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)

A new platelet aggregation inhibitor compound, 5-(2-chlorobenzyl-4,5,6,7-tetrahydrothieno[3,2-C]pyridine hydrochloride (ticlopidine), was examined for its inhibitory effects on blood-borne metastasis using three different rodent tumors (B16 melanoma, Lewis lung carcinoma, and rat ascites hepatoma, AH130). Ticlopidine was administered p.o. to the rodents. It inhibited the aggregation of platelets induced by adenosine diphosphate, thrombin, crude extract of AH130, and viable AH130 and B16 melanoma cells and also resulted in a significant decrease of pulmonary metastasis induced by i.v. injection of B16 melanoma and AH130. Spontaneous pulmonary metastasis of Lewis lung carcinoma was also inhibited by p.o. administration of ticlopidine. This new compound may be a useful agent for inhibiting platelet aggregation caused by various agents and for suppressing hematogenous pulmonary metastasis.
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PMID:Effects of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (Ticlopidine), a platelet aggregation inhibitor, on blood-borne metastasis. 730 88

Lipoperoxidation by rat liver homogenates increases after in vivo administration of CCl4, colchicine and CHM. In vitro a strong lipoperoxidative action was found for ADP/Fe3+, ethionine and glucosamine. No lipoperoxidation was elicited by hepatomatous liver or by hepatoma cells.
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PMID:Effects of various metabolic inhibitors on lipoperoxidation by homogenates of normal, regenerating and hepatomatous rat liver and by hepatoma cells. 733 Apr 58

For many years after Warburg's classic work, it was generally assumed that tumors produced large amounts of lactic acid and consequently had an acidic intracellular pHi. However, with the advent of Magnetic Resonance Spectroscopy (MRS), a non-invasive in vivo measure of tissue pH became available and demonstrated that in both human and animal tumors, pHi was higher (> 7.0) than pH epsilon (< 6.8), in contrast to normal tissues (e.g., liver) in which pHi (approximately 7.2) is lower than pH epsilon (approximately 7.4). This result has been confirmed in animal tumors using an MRS-visible extracellular marker, 3-aminopropyl phosphonate. The pH gradient across the tumor cell membrane is part of an interrelated system of ionic gradients and measurements made by both 31P MRS and by conventional analysis in Morris hepatoma 9618a and in livers demonstrated that the following ions also changed: compared with liver the Na+ content was 2-fold higher, K+ was 20% lower, total Ca2+ was 8-fold higher (7.4 mumol/g wet wt) and total Pi 2-fold higher (8.5 mumol/g wet wt), suggesting the presence of insoluble calcium phosphate, HCO3- was lower, total Mg2+ was similar in both tissues, but free [Mg2+] (calculated by two different methods) was approximately 5-fold lower in the hepatoma, as was [ATP]/[ADP][P(i)]. Because of an inadequate blood supply, tumors are often hypoxic with impaired Krebs cycle activity, low [ATP]/[ADP][P(i)] and rely mainly on glycolysis for energy. The rapid production and subsequent export of anionic lactate-from the tumor cell would be accompanied by H+. This would account for reversal of the proton gradient and activation of the Na+/H+ exchange. The elevated [Na+]i would decrease the Na+/Ca2+ exchange, which would in turn tend to cause the accumulation of Ca2+ (and P(i)). Such calcification is a very common feature of tumor pathology. The data indicate the change in gradient of one ion (H+) involves alterations in the linked equilibria of many ions and also of energy metabolites and offers new insights into properties of tumors important both diagnostically and therapeutically.
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PMID:Tumor metabolism: the lessons of magnetic resonance spectroscopy. 757 38

The transmembrane transduction mechanism coupled to purinergic receptors has been studied in a rat hepatoma cell line (N1S1) at the single cell level by a combination of microfluorimetric and electrophysiological techniques. ATP in the micromolar range causes release of Ca2+ from internal stores and consequent opening of Ca(2+)-activated K+ channels, leading to membrane hyperpolarization. The order of potency of the various nucleotides tested is UTP = ATP = ADP >> AMP, and ATP > beta, gamma-CH2 ATP, indicating that these receptors belong to the P2U subtype. The Ca2+ rise induced by various amounts of ATP exhibits an all-or-none behaviour already observable at 10 microM ATP. Intracellular injection of (10-20 microM) InsP3 or of its non-metabolizable analogue 3-F-InsP3 through the patch pipette, does not always result in a Ca2+ rise. These results may be interpreted assuming that the InsP3 receptors-Ca2+ release channels involved in the purinergic/pyrimidinergic stimulation are located in a subcellular compartment not easily accessible from the bulk cytosol and that a positive feedback loop occurs in this restricted space.
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PMID:Characteristics of the signal transduction system activated by ATP receptors in the hepatoma cell line N1S1-67. 785 82

