 microg/mouse/day, and maximum inhibition (no growth) was achieved with 100 microg/mouse/day. Daily treatment was required to sustain inhibition. This 100-microg dose of AFP also inhibited xenograft growth of E2-dependent T47 human breast carcinoma. Estrogen receptor-negative MDA MB 231 and BT20 human breast carcinoma xenografts were not inhibited by AFP (100 microg/mouse/day). Elevation in serum E2 occurred during AFP treatment. AFP did not compete with agonists for the estrogen receptor. These laboratory results are consistent with the findings of a literature search, which consistently showed an association between elevated pregnancy levels of AFP and subsequent reduced risk for breast cancer later in life. We conclude that AFP can inhibit growth of estrogen-dependent breast cancer and warrants further development as an agent for the treatment and perhaps even the prevention of human breast cancer.
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PMID:Alpha-fetoprotein derived from a human hepatoma prevents growth of estrogen-dependent human breast cancer xenografts. 982 55


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