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)

We have previously reported that from 350 amino acid (A-A) derivatives five were selected after the primary in vivo and in vitro screening tests. The five compounds which were found to possess potential antitumor activity against Ehrlich ascites carcinoma are as follows: beta-naphthalene-sulfonyl-DL-tryptophan (A-91), beta-naphthyl-aminomethyl-gamma-aminobutyric acid (A-144), N-ethylcarbaminomethyl-L-isoleucine (A-145), n-9-fluorenylactyl-L-phenylalanine (A-192), and N-propoinyl-L-valine (A-195). The effect on life prolongation and tumor growth of these selected A-A derivatives against various types of tumors, including ascites and solid tumors in mice and ascites hepatomas in rats, was examined. A-A derivatives were administered once daily 3 consecutive days starting 24 hours after tumor implantation. Experimental results showed that among the five A-A derivatives possessing considerable activity against Ehlich carcinoma, A-144 and A-145 were found to be more effective than chromomycin A and showed activity similar to that of cyclophosphamide against ascites Sarcoma 180. A-A derivatives showed slight antitumor activity against SR61 and L1210 leukemias. In rat ascites hepatoma, such as AH13, AH7974, AH60C, and Yoshida sarcoma, only A-145 showed a significant prolongation of the lifespan in the control groups. The five selected A-A derivatives significantly inhibited the growth of Nakahara-Fukuoka sarcoma and solid Sarcoma 180. These findings indicate that among the five A-A derivatives, A-15 appeared to be the most active against ascites and solid tumors.
 ...
PMID:Antitumor activity of selected amino acid derivatives against various tumor systems. 16 35

Approximately 350 amino acid derivatives were synthesized and tested for antitumor activity in four tumor systems. The effect on life prolongation and tumor growth was examined using mouse leukemia SR-61, Ehrlich ascites carcinoma, ascites sarcoma-180, and rat ascites hepatoma (AH-60C). Among these 350 derivatives, 29 compounds were found to be significantly effective in prolongation of the median life-span and inhibitory effect on tumor growth in the primary screening. Among these 29 compounds, the following five compounds were found to possess potential antitumor activity: N-(2-Naphthalene)sulfonyl-DL-tryptophan (A-91), 2-naphthylaminomethyl-gamma-aminobutyric acid (A-144), N-ethylcarbaminomethyl-L-isoleucine (A-145), N-9-fluorenylacetyl-L-phenylalanine (A-192), and N-propionyl-L-valine (A-195). These five compounds were active in prolongation of the life-span of mice bearing Ehrlich ascites carcinoma and in the inhibition of the cell growth. Some of these amino acid derivatives inhibited biosynthesis of macromolecules, DNA, RNA, and protein, in tumor cells. These results suggest that the site of action of the five amino acid derivatives appears to result from the inhibition of macromolecules and another unknown mechanism.
 ...
PMID:Antitumor activity of amino acid derivatives in the primary screening. 16 14

We have examined the mechanism of the inhibition of cholesterol synthesis in cells treated with exogenous sphingomyelinase. Treatment of rat intestinal epithelial cells (IEC-6), human skin fibroblasts (GM-43), and human hepatoma (HepG2) cells in culture with sphingomyelinase resulted in a concentration- and time-dependent inhibition of the activity of HMG-CoA reductase, a key regulatory enzyme in cholesterol biosynthesis. The following observations were obtained with IEC-6 cells. Free fatty acid synthesis or general cellular protein synthesis was unaffected by the addition of sphingomyelinase. Addition of sphingomyelinase to the in vitro reductase assay had no effect on activity, suggesting that an intact cell system is required for the action of sphingomyelinase. The products of sphingomyelin hydrolysis, e.g., ceramide and phosphocholine, had no effect on reductase activity. Sphingosine, a further product of ceramide metabolism, caused a stimulation of reductase activity. Examination of the incorporation of [3H]acetate into the nonsaponifiable lipid fractions in the presence of sphingomyelinase showed no changes in the percent distribution of radioactivity in the post-mevalonate intermediates of the cholesterol biosynthetic pathway, but there was increased radioactivity associated with the polar sterol fraction. Pretreatment of cells with ketoconazole, a known inhibitor of oxysterol formation, prevented the inhibition of reductase activity by sphingomyelinase and decreased the incorporation of [3H]acetate in the polar sterol fraction. Ketoconazole had no effect on exogenous sphingomyelinase activity in vitro in the presence or absence of cells. Endogenous sphingomyelinase activity was also unaffected by ketoconazole. Addition of inhibitors of endogenous sphingomyelinase activity, e.g., chlorpromazine, desipramine, and N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W-7), to the culture medium caused a dose-dependent stimulation of reductase activity. However, these agents had no effect on the inhibition of reductase activity by exogenous sphingomyelinase. Treatment of cells with small unilamellar vesicles of dioleyl phosphatidylcholine or high density lipoprotein3 resulted in increased efflux of cholesterol and stimulation of reductase activity. Under similar conditions, the inhibitory effect of exogenous sphingomyelinase on reductase activity was prevented by incubation with small unilamellar vesicles of phosphatidylcholine or high density lipoprotein. These results support the hypothesis that alteration of the ratio of sphingomyelin:cholesterol in the plasma membrane plays a modulatory role on the flow of membrane cholesterol to a site where it may be converted to a putative regulatory molecule, possibly an oxysterol.
 ...
PMID:Plasma membrane sphingomyelin and the regulation of HMG-CoA reductase activity and cholesterol biosynthesis in cell cultures. 201 Jun 84

