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 reduces proliferation in many different cancer cell lines. However, studies on the oncostatic effects of melatonin in the treatment of hepatocarcinoma are limited. In this study, we examined the effect of melatonin administration on HepG2 human hepatocarcinoma cells, analyzing cell cycle arrest, apoptosis and mitogen-activated protein kinase (MAPK) signalling pathways. Melatonin was dissolved in the cell culture media in 0.2% dimethyl sulfoxide and administered at different concentrations for 2, 4, 6, 8 and 10 days. Melatonin at concentrations 1000-10,000 microM caused a dose- and time-dependent reduction in cell number. Furthermore, melatonin treatment induced apoptosis with increased caspase-3 activity and poly(ADP-ribose) polymerase proteolysis. Proapoptotic effects of melatonin were related to cytosolic cytochrome c release, upregulation of Bax and induction of caspase-9 activity. Melatonin treatment also resulted in increased caspase-8 activity, although no significant change was observed in Fas-L expression. In addition, JNK 1,-2 and -3 and p38, members of the MAPK family, were upregulated by melatonin treatment. Growth inhibition by melatonin altered the percentage or cells in G0-G1 and G2/M phases indicating cell cycle arrest in the G2/M phase. The reduced cell proliferation and alterations of cell cycle were coincident with a significant increase in the expression of p53 and p21 proteins. These novel findings show that melatonin, by inducing cell death and cell cycle arrest, might be useful as adjuvant in hepatocarcinoma therapy.
 ...
PMID:Melatonin induces cell cycle arrest and apoptosis in hepatocarcinoma HepG2 cell line. 1901 62

Astragalus membranaceus has been used to ameliorate the side effects of anti-neoplastic drugs. We recently reported that total Astragalus saponins (AST) possess anti-tumor properties in human colon cancer cells and tumor xenografts. Nevertheless, the precise mechanism of action has not been fully elucidated. The present study aimed to unveil the anti-carcinogenic potential of AST in HepG2 human hepatocellular carcinoma (HCC) cells and to clarify the signaling pathway. We demonstrated here that AST downregulated expression of the HCC tumor marker alpha-fetoprotein and suppressed HepG2 cell growth by inducing apoptosis. AST also caused caspase activation, poly(ADP-ribose) polymerase (PARP) cleavage, nuclear chromatin condensation, with downregulation of the anti-apoptotic proteins bcl-2 and bcl-xL and decreased nuclear factor-kappa B (NF-kappaB)/DNA-binding activity. Concomitantly, expression of the phosphorylated form of the extracellular signal-regulated protein kinase (ERK) was prominently increased. Nevertheless, pretreatment of ERK inhibitor PD98059 did not attenuate AST-induced PARP cleavage. Taken together, these results exemplify that AST induced growth inhibition and promoted apoptosis in HepG2 cells through modulation of an ERK-independent NF-kappaB signaling pathway.
 ...
PMID:Astragalus saponins induce apoptosis via an ERK-independent NF-kappaB signaling pathway in the human hepatocellular HepG2 cell line. 1914 42

The cytotoxic effect of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is limited in some carcinoma cancer cells. However, it was found that treatment with TRAIL in combination with nontoxic concentrations of genistein sensitized TRAIL-resistant human hepatocellular carcinoma Hep3B cells to TRAIL-mediated apoptosis. Combined treatment with genistein and TRAIL-induced chromatin condensation and sub-G1 phase DNA content. These indicators of apoptosis were correlated with the induction of caspase activity that resulted in the cleavage of poly(ADP-ribose) polymerase (PARP). Both cell viability and the cleavage of PARP induced by combined treatment were significantly inhibited by caspase-3, -8 and -9 inhibitors, which demonstrates the important roles of caspases in the observed cytotoxic effects. Genistein treatment also triggered the inhibition of p38-beta mitogen-activated protein kinase (MAPK) activation. Pretreatment with SB203580 resulted in significantly increased sub-G1 population and loss of mitochondrial membrane potential (MMP) in TRAIL-induced apoptosis. By contrast, overexpression of p38 MAPK protected apoptosis by co-treatment with genistein and TRAIL, suggesting that the p38 MAPK act as key regulators of apoptosis in response to treatment with a combination of genistein and TRAIL in human hepatocellular carcinoma Hep3B cells.
 ...
PMID:Genistein enhances TRAIL-induced apoptosis through inhibition of p38 MAPK signaling in human hepatocellular carcinoma Hep3B cells. 1949 11

