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)

Resveratrol, a natural polyphenolic phytoalexin, has been considered as a potential anti-inflammatory agent because of its suppressive effect on nuclear factor-kappaB (NF-kappaB). However, we recently found that treatment of glomerular mesangial cells with resveratrol significantly and dose-dependently enhanced NF-kappaB activation triggered by proinflammatory cytokines. This finding was evidenced by different reporter assays as well as by expression of an endogenous NF-kappaB-dependent gene, intercellular adhesion molecule-1. The NF-kappaB promoting effect of resveratrol was also observed in renal tubular LLCPK1 cells, but not in HepG2 hepatoma cells. In all cell types tested, treatment with resveratrol alone did not affect NF-kappaB activity. The enhanced activation of NF-kappaB by resveratrol progressed for at least 24 h and was accompanied by sustained down-regulation of an endogenous NF-kappaB inhibitor, IkappaBbeta, but not IkappaBalpha. Although expression of inducible nitric oxide synthase was suppressed by resveratrol, nitric oxide, a negative regulator of NF-kappaB, was not involved in the regulation of NF-kappaB by resveratrol. These data elucidated, for the first time, that resveratrol may enhance activation of NF-kappaB under certain circumstances.
 ...
PMID:Enhancement of NF-kappaB activity by resveratrol in cytokine-exposed mesangial cells. 1617 59

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer related mortality worldwide. The incidence of HCC is rising worldwide, especially in the United States. The overall survival of patients with HCC is grim and currently no efficient secondary prevention or systemic treatments are available. Recent evidence suggests that COX-2 signaling is implicated in hepatocarcinogenesis and COX-2 inhibitors prevent HCC cell growth in vitro and in animal models. However, given the recently reported side effect associated with some of the COX-2 inhibitors, it is imperative to develop chemotherapeutic strategy that simultaneously targets COX-2 and other related key molecules in hepatocarcinogenesis or to utilize agents inhibiting COX-2 signaling in conjunction with other standard chemotherapy or radiation therapy. Such combinational therapeutic approaches are expected to provide synergistic anti-tumor effect with lesser side effect. In this regard, the recently delineated interplay between COX-2-derived PG signaling and other growth-regulatory pathways such as EGFR, Met, iNOS, VEGF and n-3 polyunsaturated fatty acids is expected to provide important therapeutic implications. This review summarizes the recent advances in understanding the mechanisms for COX-2-derived PG signaling in hepatocarcinogenesis and focuses on the newly unveiled interactions between PG cascade and other key signaling pathways that coordinately regulate HCC growth. Understanding these mechanisms and interplays will facilitate the development of more effective chemopreventive and therapeutic strategies.
 ...
PMID:Cyclooxygenase-2 in hepatocellular carcinoma. 1633 44

Stimulation of freshly isolated rat hepatocytes with lysophosphatidic acid (LPA) resulted in LPA1 receptor-mediated and nitricoxide-dependent up-regulation of the immediate early genes iNOS (inducible nitric-oxide synthase (NOS)) and mPGES-1 (microsomal prostaglandin E synthase-1). Because LPA is a ligand for both cell surface and intracellular receptor sites and a potent endothelial NOS (eNOS) activator, we hypothesized that NO derived from activated nuclearized eNOS might participate in gene regulation. Herein we show, by confocal microscopy performed on porcine cerebral endothelial cells expressing native LPA1-receptor and eNOS and on HTC4 rat hepatoma cells co-transfected with recombinant human LPA1-receptor and fused eNOS-GFP cDNA, a dynamic eNOS translocation from peripheral to nuclear regions upon stimulation with LPA. Nuclear localization of eNOS and its downstream effector, soluble guanylate cyclase, were demonstrated in situ in rat liver specimens by immunogold labeling using specific antibodies. Stimulation of this nuclear fraction with LPA and the NO donor sodium nitroprusside resulted, respectively, in increased production of nitrite (and eNOS phosphorylation) and cGMP; these separate responses were also correspondingly blocked by NOS inhibitor L-NAME and soluble guanylate cyclase inhibitor ODQ. In addition, sodium nitroprusside evoked a sequential increase in nuclear Ca2+ transients, activation of p42 MAPK, NF-kappaB binding to DNA consensus sequence, and dependent iNOS RNA. This study describes a hitherto unrecognized molecular mechanism by which nuclear eNOS through ensuing NO modulates nuclear calcium homeostasis involved in gene transcription-associated events. Moreover, our findings strongly support the concept of the nucleus as an autonomous signaling compartment.
 ...
PMID:Nitric oxide signaling via nuclearized endothelial nitric-oxide synthase modulates expression of the immediate early genes iNOS and mPGES-1. 1657 49

