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)

Cellular uptake of T3 was examined using rat H4 hepatoma cells. Uptake of [125I]T3 (10(-11) M) from serum-free medium was measured as the cell-associated counts retained by washed cells (2 X 10(6) per well). Displaceable uptake was 84% of total uptake at 2 min (2.9% of total counts). T4, tetraiodothyroacetic acid, triiodothyroacetic acid, rT3, and D-T3 were 2-5% as effective as T3 in displacing uptake. Nonequilibrium kinetics indicated a half-maximal uptake at 680 nM T3 with approximately 7 million sites per cell. Displaceable uptake was time and temperature dependent and was 73% inhibited by 2 mM KCN and 52% by 10 mM bacitracin but not by 2 mM ouabain or 10 microM cytochalasin B. Phloretin, 100 microM, inhibited uptake by 66%. T3 uptake was directly related to the free T3 concentration over the range of albumin concentrations, 0-10 g/liter. The nonbile acid cholephil compounds, bromosulfophthalein, iopanoic acid, and indocyanine green (all 100 microM) inhibited T3 uptake to 62%, 17%, and 5% of control, respectively. Taurocholate, methylaminoisobutyric acid, and oleic acid were noninhibitory. The half-inhibitory concentrations of reactive nonsteroidal antiinflammatory drugs were: meclofenamic acid (25 microM), mefenamic acid (45 microM), fenclofenac (69 microM), flufenamic acid (100 microM), and diclofenac (230 microM). Aspirin, ibuprofen, oxyphenbutazone, and phenylbutazone (all 100 microM) were noninhibitory. Diphenylhydantoin inhibited uptake to 50% at 75 microM. These findings suggest that T3 uptake by cultured rat hepatocytes is by an energy-dependent, saturable, stereo-selective mechanism that is dependent on cell membrane proteins. This mechanism appears to be shared by a number of other ligands, including nonbile acid cholephils and several nonsteroidal antiinflammatory drugs of the anthranilic and phenylacetic acid classes, as well as diphenylhydantoin. The bile acid taurocholate, oleic acid, and a probe for type A amino acid uptake were inactive. The extent to which these effects may modify expression of thyroid hormone action remains to be established.
 ...
PMID:Uptake of 3,5,3'-triiodothyronine by cultured rat hepatoma cells is inhibitable by nonbile acid cholephils, diphenylhydantoin, and nonsteroidal antiinflammatory drugs. 291 9

The main adverse effects of tamoxifen, aspirin, oral contraceptives (OCs) and retinoids used as chemopreventive agents in humans are reviewed and quantified here. With regard to tamoxifen, there are suggestions of some excess risk of liver, and perhaps gastrointestinal, cancers. The public health impact of such associations, if any, is still unclear. Tamoxifen use is associated with endometrial and myometrial hyperplasia. Data from five studies based on 174 cases indicate that the overall relative risk (RR) of endometrial cancer in ever tamoxifen users is 1.73 (95% confidence interval = 1.1-2.6). However, there is a significant difference between the results of American and European studies, so the relationship between tamoxifen and endometrial cancer remains open to debate. The major side-effect of aspirin is gastrointestinal lesions; the risk of these is increased two- to tenfold, depending on the dose. Aspirin is also associated with an increased risk of haemorrhagic stroke, although its protection against other types of stroke and against myocardial infarction leads to a favourable pattern of risk for all cardiovascular conditions. Short-term side-effects of OCs include vascular diseases and a moderately increased risk of breast cancer. The RR of cervical cancer and hepatocellular carcinoma are also increased in OC users, although the public health impact of such associations is small. Toxicity associated with retinoid treatment is rarely serious as most effects observed are reversible on stopping use. Side-effects include changes in the skin and mucous membranes (dry skin, hair loss, dry nose, conjunctivitis), musculoskeletal symptoms, ophthalmological effects, changes in transaminase activity, changes in clinical chemistry markers (increase in serum triglycerides and decrease in high-density lipoproteins) and, rarely, central nervous system effects. A serious toxicological aspect of retinoid treatment is teratogenesis; its use should therefore be avoided in women with childbearing potential, and, in cases of use, conception should be delayed for a long time after stopping treatment. Thus, when considering side-effects of chemoprevention, the major issues of concern are the rare long-term effects (chiefly neoplasms), and the need for more precise overall risk-and cost-benefit assessment, particularly for healthy people.
 ...
PMID:Adverse effects of preventive therapy in humans. 892 25

