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)

Melatonin, the major secretory product of the pineal gland, is in focus of many research areas because of its ability to scavenge free oxygen radicals and thereby protect cells and tissues from radical damage. Some studies suggest melatonin may be a possible therapeutic agent with potential clinical applications against pathological states due to reactive oxygen species. Here, we investigated the effects of melatonin on the mouse hepatoma cell line HEPA 1-6, coincubated with ethanol, and tamoxifen, respectively. Cell proliferation rates were detected by the 3-[4,5 dimethylthiazol-2-y1]-2,5-diphenyltetrazolium bromide (MTT) proliferation assay. A dose-dependent inhibition of the proliferative activity by melatonin was observed from 640 microM to 3 mM, which was significantly higher (P < 0.01) than with the solvent (ethanol) alone. Concentrations of 320 microM and less had no effect on cell proliferation. This antiproliferative effect might be because of the prolonged activation of mitogen-activated protein kinase which was activated by phosphorylation 15 min after the induction with melatonin. Furthermore, apoptosis was found to be enhanced by melatonin (75% more than with the solvent alone, P < 0.001). Finally, we show that the inhibitory effect of tamoxifen (25 microM) is markedly enhanced by the coincubation with melatonin (1.3 mM) up to 75% (P < 0.001). These data show that the antiproliferative effects of tamoxifen and ethanol, respectively, on mouse hepatoma cell line HEPA 1-6 are enhanced by melatonin. Although at the conditions described here the antiproliferative effects of melatonin occur at supraphysiological concentrations, these data may help to support clinical studies where melatonin is given simultaneously with tamoxifen or other standard chemotherapeutica.
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PMID:Potentiation of antiproliferative effects of tamoxifen and ethanol on mouse hepatoma cells by melatonin: possible involvement of mitogen-activated protein kinase and induction of apoptosis. 1212 80

A disulfated tetrasaccharide fragment with a spacer arm of human hepatocellular carcinoma carbohydrate antigen SB(1a), namely, 2-aminoethyl 3-O-sulfo-beta-D-galactopyranosyl-(1 --> 3)-2-acetamido-2-deoxy-beta-D-galactopyranosyl-(1 --> 4)-3-O-sulfo-beta-D-galactopyranosyl-(1 --> 4)-beta-D-glucopyranoside was synthesized via a [2 + 1 + 1] block building mode. In the last coupling step toward the trisaccharide acceptor 8, benzoyl protected galactosyl bromide donor 14 was found to be much more reactive than the acetyl-protected donors.
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PMID:Synthesis of a spacer-armed disulfated tetrasaccharide of SB1a, a carbohydrate hapten associated with human hepatocellular carcinoma. 1243 58

Chitosan has the potential for DNA complexation and is useful as a non-viral vector for gene delivery. Highly purified low molecular weight chitosan (LMWC) was prepared. Lactobionic acid (LA) bearing galactose group was coupled with LMWC for liver-specificity. A series of galactosylated-LMWC (gal-LMWC) samples covering a range of galactose group contents were prepared. The chitosan/DNA complexes were obtained using a complex coacervation process. Gal-LMWCs were used to transfer pSV-beta-galactosidase reporter gene into human hepatocellular carcinoma cell (HepG2), L-02, SMMC-7721, and human cervix adenocarcinoma cell line (HeLa) cell lines in vitro. Transfection efficiency of gal-LMWCs was evaluated by beta-galactosidase assay and compared with those of lipofectin, calcium phosphate (CaP), high molecular weigh chitosan (HMWC) and LMWC. Gal-LMWC/DNA complex shows a very efficient cell selective transfection to hepatocyte. The transfection efficiency of gal-LMWCs increased with the improvement of the galactosylation degree. Cytotoxicity of gal-LMWC was determined by 3-(4,5-dimethylthiazd-2-yl)-2,5-diphenyltentrazolium bromide (MTT) assay and the results show that the modified chitosan has relatively low cytotoxicity, giving the evidence that the modified chitosan vector has the potential to be used as a safe gene-delivery system.
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PMID:Galactosylated low molecular weight chitosan as DNA carrier for hepatocyte-targeting. 1267 2

Based on the ability of bile acids to vectorialize the cytostatic activity of other agents, we have designed and synthesized a new series of platinum and gold complexes. These compounds were studied and characterized by elemental analysis, FT-IR, FAB(+)/MS, 1H, 13C and 195Pt NMR, UV-Vis spectroscopy and conductivity measurements in solution, among other techniques. Kinetic studies carried out in aqueous solution and in the presence of different NaCl concentrations: 4 mM (similar to cytoplasmic concentration), 150 mM (similar to plasmatic concentration). The effects on the electrophoretic mobility of the pUC18 plasmid, the DNA denaturation temperature, and ethidium bromide (EtBr) binding to DNA were studied. The complexes are able to inter-react with DNA to inhibit DNA synthesis and hence, to reduce cell proliferation. The complexes were evaluated for in vitro cytostatic activity against human colon adenocarcinoma, mouse hepatoma, human hepatoma, mouse leukemia, etc. The antitumor effect of some of the compounds prepared was similar to that of cisplatin. However, other compounds had lower cytostatic activity. This different behavior can be accounted for by the structure/activity relationship (SAR), although other factors, such as uptake and the different kinetic behavior in solution, may be responsible for these differences.
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PMID:New organotropic compounds. Synthesis, characterization and reactivity of Pt(II) and Au(III) complexes with bile acids: DNA interactions and 'in vitro' anticancer activity. 1288 66