In the present study, the effect of an extract of immature Prunus salicina Lindl. cv. Soldam fruit on the viability and induction of apoptosis in human hepatocellular carcinoma HepG2 cells was investigated. The results showed that in comparison with other cancer cells, the growth inhibition exerted by immature plum extracts was greatest in HepG2. Apoptosis in HepG2 cells mediated by immature plums was associated with "death receptor signaling." Immature plum extracts significantly increased the activation of caspase-8, -10, and -3 and expression of the caspase-3 target proteins alpha-fodrin (induces membrane blebbing and cell shrinkage), poly(ADP-ribose) polymerase (a nuclear enzyme that is involved in DNA repair following DNA nicks), and DNA fragmentation factor (induces apoptotic DNA fragmentation). The total yield of identified polyphenols in immature plum extract was 10 g/kg dry weight. The major components, (-)-epicatechin and (-)-gallocatechin gallate, were 34.7% and 28.6% of total polyphenols, respectively. (+)-Catechin, (-)-epicatechin gallate, and (-)-catechin gallate were also found. On the basis of these results, the immature plum (P. salicina Lindl. cv. Soldam) and its active compound, (-)-epicatechin, are expected to be a natural resource for developing novel therapeutic agents for cancer prevention and treatment.
 ...
PMID:Induction of apoptosis by immature plum in human hepatocellular carcinoma. 1962 99

Posttranslational modifications play a key role in recruiting chromatin remodeling and modifying enzymes to specific regions of chromosomes to modulate chromatin structure. Alc1 (amplified in liver cancer 1), a member of the SNF2 ATPase superfamily with a carboxy-terminal macrodomain, is encoded by an oncogene implicated in the pathogenesis of hepatocellular carcinoma. Here we show that Alc1 interacts transiently with chromatin-associated proteins, including histones and the poly(ADP-ribose) polymerase Parp1. Alc1 ATPase and chromatin remodeling activities are strongly activated by Parp1 and its substrate NAD and require an intact macrodomain capable of binding poly(ADP-ribose). Alc1 is rapidly recruited to nucleosomes in vitro and to chromatin in cells when Parp1 catalyzes PAR synthesis. We propose that poly(ADP-ribosyl)ation of chromatin-associated Parp1 serves as a mechanism for targeting a SNF2 family remodeler to chromatin.
 ...
PMID:Poly(ADP-ribosyl)ation directs recruitment and activation of an ATP-dependent chromatin remodeler. 1966 85

Hepatoblastoma (HB) represents the most common malignant liver tumor in children with a dismal prognosis for patients with advanced disease. This study provides evidence that the naturally occurring pentacyclic triterpenoid betulinic acid (BA) is highly effective against HB. We demonstrate that BA has a strong cytotoxic effect on HB cells in a dose-dependent manner by impinging on cell viability and causing massive induction of programmed cell death. Apoptotic features including morphological changes, membrane asymmetry and proteolytic cleavage of caspase 3 and poly(ADP-ribose) polymerase were frequently found in BA-treated HB cells, which is suggestive of the mitochondrial intrinsic apoptotic pathway. In contrast, the hepatocellular carcinoma (HCC) cell line HepG2 was resistant to BA treatment. This insensitivity was dependent on the high expression of survival factors, such as Survivin and BCL2. Interestingly, BA treatment led to a significant decrease in expression of the hedgehog target genes GLI1, PTCH1 and IGF2 in HepT3 cells. In conclusion, we demonstrate that BA is capable of inducing apoptosis in HB cells and thereby might be a hopeful new strategy for treating HB, especially those with an activated hedgehog signaling pathway.
 ...
PMID:Betulinic acid treatment promotes apoptosis in hepatoblastoma cells. 1972 25

Millettia reticulata Benth is cultivated in Asian countries. M. reticulata Benth has multiple biological functions and is one of the oldest tonic herbs in traditional Chinese medicine. It has been elevated to one of the most commonly used herbs in modern Chinese medicine. The aims of this work were to study the in vitro anticancer activity of flavonoid derivatives isolated from the stems of M. reticulata Benth. Six flavonoid derivatives including (-)-epicatechin (1), naringenin (2), 5,7,3',5'-tetrahydroxyflavanone (3), formononetin (4), isoliquiritigenin (5), and genistein (6) were isolated from the stems of M. reticulata Benth. The structures of 1-6 were determined by spectroscopic methods. The effects of flavonoid derivatives (1-6) on the viability of human cancer cells (including HepG2, SK-Hep-1, Huh7, PLC5, COLO 205, HT-29, and SW 872 cells) were investigated. The results indicated that genistein (6) had the strongest inhibitory activity with an IC(50) value of 16.23 microM in SK-Hep-1 human hepatocellular carcinoma cells. Treatment of SK-Hep-1 cells with genistein (6) caused loss of mitochondrial membrane potential. Western blot data revealed that genistein (6) stimulated an increase in the protein expression of Fas, FasL, and p53. Additionally, treatment with genistein (6) changed the ratio of expression levels of pro- and anti-apoptotic Bcl-2 family members and subsequently induced the activation of caspase-9 and caspase-3, which was followed by cleavage of poly(ADP-ribose) polymerase (PARP). These results demonstrate that genistein (6) induces apoptosis in SK-Hep-1 cells via both Fas- and mitochondria-mediated pathways.
 ...
PMID:Anticancer effects of flavonoid derivatives isolated from Millettia reticulata Benth in SK-Hep-1 human hepatocellular carcinoma cells. 1999 90