High serum lipoprotein(a) (Lp(a)) is a risk factor for vascular disorders. Our preliminary observations suggest that, in some patients with coronary heart disease with high serum Lp(a) levels, administration of aspirin reduced Lp(a) levels. Therefore, we aimed to analyze the effects of aspirin on the production of apo(a), the expression of apolipoprotein(a) (apo(a)) mRNA and the transcriptional activity of apo(a) gene promoter. Aspirin (5 mM) reduced the apo(a) levels in culture medium of human hepatocytes and suppressed apo(a) mRNA expression to 73% and 85% of the controls, respectively. Aspirin also reduced the transcriptional activity of apo(a) gene transfected into HepG2 hepatoma cells in a dose-dependent manner, with a maximal effect at 5 mM (44.3 +/- 1.5% of the control). Sodium salicylate (5 mM) also reduced apo(a) gene transcription, whereas indomethacin (10 microM) had no effect. Deletion analysis of apo(a) gene promoter showed that promoter region extending from -30 to +138 is critical for the effect of aspirin. Furthermore, enhanced production, mRNA expression, and gene transcription of apo(a) by interleukin-6 were also inhibited by aspirin. These results demonstrate that aspirin reduces apo(a) production from hepatocytes via reduction of the transcriptional activity of apo(a) gene with suppression of apo(a) mRNA expression. The suppression of apo(a) production by aspirin may at least in part play a role in the anti-atherogenic effect of aspirin in vascular disorders.
 ...
PMID:Aspirin reduces apolipoprotein(a) (apo(a)) production in human hepatocytes by suppression of apo(a) gene transcription. 1056 80

Meta-analysis is increasingly used in hepatogastroenterology. Meta-analysis is of value to provide a systematic review of related trials and to display their results in an objective, easily understandable manner. When the trials are sufficiently homogeneous, meta-analysis can document the superiority, (a), or the lack of superiority (b) of a treatment with respect to another (e.g., (a) Interferon plus ribavirin vs Interferon for chronic hepatitis; (b) 5-ASA vs sulfasalazine for maintaining remission in ulcerative colitis). However the interpretation of meta-analysis requires caution. Meta-analysis can be unreliable or unstable if based on a few, small trials (e.g., Tamoxifen vs non-active treatment for hepatocellular carcinoma), or if distorted by confounding variables and publication bias (e.g., glucocorticoids vs standard treatment in alcoholic hepatitis). Eventually, qualitative heterogeneity makes the pooled results of meta-analysis meaningless or questionable (e.g., endoscopic sclerotherapy for prevention of first variceal bleeding in cirrhosis) and should prompt the search for its sources to plan future studies. Finally, meta-analysis of trials measuring the treatment effect of a drug vs a placebo when an active drug is available for comparison provides the limited informative content for the physician of the individual trials (e.g. 5-ASA vs placebo for maintaining remission in ulcerative colitis).
 ...
PMID:Meta-analysis as a source of evidence in gastroenterology: a critical approach. 1073 May 66

The liver undergoes pathogenic changes such as hepatitis, fibrosis and cirrhosis under continuous stimulation by hepatitis virus or alcohol intake, leading to the development of hepatocellular carcinoma. The metastatic potential of HCC can be positively or negatively regulated by pathogenic alterations of liver. We investigated whether the metastatic abilities of HCC after orthotopic implantation can be influenced in the fibrotic liver by continuous injection of carbon-tetrachloride (CCl4) for seven weeks. The incidence of lung metastasis after orthotopic implantation of murine HCC (CBO140C12) fragments into CCl4-treated livers was higher than into normal livers. The amount of mRNA for MMP-2 increased in the CCl4-treated livers as compared with normal livers, and CBO140C12 cells constitutively expressed mRNA for MT1-MMP in early amplification cycles by RT-PCR. In addition, we found that the culture of CBO140C12 cells on the substrates pre-coated with ECM components increased the expression of MMP-2 mRNA. Thus, enhanced incidence of lung metastasis in the fibrotic liver might be partly due to: i) over-expression of MMP-2 in the fibrotic liver in cooperation with MT1-MMP on the CBO140C12 cell surface, ii) over-expression of MMP-2 in CBO140C12 cells, possibly mediated by the interaction of tumor cells (surface integrins) with accumulated ECM in the fibrotic liver. This is the first report showing that increase of MMP-2 in the fibrotic liver can influence the metastatic potential of HCC cells.
 ...
PMID:Accumulation of extracellular matrix in the liver induces high metastatic potential of hepatocellular carcinoma to the lung. 1140 24