Intensive apoptotic death of thymocytes is a possible mechanism of thymus involution during tumor growth. We studied the role of hypercholesterolemia and lactate acidosis in the induction of increased sensitivity of thymocytes to apoptosis during growth of transplanted hepatoma 22a in mice. Spontaneous apoptosis in thymocytes during tumor growth in mice was studied in vitro by acridine orange/ethidium bromide staining and diphenylamine test. Plasma levels of lactate, total cholesterol, alpha-cholesterol, and triglycerides were measured. A positive correlation was found between intensification of apoptosis (diphenylamine test) and increased concentration of total plasma cholesterol on days 21 and 28 after inoculation of tumor cells. Plasma lactate content did not increase at this term. We hypothesize that hypercholesterolemia accompanying tumor growth acts as a factor increasing thymocyte sensitivity to apoptosis.
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PMID:Effect of metabolic factors on apoptosis in thymocytes during tumor growth. 1291 Feb 89

Inhibitors of differentiation and DNA binding-1 (Id-1) have been demonstrated to oppose Ets-mediated activation of p16INK4a. As p16INK4a protein is inactivated in hepatocellular carcinoma (HCC), we aimed to investigate the role of Id-1 in regulating p16INK4a expression during the development of HCC in HCC patients and direct ectopic Id-1 introduction into the PLC/PRF/5 HCC cell line. Sixty-two HCC samples were recruited for evaluation of Id-1 and proliferating cell nuclear antigen (PCNA) protein expression. The messenger RNA (mRNA) expression of Id-1 and p16INK4a was detected by quantitative reverse transcription-polymerase chain reaction. For in vitro Id-1 transfection, five Id-1 transfected clones were isolated and the effect of ectopic Id-1 introduction was investigated by 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, flow cytometry, immunostaining and western blot. Our results showed that Id-1 was over-expressed in HCC specimens both at mRNA and protein levels. Over-expression of Id-1 protein was correlated with PCNA (r = 0.334, P = 0.033). HCC samples showing low Id-1 protein expression had a lower Id-1 mRNA level (340.2 versus 1467%, P = 0.039) and higher p16INK4a expression (195 versus -78.6%, P = 0.039) than samples with high Id-1 protein expression. In the PLC/PRF/5 HCC cell line study, ectopic Id-1 expression resulted in proliferation of HCC cells and an increased percentage of S phase cells and PCNA expression. The results showed that over-expression of Id-1 induces cell proliferation in HCC through inactivation of p16INK4a/retinoblastoma pathway. In conclusion, the results provided an insight for the understanding of the role of Id-1 in functional inactivation of p16INK4a in HCC.
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PMID:Over-expression of Id-1 induces cell proliferation in hepatocellular carcinoma through inactivation of p16INK4a/RB pathway. 1294 53

Cadmium is a toxic transition heavy metal of continuing occupational and environmental concern, with a wide variety of adverse effects on regulation of gene expression and cellular signal transduction pathways. Injury to cells by cadmium leads to a complex series of events that can culminate in the death of the cell. It has been reported that cadmium induces apoptosis in many cell lines. However, the morphological characteristics leading to apoptosis or subsequent regeneration in cells exposed to cadmium have not been clarified. We evaluated whether human hepatoma cells maintained in culture undergo apoptosis when exposed to cadmium. Cytotoxic activity of cadmium on Hep G2 cells determined using 3-[4,5-dimethylthiazol-2-yl]-2,5- diphenyltetrazolium bromide assay. A DNA ladder assay was performed by electrophoresis. Cell cycle analysis was quantified by flow cytometry. Nuclear morphology was studied by fluorescence microscopy after staining with propidium iodide and Hoechst 33342. Morphologic alterations in culture hepatocytes treated with CdCl2 were observed by transmission electron microscopy. We have demonstrated that apoptosis is a major mode of elimination of damaged HepG2 cells in cadmium toxicity and it precedes necrosis.
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PMID:Characterization of the cellular response during apoptosis induction in cadmium-treated Hep G2 human hepatoma cells. 1464 95