Preincubation of hepatoma cells and human skin fibroblasts in the presence of the calmodulin antagonists trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide resulted in a dose-dependent suppression of [14C]mevalonolactone incorporation into cholesterol. At a calmodulin antagonist concentration of 25 mumol, the incorporation of [14C]mevalonolactone into cellular cholesterol was suppressed to about 30% (hepatoma cells) and 10% (human skin fibroblasts) of control values. When the total nonsaponifiable [14C]lipids were separated and analyzed by two-dimensional thin layer chromatography, an accumulation of [14C]desmosterol was observed along with reduced formation of [14C]cholesterol. However, when cells were preincubated in the presence of [14C]dihydrolanosterol, [14C]cholesterol formation was not inhibited by the calmodulin antagonists. About 25% of the cell-associated dihydrolanosterol radioactivity was converted to cholesterol in both control and calmodulin antagonist-pretreated cells. The data suggest that calmodulin antagonists prevent the conversion of desmosterol into cholesterol by inhibiting sterol delta 24 reductase and that the enzymes catalyzing sterol ring modifications are not affected by the inhibitors.
 ...
PMID:Calmodulin antagonists suppress cholesterol synthesis by inhibiting sterol delta 24 reductase. 303 32

PLC/PRF/5 hepatoma cells cultured with a tumor promoter teleocidin showed polygonal cellular appearance with many vacuole-like structures, and reduced both c-myc mRNA level and growth rate. These teleocidin effects were partly mimicked by sodium butyrate but not by a protein kinase C stimulant 1-oleoyl-2-acetylglycerol(OAG). Protein kinase C inhibitor 1-(5-isoquinolinyl-sulfonyl)-2-methyl-piperazine(H7), calmodulin-dependent protein kinase antagonist N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide(W7) and topoisomerase II inhibitor novobiocin failed to inhibit the effects of teleocidin. These results may suggest the presence of still unknown biochemical pathways which mediate the actions of teleocidin.
 ...
PMID:Effects of teleocidin on the morphology and c-myc expression of hepatoma cells which are not inhibited by protein kinase antagonists. 310 17

A novel pathway of polycyclic aromatic hydrocarbon (PAH) metabolism involves the oxidation of non-K-region trans-dihydrodiols by dihydrodiol dehydrogenase (DD) to yield PAH o-quinones whose cytotoxicity and genotoxicity are unknown. The cytotoxicity of several PAH o-quinones derived from this reaction [naphthalene-1,2-dione (NPQ), benzo[a]pyrene-7,8-dione (BPQ), and 7,12-dimethylbenz[a]anthracene-3,4-dione (DMBAQ)] was examined in rat (H-4IIe) and human (Hep-G2) hepatoma cells which are known to express DD. 2-Methylnaphthalene-1,4-dione (menadione), a known cytotoxic p-quinone, was used as a positive control. Hepatoma cells (1 x 10(6) cells/mL) were exposed to PAH o-quinones (1-100 microM) for 0-4 h, and cell viability and survival were measured and related to O2.- production and changes in redox potential [GSSG/GSH and NAD(P)+/NAD(P)H]. Three different modes of cytotoxicity were observed: (1) NPQ (no bay region) and DMBAQ (methylated bay region) were as cytotoxic as menadione in reducing cell survival but had less effect on cell viability. These o-quinones adversely affected GSH levels and the redox state of the cell and caused an increase in the production of O2.- in cell suspensions. This cytotoxicity was not enhanced by dicoumarol (10 microM), a DT-diaphorase inhibitor, implying that this enzyme is unable to prevent these PAH o-quinones from entering one-electron redox-cycles. (2) BPQ (bay region only) was the least cytotoxic of the PAH o-quinones studied. BPQ decreased cell viability (< 40% at 20 microM) but did not adversely affect cell survival or the redox state of the cell.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Cytotoxicity of polycyclic aromatic hydrocarbon o-quinones in rat and human hepatoma cells. 768 7