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity and are considered to exert antitumor actions in a variety of cancer cells, although the effects are unlikely entirely due to COX inhibition. Because clinical observations suggest that hepatocyte growth factor (HGF) can promote metastasis of hepatoma cells while stimulating tumor invasiveness, we investigated the effect of aspirin and NS-398, a selective COX-2 inhibitor, on HGF-mediated invasiveness of HepG2 human hepatoma cells. HGF stimulated the invasiveness of HepG2 cells in Matrigel cell invasion assay, together with increased expression of matrix metalloproteinase (MMP) 9. Addition of aspirin or NS-398, similar to PD98059, which acts as a specific inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK), an upstream kinase regulating extracellular signal-regulated kinase (ERK)1/2, abrogated such actions of HGF without affecting cell viability. Aspirin and NS-398, in contrast to PD98059, did not suppress ERK1/2 phosphorylation induced by HGF. However, both agents inhibited the kinase activity of ERK1/2 induced by HGF and repressed HGF-induced phosphorylation of 90-kd ribosomal S6 kinase (RSK) and Elk-1, key downstream substrates of ERK1/2, resulting in the suppression of transcriptional activity of Elk-1 as well as nuclear factor kappaB (NF-kappaB) and AP-1, which are involved in MMP-9 gene regulation. In conclusion, our results suggest that aspirin and NS-398 inhibit HGF-induced invasiveness of HepG2 human hepatoma cells through ERK1/2.
 ...
PMID:Aspirin and NS-398 inhibit hepatocyte growth factor-induced invasiveness of human hepatoma cells. 1198 61

Two isoforms of cyclooxygenase (COX) participate in growth control; COX-1 is constitutively expressed in most cells, and COX-2 is an inducible enzyme in response to cellular stimuli. An induction of COX-2 found in neoplastic tissues results in increased cell growth, inhibition of apoptosis, activation of angiogenesis, and decreased immune responsiveness. Although both COX-1 and COX-2 inhibitors are suppressors of cell proliferation and appear to be chemopreventive agents for tumorigenesis, the molecular mechanisms mediating antiproliferative effect of COX inhibitors are still not well defined. This study contrasts and compares the effects of aspirin and celecoxib, inhibitors of COX-1 and COX-2, in rat hepatoma HTC-IR cells. The following were assessed: cell proliferation and apoptosis, ornithine decarboxylase (ODC) activity, and pattern expression of three immediate-early genes, c-myc, Egr-1, and c-fos. We have shown that the treatment of hepatocytes in vitro with the selective COX-2 inhibitor, celecoxib, was associated with induction of apoptosis and complete inhibition of cellular proliferation. Aspirin exhibited a small antiproliferative effect that was not associated with apoptosis. Treatment with celecoxib produced dose- and time-dependent decrease in ODC activity. In addition, at higher drug concentration the decrease in ODC activity was greater in proliferating than in resting cells. Much lesser inhibitory effect on ODC activity was observed in aspirin-treated cells. The two COX inhibitors did not change c-myc expression, significantly decreased the expression of Egr-1, and differentially altered expression of c-fos; aspirin did not change, but celecoxib dramatically decreased the levels of c-fos-mRNA. Our study revealed that celecoxib and aspirin share the ability to inhibit ODC activity and alter the pattern of immediate-early gene expression. It seems that some of the observed effects are likely to be related to COX-independent pathways. The precise mechanisms of action of COX inhibitors should be defined before using these drugs for cancer chemopreventive therapy.
 ...
PMID:Do altering in ornithine decarboxylase activity and gene expression contribute to antiproliferative properties of COX inhibitors? 1267 17

Here we studied whether aspirin (ASA) has any influence on viability of human hepatoma-derived SKHep-1 cells and whether hydrogen peroxide (H(2)O(2)) has any relation with this effect. ASA inhibited SKHep-1 cell proliferation dose- and time-dependently. Intracellular H(2)O(2) increased as early as 15 min after ASA supplementation. Cellular apoptosis correlated with an increase in intracellular H(2)O(2) level. Moreover, in the presence of a catalase inhibitor-aminotriazol, ASA showed more apoptotic effect on SKHep-1 cells with increasing intracellular H(2)O(2) level. In conclusion, the present results shows that ASA induced SKHep-1 cell apoptosis has a relation with an early increase in intracellular H(2)O(2) level and catalase inhibitor synergizes to induce this process.
 ...
PMID:Aspirin induces hepatoma-derived cell apoptosis via a hydrogen peroxide-dependent pathway. 1278 4