Starvation of mouse hepatoma cells for essential amino acids or glucose results in the ADP-ribosylation of the molecular chaperone BiP/GRP78. Addition of the missing nutrient to the medium reverses the reaction. The signal mediating the response to environmental nutrients involves the translational efficiency. An inhibitor of proteins synthesis, cycloheximide, or reduced temperature, both of which reduce translational efficiency, stimulate the ADP-ribosylation of BiP/GRP78. Inhibition of N-linked glycosylation of proteins results in the overproduction of BiP/GRP78. The over produced protein is not ADP-ribosylated suggesting that this is the functional form of BiP/GRP78. The over produced BiP/GRP78 can, however, be ADP-ribosylated if the cells are starved for an essential amino acid. BiP/GRP78 resides in the lumen of the endoplasmic reticulum where it participates in the assembly of secretory and integral membrane proteins. ADP-ribosylation of BiP/GRP78 during starvation is probably part of a nutritional stress response which conserves limited nutrients by slowing flow through the secretory pathway.
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PMID:ADP-ribosylation of the molecular chaperone GRP78/BiP. 789 57

In heparinized human platelet-rich plasma (PRP), J-7 human hepatoma cells initially induced platelet aggregation; then a clot formed. ADP-scavenger systems, apyrase and creatine phosphate/creatine phosphokinase did not inhibit this tumor-cell-induced platelet aggregation (TCIPA), whereas hirudin and concanavalin A completely blocked it. J-7 cells also shortened the recalcification time of normal and of Factor-VIII- and IX-deficient human plasma, although it was inactive in shortening the recalcification time of Factor-VII-deficient plasma. After treatment with phorbol 12,13-dibutyrate (PDBu) for 5 to 90 min, the aggregation and coagulation abilities of J-7 cells were unaffected. Prolonged treatment of J-7 cells with PDBu but not with alpha-PDBu for 24 and 72 hr resulted in gradual loss of aggregation and coagulation. Staurosporine antagonized the effect of PDBu and restored aggregation and coagulation in J-7 cells. Protracted treatment with PDBu (24 or 72 hr) did not affect adherence of J-7 cells to the extracellular-matrix proteins (i.e., fibrinogen, fibronectin, laminin, vitronectin and collagen types I and IV) or to the surface of plastic culture dishes. The treatment also did not affect J-7 cell detachment from plastic culture dishes. These in vitro results demonstrate that protracted phorbol ester treatment diminishes TCIPA and blood coagulation of tumor cells.
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PMID:Protracted treatment with phorbol ester modulates J-7 human hepatoma-cell-induced aggregation and coagulation of human platelet-rich plasma. 796 Feb 44

1. The distribution of control of the rate of state 3 respiration of AS-30D hepatoma mitochondria was determined. 2. The ATP/ADP carrier (flux control coefficient, Ci = 0.70) and the ATP synthase (Ci = 0.19-0.32) were the only steps that exerted significant control on the phosphorylating flux supported by either glutamate+malate, pyruvate+malate, or succinate+rotenone. This is in contrast to liver mitochondria where the control is distributed between several steps. 3. It is suggested that this pattern of control of phosphorylation in hepatoma mitochondria is a consequence of a lower content of adenine nucleotides or a higher content of Mg2+.
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PMID:Control of oxidative phosphorylation in AS-30D hepatoma mitochondria. 809 69