Infection and chronic inflammation are proposed to contribute to carcinogenesis through inflammation-related mechanisms. Infection with hepatitis C virus, Helicobacter pylori and the liver fluke, Opisthorchis viverrini (OV), are important risk factors for hepatocellular carcinoma (HCC), gastric cancer and cholangiocarcinoma, respectively. Inflammatory bowel diseases (IBDs) and oral diseases, such as oral lichen planus (OLP) and leukoplakia, are associated with colon carcinogenesis and oral squamous cell carcinoma (OSCC), respectively. We performed a double immunofluorescence labeling study and found that nitrative and oxidative DNA lesion products, 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), were formed and inducible nitric oxide synthase (iNOS) was expressed in epithelial cells and inflammatory cells at the site of carcinogenesis in humans and animal models. Antibacterial, antiviral and antiparasitic drugs dramatically diminished the formation of these DNA lesion markers and iNOS expression. These results suggest that oxidative and nitrative DNA damage occurs at the sites of carcinogenesis, regardless of etiology. Therefore, it is considered that excessive amounts of reactive nitrogen species produced via iNOS during chronic inflammation may play a key role in carcinogenesis by causing DNA damage. On the basis of our results, we propose that 8-nitroguanine is a promising biomarker to evaluate the potential risk of inflammation-mediated carcinogenesis.
 ...
PMID:Oxidative and nitrative DNA damage in animals and patients with inflammatory diseases in relation to inflammation-related carcinogenesis. 1660 33

A variety of sulfone derivatives including three dimethyl arylsulfonyl malonates (1-3), two bis-(arylethenesulfonyl)-vinyl benzenes (4 and 5) and a sulfone triazole (6) were evaluated for their anti-inflammatory as well as tumor cells growth inhibitory activities in vitro. The sulfone derivatives 1, 2, 3 and 6 significantly and dose-dependently inhibited the production of inflammatory mediators such as nitric oxide (NO), and cytokines (tumor necrosis factor (TNF)-alpha and interleukin (IL)-12), in lipopolysaccharide (LPS) and interferon (IFN)-gamma activated murine peritoneal macrophages, without displaying cytotoxicity. The inhibitory mechanism is found through reducing iNOS protein expression. In addition, the derivatives 1-3 significantly arrest mitogen-stimulated spleen cells in G0/G1 stage, whereas compounds 4-6 blocked the same in the G2/M phase. Furthermore, the sulfone derivatives 3 and 6 showed dramatically reduction in the ratio of IFN-gamma to IL-4 production from mitogen-stimulated spleen cells. On the other hand, the novel compounds exhibited interesting cytotoxic activities against a panel of cell lines, particularly, 20 muM of compound 3 showed 50% cytotoxic effect on human hepatoma cell line, but has no effect on normal human peripheral blood mononuclear cells. In conclusion, compound 3 showed interesting anti-inflammatory and tumor cells growth inhibitory functions.
 ...
PMID:Biological evaluation of sulfone derivatives as anti-inflammatory and tumor cells growth inhibitory agents. 1697 24