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental contaminant, that has been linked with a variety of deleterious effects on human health, including increased cancer rates and reproductive anomalies. The detrimental effects of TCDD are mediated via the aryl hydrocarbon receptor (AhR), a transcription factor that regulates the expression of the carcinogen-activating enzymes cytochromes P-450 (CYP) 1A1, 1A2, and 1B1. In the present study, we examined the ability of synthetic derivatives of salicylic acid to affect TCDD-stimulated AhR-mediated signal transduction in human hepatoma HepG2 cells. Salicylamide (SAL), an analgesic drug, caused a potent and long-lasting inhibition of TCDD-induced CYP enzyme activity. Acetylsalicylic acid (aspirin) and the naturally occurring phytochemical salicylic acid had no effect on CYP activity. SAL inhibited the increase in CYP1A1, -1A2, and -1B1 mRNA levels that occurs on exposure to TCDD. TCDD-induced transcription of these genes was also inhibited by SAL, but not by aspirin or salicylic acid, as demonstrated by luciferase reporter assays. The transcription of the CYP1 family of genes is regulated by the interaction of TCDD-activated AhR with the xenobiotic-responsive element present in the promoter regions of these genes. As shown by electrophoretic mobility shift assay, SAL completely blocked the binding of TCDD-activated AhR to the xenobiotic responsive element. Also, SAL substantially blocked the binding of TCDD to the cytosolic AhR. These results demonstrate that SAL, a commonly used analgesic, is a potent inhibitor of AhR-mediated signal transduction, and may be an effective agent in the prevention of TCDD-associated disease.
 ...
PMID:The drug salicylamide is an antagonist of the aryl hydrocarbon receptor that inhibits signal transduction induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin. 1472 55

Although the overview above provides a partial molecular picture of the early stages of stepwise hepatocarcinogenesis. it should be emphasized that tumor and nontumor liver contain multiple changes, and that there is variability in their profile among different patients even within single studies. Variability in the number and types of genetic changes has also been observed geographically, and may be dependent upon the etiology of the tumor (viral, chemical or both). Interestingly, HBxAg inactivates tumor suppressors (such as p53 [by direct binding] and Rb [by stimulating its phosphorylation]) early in carcinogenesis that are mutated later during tumor progression. HBxAg also constitutively activates signal transduction pathways, such as those involving c-jun and ras, and activates oncogenes,such as c-nloc, that are otherwise activated by 3-catenin mutations. These findings suggest common molecular targets in hepatocarcinogenesis, despite different mechanisms of activation or inactivation. These observations need to be exploited in future drug discovery and in the development of new therapeutics. Heterogeneity in the mechanisms of tumor development, evidenced by the differences in the up- and down regulated genes reported in micro array analyses, as well as in the genetic loci that undergo mutation or LOH indifferent reports, has now been well documented. This suggests that there are multiple pathways to HCC, and that there is redundancy in the pathways that regulate cell growth and survival. These findings also reflect that,although hepatocarcinogenesis is multistep, the molecular changes that underpin histopathological changes in tumor development are likely to be different or only partially overlapping in individual tumors. Overall, the consequences of these changes suggest that the pathogenesis of HCC is accompanied by a progressive loss of differentiation, loss of normal cell adhesion, loss of the ECM, and constitutive activation of selected signal transduction pathways that promote cell growth and survival. Although mechanisms are important, attention also has to be paid to the target genes whose altered expression actually mediate the neoplastic phenotype. Other key avenues of work need to be explored. For example, it will be important to try to identify germline mutations in HBV-infected patients that are passed on to their children, resulting in the development of HCC in childhood. Clinical materials will also be important for the validation of new markers with diagnostic or prognostic potential. In this context, there is an urgent need to establish simple and low-cost tests based upon molecular changes that are hallmarks of HCC development. Identification of patients with early HCC will also significantly increase survival through its impact upon treatment. The discovery and validation of HCC markers may permit accurate staging of lesions, determine the proximity of such lesions to malignancy, and determine whether lesions with a particular genetic profile are still capable of remodeling through appropriate therapeutic intervention. The efficient reintroduction of the relevant tumor suppressors, or the inhibition of oncogene expression by siRNA, provide just some of the additional opportunities that will ultimately be useful in patient treatment. Together, these approaches will go far in reducing the very high morbidity and mortality associated with HCC.
 ...
PMID:Early molecular and genetic determinants of primary liver malignancy. 1506 49


1 2 3 4 5 6 7 8 Next >>