Fractions A (salted out by ammonium sulphate between 21-30% saturation), and fractions B (salted out between 51-70% saturation) of pyruvate kinase (EC 2.7.1.40.) corresponding respectively to pyruvate kinase types L and M2 from rat liver and Morris hepatoma 7777 were purified by an affinity chromatography on Blue Sepharose CL-6B. Peaks of inactive proteins were eliminated and the enzyme fractions bound biospecifically to the gels were eluted by free ADP. The molecular mass of purified hepatoma pyruvate kinase fraction B was smaller than that of liver pyruvate kinase fraction B. Morris hepatoma pyruvate kinase fraction B represented a variant of type M2, characterised by greatest affinity to 2-phosphoenolpyruvate as a main substrate and different sensitivity to low-molecular effectors in comparison with types L from both liver and hepatoma and in comparison with type M2 from normal rat liver. Only this hepatoma fraction B showed a tumour specific sensitivity to L-cysteine and was insensitive to normal signal molecules i.e. to ATP and fructose-1,6-diphosphate which influence liver pyruvate kinase activity. L-Cysteine inhibited the tumour fraction B of pyruvate kinase by decreasing its Vmax and increasing the Km values in relation to 2-phosphoenolpyruvate.
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PMID:Comparison of pyruvate kinase variants from rat liver and Morris hepatoma 7777, obtained by an affinity chromatography on blue sepharose CL-6B. 821 64

The hepatocyte has an organic anion transport system that recognizes compounds such as bilirubin and sulfobromophthalein. These anions circulate bound tightly to albumin from which they are extracted rapidly by hepatocytes by an electroneutral process that requires extracellular inorganic anions such as Cl- for activity. Transport activity is reduced by depletion of intracellular ATP, but whether ATP interacts directly with this transporter is not known. In this study, the influence of extracellular ATP on the hepatocyte organic anion transport mechanism has been characterized. In the presence of 2.5 mM Ca2+ and 2 mM Mg2+, initial uptake of [35S]sulfobromophthalein was reduced by 50% at 1 mM ATP. In the absence of divalent cations sensitivity to ATP was 10-fold greater. Other nucleotides including UTP, CTP, GTP, ADP, AMP, and AMP-PCP (adenosine 5'-(beta,gamma-methylene)triphosphate) were inactive. Decreased transport activity was rapidly reversible, was non-competitive with respect to ATP, did not require ATP hydrolysis, and did not correlate with P2y purinergic receptor activity. Differential activity of ATP on sulfobromophthalein transport in the presence and absence of divalent cations was not due to ecto-ATPase activity but rather to alteration in [ATP4-]. Although an ATP4- receptor in macrophages mediates increased cellular permeability, reduced organic anion permeability is seen in hepatocytes. This effect is not seen in the hepatoma cell line HepG2. Modulation of activity of the organic anion transporter by extracellular ATP may have important pathophysiological consequences in conditions resulting in liver cell injury.
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PMID:Extracellular ATP4- modulates organic anion transport by rat hepatocytes. 834 Mar 70

The response of normal and transformed rat hepatocytes to oxidative stress was investigated. Isolated normal rat hepatocytes and differentiated hepatoma cells (the Fao cell line was derived from the Reuber H 35 rat hepatoma) in suspension were incubated with the ADP/Fe3+ chelate for 30 min at 37 degrees C. Membrane lipid oxidation was assessed by measuring (i) free malondialdehyde (MDA) production by a high-performance liquid chromatography (HPLC) procedure, (ii) membrane fatty acid disappearance as judged by capillary gas chromatography, and (iii) alpha-tocopherol oxidation as determined by HPLC and electrochemical detection. The addition of iron led to increased MDA production in normal as well as in transformed cells, and to simultaneous consumption of polyunsaturated fatty acids (PUFA) and alpha-tocopherol. In addition, in Fao cells more alpha-tocopherol was consumed during lipid peroxidation while less PUFA was oxidized. Lipid peroxidation was lower in tumoral hepatocytes than in normal cells. This could be due to a difference in membrane lipid composition because of a lower PUFA content and a higher alpha-tocopherol level in Fao cells. During oxidation, Fao cells produced 1.5 to 2 times less MDA than normal cells, while in the tumoral cells the amount of oxidized PUFA having 3 or more double bonds was 7 to 8 times lower. Therefore, measuring MDA alone as an index of lipid peroxidation did not allow for proper comparison of the membrane lipid oxidizability of transformed cells vs. the membrane lipid oxidizability of normal cells.
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PMID:The relationship between fatty acid peroxidation and alpha-tocopherol consumption in isolated normal and transformed hepatocytes. 844 36


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