The stilbene resveratrol exerts antiproliferative and proapoptotic actions on a number of different cancer cell lines, through diverse mechanisms, including antioxidant effects, enzyme, growth factor and hormone receptor binding, and nucleic acid direct or indirect interactions. Although resveratrol accumulates in the liver, its effect on hepatocellular carcinoma has not been extensively studied. We have used the human hepatocyte-derived cancer cell line HepG2 to address the possible action of resveratrol on cell growth and to examine some possible mechanisms of action. Our results indicate that the stilbene inhibits potently cell proliferation, reduces the production of reactive oxygen species and induces apoptosis, through cell cycle arrest in G1 and G2/M phases. Furthermore it modulates the NO/NOS system, by increasing iNOS and eNOS expression, NOS activity and NO production. Inhibition of NOS enzymes attenuates its antiproliferative effect. These data could be of value in possible prevention or adjuvant treatment of hepatocellular carcinoma, through an increased consumption of resveratrol-rich foods and beverages.
 ...
PMID:Resveratrol exerts its antiproliferative effect on HepG2 hepatocellular carcinoma cells, by inducing cell cycle arrest, and NOS activation. 1705 55

Response to interferon-gamma (IFN-gamma)-induced apoptosis of human hepatoma cell lines (HHCLs) is variable. We analyzed this different behavior in Hep3B, Chang-liver, HepG2, and HuH7 cells. We studied (1) IFN-gamma-induced apoptosis, (2) protein expression of Stat1, (3) binding of nuclear proteins to IFN-gamma activated sequence (GAS), (4) mRNA and expression of proteins acting in apoptosis, and (5) HuH7 sensitivity after inducible nitric oxide synthase (iNOS) siRNA transfection. IFN-gamma induced apoptosis in Hep3B and Chang-liver cells only. In all HHCLs, Stat1 protein increased. Binding of proteins and transactivation activity of GAS increased much more in HuH7. In all HHCLs, caspase activity and apoptotic proteins were not implicated in resistance or sensitivity. iNOS mRNA and protein expression increased in HuH7, disappeared in Hep3B, and remained unchanged in Chang-liver and HepG2. We compared the role of iNOS in Hep3B and HuH7. The iNOS inhibitor, L-NAME, sensitized HuH7 to IFN-gamma, Hep3B/HuH7 coculture partially inhibited Hep3B apoptosis, and HuH7 transfection with iNOS siRNA induced a 50% inhibition of iNOS protein and cell apoptosis. GAS activity and overexpression of iNOS in HuH7, but not in the other HHCLs, suggest that this enzyme could play an important role in the resistance of HuH7 to IFN-gamma-induced apoptosis, perhaps by the antiapoptotic action of NO.
 ...
PMID:Inducible nitric oxide synthase (iNOS) activity could be responsible for resistance or sensitivity to IFN-gamma-induced apoptosis in several human hepatoma cell lines. 1723 33

We previously demonstrated that tumor necrosis factor alpha (TNF-alpha) and lipopolysaccharide (LPS) downregulate aryl hydrocarbon receptor (AhR)-regulated genes, such as cytochrome P450 1a1 (Cyp1a1) and NADPH: quinone oxidoreductase 1 (Nqo1) gene expression, yet the mechanisms involved remain unknown. The correlation between the inflammation-mediated suppression of AhR-regulated genes and the TNF-alpha or LPS-induced nitric oxide (NO) production especially in murine hepatoma Hepa 1c1c7 cells has been questioned; therefore we investigated whether NO is involved in the modulation of Cyp1a1 and Nqo1 by TNF-alpha or LPS in Hepa 1c1c7 cells. A significant dose-dependent increase in the inducible nitric oxide synthase (NOS2) expression and NO production were observed by various concentrations of TNF-alpha (1, 5, and 10 ng/mL) and LPS (1 and 5 microg/mL) which was completely inhibited by a NOS2 inhibitor, L-N6-(1-iminoethyl) lysine (L-NIL) (1 mM). Furthermore, TNF-alpha and LPS significantly induced NOS2 expression. Both TNF-alpha and LPS repressed the beta-naphthoflavone (betaNF)-mediated induction of Cyp1a1 and Nqo1 at mRNA and activity levels. The downregulation of Cyp1a1, but not Nqo1, was significantly prevented by L-NIL. However, proxynitrite decomposer, iron tetrakis (N-methyl-4'-pyridyl) porphyrinato (FeTMPyP) (5 microM) did not affect TNF-alpha- and LPS-mediated downregulation of Cyp1a1 and Nqo1 at mRNA and activity levels. These results show that NO, but not peroxynitrite, may be involved in TNF-alpha- and LPS-mediated downregulation of Cyp1a1 without affecting the downregulation of Nqo1.
 ...
PMID:Role of nitric oxide in downregulation of cytochrome P450 1a1 and NADPH: Quinone oxidoreductase 1 by tumor necrosis factor-alpha and lipopolysaccharide. 1758 58