CHM-1 (2'-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone) has been identified as a potent antitumor agent in human hepatocellular carcinoma; however, its role in tumor angiogenesis is unclear. This study investigated the effects of CHM-1 and the mechanisms by which it exerts its antiangiogenic and vascular disrupting properties. Using a xenograft model antitumor assay, we found that CHM-1 significantly inhibits tumor growth and microvessel formation. Flow cytometry, immunofluorescence microscopy, and cell death enzyme-linked immunosorbent assay kit revealed that CHM-1 inhibits growth of human umbilical vein endothelial cells (HUVEC) by induction of apoptotic cell death in a concentration-dependent manner. CHM-1 also suppresses HUVEC migration and capillary-like tube formation. We were able to correlate CHM-1-induced apoptosis in HUVEC with the cleavage of procaspase-3, -7, and -8, as well as with the cleavage of poly(ADP-ribose) polymerase by Western blotting assay. Such sensitization was achieved through up-regulation of death receptor 5 (DR5) but not DR4 or Fas. CHM-1 was also capable of increasing the expression level of p53, and most importantly, the induction of DR5 by CHM-1 was abolished by p53 small interfering RNA. Taken together, the results of this study indicate that CHM-1 exhibits vascular targeting activity associated with the induction of DR5-mediated endothelial cell apoptosis through p53 up-regulation, which suggests its potential as an antivascular and antitumor therapeutic agent.
 ...
PMID:CHM-1, a new vascular targeting agent, induces apoptosis of human umbilical vein endothelial cells via p53-mediated death receptor 5 up-regulation. 2000 68

The aim of the present study was to determine the cytotoxic consequences of high-linear energy transfer (LET) irradiation in the presence of oxaliplatin on hepatocellular carcinoma (HCC) cells in vitro. We attempted to correlate the induction of apoptosis and autophagy with the formation of DNA double-strand breaks (DSBs). SK-Hep1 cells were irradiated by 65 MeV neutrons in the presence of oxaliplatin and/or the poly(ADP-ribose) polymerase (PARP) inhibitor PJ34. DSBs were measured by the formation of gammaH2AX foci. Results show that in SK-Hep1 cells exposed to fast neutrons in the presence of oxaliplatin, DSBs occurred and persisted with time after irradiation. While apoptosis remained low in co-treated cells, autophagy was considerably increased after irradiation and augmented by the addition of oxaliplatin. Thus, autophagic cell death appears to play a prominent role in the cytotoxicity of the combined treatment and may be linked to the generation of heavy damage to DNA.
 ...
PMID:Pharmacological enhancement of autophagy induced in a hepatocellular carcinoma cell line by high-LET radiation. 2033 33

Hepatitis C virus (HCV) often establishes a persistent infection that most likely involves a complex host-virus interplay. We previously reported that the HCV nonstructural protein 5A (NS5A) bound to cellular protein FKBP38 and resulted in apoptosis suppression in human hepatoma cell line Huh7. In the present research we further found that NS5A increased phosphorylation levels of two mTOR-targeted substrates, S6K1 and 4EBP1, in Huh7 in the absence of serum. mTOR inhibitor rapamycin or NS5A knockdown blocked S6K1 and 4EBP1 phosphorylation increase in NS5A-Huh7 and HCV replicon cells, suggesting that NS5A specifically regulated mTOR activation. Overexpression of NS5A and FKBP38 mutants or FKBP38 knockdown revealed this mTOR activation was dependent on NS5A-FKBP38 interaction. Phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 treatment in NS5A-Huh7 showed that the mTOR activation was independent of PI3K. Moreover, NS5A suppressed caspase 3 and poly(ADP-ribose) polymerase activation, which was abolished by NS5A knockdown or rapamycin, indicating NS5A inhibited apoptosis specifically through the mTOR pathway. Further analyses suggested that apoptotic inhibition exerted by NS5A via mTOR also required NS5A-FKBP38 interaction. Glutathione S-transferase pulldown and co-immunoprecipitation showed that NS5A disrupted the mTOR-FKBP38 association. Additionally, NS5A or FKBP38 mutants recovered the mTOR-FKBP38 interaction; this indicated that the impairment of mTOR-FKBP38 association was dependent on NS5A-FKBP38 binding. Collectively, our data demonstrate that HCV NS5A activates the mTOR pathway to inhibit apoptosis through impairing the interaction between mTOR and FKBP38, which may represent a pivotal mechanism for HCV persistence and pathogenesis.
 ...
PMID:Hepatitis C virus NS5A activates the mammalian target of rapamycin (mTOR) pathway, contributing to cell survival by disrupting the interaction between FK506-binding protein 38 (FKBP38) and mTOR. 2043 63


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