The influence of calcium-related mechanisms on cellular uptake of triiodothyronine (T3) has not yet been defined, although it is known that T3 can stimulate cellular entry of calcium. We therefore investigated the saturable uptake of [125I]-T3 (10(-11) mol/L) from serum-free medium in vitro by hepatoma (H4) cells and skeletal myoblast (L6) cells to establish the calcium-dependency of this process. We studied the effects of the following three structurally distinct types of calmodulin antagonists in H4 cells: the naphthalene sulfonamides W7, W12, and W13, calmidazolium, and trifluoperazine. Uptake of [125I]-T3 as a percentage of control values (n = 4, 10(-4) mol/L antagonist) was as follows: W7, 42.0% +/- 3.3% (P < .001); W12, 87.5% +/- 4.5% (NS); W13, 79.5% +/- 2.5% (P < .05); calmidazolium (10(-6) mol/L, n = 8), 55.1% +/- 2.2% (P < .001); and trifluoperazine (10(-5) mol/L, n = 6), 65.7% +/- 4.1% (P < .001). To investigate whether the calmodulin sensitivity of uptake was mediated via transmembrane calcium flux, we also studied the effects of three structurally distinct types of organic calcium channel blockers in both H4 and L6 cells. [125I]-T3 uptake as a percent of control values (10(-4) mol/L blocker, n = 4) was as follows: nifedipine, 8.6% +/- 0.9% (H4) and 16.7% +/- 7.2% (L6); verapamil, 24.6% +/- 3.2% (H4) and 61.9% +/- 4.2% (L6); diltiazem, 62.7% +/- 3.6% (H4) and 36.1% +/- 5.4% (L6); all P < .001. Eadie-Hofstee analysis indicated competitive inhibition of T3 uptake for both calmidazolium and nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Influence of calmodulin antagonists and calcium channel blockers on triiodothyronine uptake by rat hepatoma and myoblast cell lines. 848 58

Eight polycyclic aromatic hydrocarbon (PAH) ortho-quinones that can be generated by dihydrodiol dehydrogenase (DD) were examined for their cytotoxicity in H-4-II-e (rat hepatoma) cells and for their mutagenicity in the Ames test. Seven of the PAH otrtho-quinones were potent cytotoxins yielding IC50 values for cell survival in the range 1-30 microns. PAH ortho-quinones were grouped into three classes based on their cytotoxicity profiles: group I contained ortho-quinones (e.g., naphthalene-1,2-dione and 7,12-dimethylbenz[alpha]anthracene-3,4-dione) which reduced cell viability and cell survival; group II contained ortho-quinones (e.g., benz[alpha]anthracene-3,4-dione and 5-methylchrysene-1,2-dione which reduced cell survival but had no effect on cell viability; and group III contained ortho-quinones (e.g., benzo[alpha]pyrene-7,8-dione) which had a pronounced effect on cell viability but minimal effects on cell survival. Using hepatoma cell suspensions and rat liver subcellular fractions, it was found that ortho-quinones underwent preferential enzymatic one-electron redox-cycling and produced superoxide anion radical (O2-.) and/or ortho-semiquinone anion or alternant radicals. ortho-Quinones that reduced cell viability produced O2-. and caused the most total free radical formation, while those that reduced cell survival produced ortho-semiquinone anion or alternant radicals only. PAH ortho-quinones were also tested as direct-acting mutagens in Salmonella typhimurium tester strains TA97a, TA98, TA100, TA102 and TA104. They were found to be more mutagenic than the test mutagens used for each tester strain, and were predominantly frameshift mutagens. The presence of an activating system (Aroclor-induced rat liver S9 plus NADPH) did not increase the mutagenicity of ortho-quinones in tester strains that are sensitive to oxidative mutagens (TA102 and TA104). These data suggest that PAH ortho-quinones produced by DD are cytotoxic and mutagenic by different mechanisms. The mechanism of cytotoxicity involves the formation of reactive oxygen species and/or ortho-semiquinone anion or alternant radicals. The mechanism of mutagenicity is independent of free radical formation and is related to the ability of PAH orthooffinones to intercalate and covalently modify DNA.
 ...
PMID:Cytotoxicity and mutagenicity of polycyclic aromatic hydrocarbon ortho-quinones produced by dihydrodiol dehydrogenase. 862 May 79