A potent inhibitor of serine/threonine kinases, staurosporine exerts antiproliferative and apoptotic effects in many cancer cells, although the exact mechanism of its action is still unclear. This study examines the effects of staurosporine on Chang liver cells, an immortalized non-tumor cell line, in comparison with those caused in HuH-6 and HepG2 cells, two human hepatoma cell lines. Our results provide evidence that staurosporine promotes apoptosis in Chang liver cells as observed by flow cytometric analysis and acridine orange/ethidium bromide staining. The effect appeared already after 8 h of treatment and increased with treatment time and dose. After 48 h of exposure to 200 nM staurosporine clear apoptotic signs were observed in about 50% of the cells. Western blotting analysis showed that in Chang liver cells staurosporine induced a marked decrease in the levels of the antiapoptotic factors Bcl-2 (-75%) and Bcl-XL (-50%). Staurosporine also caused loss of mitochondrial transmembrane potential, release of cytochrome c from mitochondria and activation of caspase-3. The involvement of caspases in staurosporine-induced cell death was also suggested by the observation that the addition of z-VAD-fmk, a general inhibitor of caspases, suppressed apoptosis. In HuH-6 and HepG2 cells treatment with staurosporine induced the arrest of cells in G2/M phase of cell cycle. This effect was not modified by z-VAD-fmk and was not accompanied by the appearance of biochemical signs of apoptosis. We conclude that staurosporine induced apoptosis in Chang liver cells by a mitochondria-caspase-dependent pathway which was closely correlated with a decrease in Bcl-2 and Bcl-XL levels, while in HuH-6 and HepG2 hepatoma cells the drug caused only an antiproliferative effect.
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PMID:Staurosporine-induced apoptosis in Chang liver cells is associated with down-regulation of Bcl-2 and Bcl-XL. 1501 Aug 57

In the present paper we describe the synthesis and toxicity studies of well-defined tailor made oligo-[R,S]-3-hydroxybutyrates (OHBs). The results indicate potential applicability of these nano-polymers as drug delivery carriers. Several OHBs of number average molecular weight (M(n)) ranging from 800 to 2400 have been synthesized and tested on transformed hamster V79 fibroblasts and murine melanoma B16(F10) cells using the 3-[4,5-dimethylthiazol-2-yl]2,5-diphenyltetrazolium bromide (MTT) based drug resistance and clonogenic survival assays. We show that 96-h incubation of cells with 1-9 microg/ml of OHBs did not affect cell viability. Incubation of OHBs with rat hepatoma FTO-2B cells stably transfected with chloramphenicol acetyltransferase (CAT) gene ligated to heat-inducible hsp70i gene promoter demonstrated that OHBs did not induce cellular stress response. Finally, we demonstrate that doxorubicin conjugated with OHB is effectively taken up by murine melanoma B16(F10) cells in vitro and localizes in the cytoplasm. These data show for the first time that tailor-made biodegradable and biocompatible oligomers of 3-hydroxybutyric acid can be taken into consideration as effective, non-toxic vectors for delivery of drugs in a conjugated form.
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PMID:Oligo-3-hydroxybutyrates as potential carriers for drug delivery. 1511 Apr 78

Despite the hepatic arterial infusion chemotherapy (HAI) has been advocated as an effective therapy for hepatocellular carcinoma (HCC) with multiple intrahepatic metastases, chemosensitivity of HCC for HAI with multidrug regimen has not been sufficiently investigated. The purpose of this study was to evaluate the in vitro chemosensitivity of HCC using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT) assay with the combinations of various antitumor drugs, and compared with the clinical results of HAI for patients with multiple intrahepatic recurrences of HCC. To evaluate the in vitro chemosensitivity of HCC to the combinations of antitumor drugs, 54 resected specimens of HCC were assayed using MTT assay with seven antitumor agents, 5-fluorouracil (5-FU), mitomycin C (MMC), adriamycin (ADM), etoposide (VP-16), cisplatin (CDDP), methotrexate (MTX) and CPT-11 (SN-38), exposed singly, or in combination. The data were compared with the clinical results of HAI for patients who manifested the multiple intrahepatic recurrence. In addition, the in vitro combined effect of CDDP and 5-FU for human hepatocellular carcinoma cell, KYN-1 and KYN-2, was analysed quantitatively. Of 54 resected specimens, 40 specimens assayed successfully, and an increased in vitro chemosensitivity of HCC when treated with combinations of antitumor drugs was observed: single drug 12.2%, two drugs combined 50.9% and three drugs combined 67.0%. The results of in vitro assay were well correlated, 85.7% in predicting accuracy, with the clinical results of 14 patients who underwent HAI for multiple recurrence of HCC, and also correlated with the experimental results of the combined use of CDDP and 5-FU in KYN-1 and KYN-2 in terms of pharmacokinetic reactions, i.e. synergism or antagonism. The MTT assay with the combinations of antitumor drugs represents an informative chemosensitivity test to HAI with multidrug regimen for recurrence of HCC.
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PMID:In vitro chemosensitivity of hepatocellular carcinoma for hepatic arterial infusion chemotherapy using the MTT assay with the combinations of antitumor drugs. 1515 Aug 97


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