This study was carried out to investigate the apoptotic effects of glycine- and proline-rich glycoprotein [Solanum nigrum Linne (SNL) glycoprotein, 150-kDa] isolated from SNL, which has been used as an antipyretic and anticancer agent in Korean herbal medicine. We found that SNL glycoprotein has obviously cytotoxic and apoptotic effects at 80 microg/ml of SNL glycoprotein for 4 h in Hep3B cells (hepatocellular carcinoma cells). In mitochondria-mediated apoptosis pathway, SNL glycoprotein has abilities to stimulate release of mitochondrial cytochrome c, activations of caspase-9 and caspase-3, cleavage of poly(ADP-ribose)polymerase and production of intracellular reactive oxygen species in Hep3B cells. In nuclear factor-kappa B (NF-kappaB)-mediated apoptosis pathway, the results showed that SNL glycoprotein dose-dependently blocked DNA binding activity of NF-kappaB, activity of inducible nitric oxide synthase (iNOS) and production of inducible nitric oxide (NO). Interestingly, pyrrolidine dithiocarbamate (for NF-kappaB inhibitor) and Nomega-nitro-l-arginine methylester hydrochloride (for NO inhibitor) effectively stimulated the caspase-3 activation and induced apoptosis in Hep3B cells. These results indicate that SNL glycoprotein transfers its cell death signal from cytochrome c to caspase 3 by inhibiting NF-kappaB and iNOS activation in Hep3B cells. Here, we speculate that SNL glycoprotein is one of the chemotherapeutic agents to modulate mitochondria-mediated apoptosis signals in Hep3B cells.
 ...
PMID:Cell death signal by glycine- and proline-rich plant glycoprotein is transferred from cytochrome c and nuclear factor kappa B to caspase 3 in Hep3B cells. 1758 35

Genomic instability during hepatocarcinogenesis causes changes in signal transduction network. Strategies for identification of new markers/therapeutic targets include discovery of early molecular changes during hepatocarcinogenesis, relevant to preneoplastic lesions progression to full malignancy in rodent models, and evaluation of these changes in human hepatocellular carcinomas (HCCs). Activation of ERB receptor family, MAPK, JAK-STAT, beta-Catenin cascades, c-Myc targets, iNOS-IKK/MAT1A-NF-kB axis, Ornithine decarboxylase, Cyclins and CDKs occurs in human and rodent hepatocarcinogenesis. This is associated with downregulation of the cell cycle inhibitors p16(INK4A) and p53 and TGF-beta/SMAD signaling. Oncosuppressor genes, including p16(INK4A), E-CAD, and DLC-1 are often hypermethylated in humans and rodents. Moreover, protection of cell cycle from p16(INK4A) inhibition by upregulation of CDC37, HSP90, and CRM1 correlates to HCC progression. A body of evidence indicates that inhibition of key genes of aforementioned signaling pathways by antisense or siRNA approaches or specific inhibitors restraints growth of in vitro cultured or in vivo xenografted HCCs. Efforts are currently dedicated to improve transduction efficiency. HCC cells may escape gene therapy by various mechanisms. Attempts to overcome this difficulty include discovery of new therapeutic targets, gene therapy directed to different molecular targets essential for tumor cell survival and specifically directed to HCC subtypes.
 ...
PMID:Dissection of signal transduction pathways as a tool for the development of targeted therapies of hepatocellular carcinoma. 1847 8


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>