A novel synthetic retinoid, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437), is a selective ligand of the RARgamma nuclear receptor. We examined the in vitro effects of CD437 and found that CD437 induces S phase arrest within 24 to 48 h, followed by cell death, in the p53-negative Hep3B and the p53-positive HepG2 human hepatoma cell lines. Based on observations of cellular and nuclear fragmentation, chromatin condensation, and DNA fragmentation, the CD437-mediated cell-killing effect appears to be due to apoptosis. On morphological examination, a number of CD437-treated cells were found to have increased 5- to 10-fold in size and persisted as single giant cells without cell division, while the remainder underwent nuclear division (multiple nuclei) but were unable to complete cytokinesis, and finally all died by apoptosis. In HepG2 cells that possessed wild-type p53, CD437-induced S phase arrest and apoptosis were accompanied by the up-regulation of cyclin A, cyclin B, p53, p21(CIP1/Waf1), Bad, and Bcl-Xs proteins and by a decrease in Bcl-2 protein levels. In Hep3B cells, CD437-mediated S phase arrest and apoptosis were also associated with a concomitant up-regulation of cyclin A, cyclin B, Bad, and Bcl-Xs. However, Hep3B cells did not express p53 or Bcl-2 messages. Olomoucine and roscovitine, the potent p34(cdc2) and CDK2 inhibitors, effectively blocked CD437-mediated cyclin A- and B-dependent kinase activation and prevented CD437-induced cell death. Furthermore, antisense oligonucleotide complementary to cyclin A and B mRNA significantly rescued CD437-induced apoptosis. These findings suggest that activation of cyclin A- and B-dependent kinases is a critical determinant of apoptotic death mediated by CD437.
 ...
PMID:Involvement of cyclin-dependent kinase activities in CD437-induced apoptosis. 1052 23

An alternative method of evaluating the toxicology of a chemical is to use cultured mammalian cells in a novel cell culture analogue reactor (CCA) together with a corresponding physiologically based pharmacokinetic model (PBPK). The PBPK is a mathematical model that divides the body into compartments representing organs, integrating the kinetic, thermodynamic, and anatomical parameters of the animal. The bioreactor is a physical replica of the PBPK; where the PBPK specifies an organ or tissue compartment, the bioreactor contains compartments with a corresponding cell type. The device is a continuous, dynamic system composed of multiple cell types that interact through a common circulating cell culture medium. The bioreactor and the model are coupled to evaluate the plausibility of the molecular mechanism that is input into the model. This concept is tested with naphthalene as a model of PAH (polycyclic aromatic hydrocarbons) toxicants. Two physically different CCA reactors were tested with naphthalene, and different results were observed. In the prototype system using cells attached to glass dilution bottles, naphthalene dosing resulted in generation of a circulating metabolite from the "liver" compartment (based on H4IIE cells from a rat hepatoma) that caused cell death in the "lung" compartment (L2 cells from a rat lung), as well as depletion of glutathione in the L2 cells. An improved CCA using packed bed reactors of microcarrier cultured cells did not show differences between naphthalene-dosed and nondosed controls. To explain the different responses of the two CCA designs, PBPKs of the two reactors were tested with variations in physical and kinetic parameters, and toxic mechanism. When the toxic metabolite of naphthalene was naphthoquinone rather than naphthalene epoxide as initially assumed, the PBPK results were consistent with the results of the two CCA designs. This result indicates that the mechanism of naphthalene toxicity in the CCAs may be mediated through naphthoquinone formation. The CCA-PBPK concept is demonstrated to be applicable to the study of toxic mechanisms. In particular, use of this approach suggests that in vitro naphthalene toxicity is mediated through the naphthoquinone metabolite.
 ...
PMID:Combining cell culture analogue reactor designs and PBPK models to probe mechanisms of naphthalene toxicity. 1083 32


1 2 3 Next >>