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)

Sphingolipid metabolites are important regulators of cell growth and differentiation. Recent studies have suggested that sphingosine-1-phosphate, a biologically active sphingolipid metabolite, acts as a crucial messenger in apoptosis. In the present work, we examined the expression levels of the members of the bcl-2-related gene family to determine their roles in sphingosine-1-phosphate-induced apoptosis is human hepatoma cells. Our results indicate that sphinogosine-1-phosphate-induced apoptosis is associated with enhanced expression of Bax protein. Moreover, the regulation of bax gene expression by sphingosine-1-phosphate is independent of the p53 tumor suppressor.
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PMID:Induction of apoptosis by sphingosine-1-phosphate in human hepatoma cells is associated with enhanced expression of bax gene product. 895 76

Mutations in the tumor suppressor p53 are a common event in hepatocellular carcinoma (HCC). Because HCCs typically occur in livers with chronic injury and impaired function, we have explored the role of wild-type p53 in regulating the growth and differentiation of Hep 3B hepatoma cells, a p53-negative line derived from a liver cancer. Stable Hep 3B cell lines were generated in which inducible p53 was introduced using either a temperature-sensitive mutant (p53val135) or a tamoxifen-regulated p53-estrogen receptor chimera (p53-mERtm-pBabepuro). In both cell lines, induction of transcriptionally active p53 was confirmed by assessing several p53 targets: Mdm2 protein, p21waf1 mRNA and protein, and the cyclin G promoter. Despite marked induction of p21waf1, cells with active p53 failed to undergo growth arrest, which is probably due to the presence of a non-functional retinoblastoma protein (pRb) in these cells. Apoptosis also was not observed, even after prolonged (48 h) serum starvation or exposure to cisplatinum. Lack of apoptosis was correlated with unchanged bax mRNA levels following p53 induction. Additionally, albumin mRNA levels remained unchanged, and there was no change in basal transactivation of a reporter containing the promoter of the haptoglobin gene, encoding an acute phase protein. This suggests that growth arrest may be required to promote liver-specific gene expression. Overall, our data demonstrate that introduction of transcriptionally active p53 does not alter the malignant, dedifferentiated phenotype of Hep 3B hepatoma cells. Hence, not all cancer cells are equally responsive to the re-activation of wild-type 53. The ability of a cancer cell to undergo p53-mediated phenotypic alterations may depend on the retention of functional downstream effector pathways.
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PMID:Resistance to p53-mediated growth arrest and apoptosis in Hep 3B hepatoma cells. 923 78

We demonstrated that introduction and expression of wild-type p53 gene in the human hepatocellular carcinoma cell line, Hep3B, resulted in up-regulation of both p21WAF1/CIP1 and bax gene expression and apoptosis. This cell line contains integrated hepatitis B virus sequences and lacks the expression of both p53 and retinoblastoma tumor suppressor genes because of deletions. Our results suggest that whereas an increased level of bax expression mediates apoptosis, an increased level of p21WAF1/CIP1 expression does not induce arrest of cell growth, presumably because of the deletion of the retinoblastoma gene. This study also confirms reported observations that p53 is a tumor suppressor gene, which induces apoptosis in malignant cells that lack normal p53 activity because of mutation, deletion, or inactivation of the gene by the presence of oncogenic viral proteins.
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PMID:Wild-type p53 induces apoptosis in Hep3B through up-regulation of bax expression. 935 71

The effect of dietary administration of cholic acid on tumorigenesis in the liver was investigated in male Fischer-344 rats after carcinogenic initiation by diethylnitrosamine (DEN); progression of liver tumors was examined in the rats fed 0.4% cholic acid-containing diet (CA group) and the rats fed standard diet (C group) at 15, 20 and 25 weeks after administration of DEN. The total bile acids and cholic acid in serum of CA group were 150 nmol/ml and 117 nmol/ml, being 31-fold and 51-fold higher than those in C group (p<0.0001, each). Serum AST and ALT were significantly higher in CA group than in C group at 15 weeks (p<0.01). Serum ALP was significantly higher in CA group than C group at each time point (p<0.01, each). Liver tumors, whose histology was hepatocellular carcinoma, developed at 15 weeks in both CA and C groups. However, tumor volume and tumor weight were significantly increased in CA group, compared to those in C group at each time point (p<0.001, p<0. 001, p<0.01, p<0.001, p<0.01 and p<0.05). The percentage of apoptotic cells in CA group at each time point was significantly lower than C group (p<0.05, p<0.01 and p<0.05). The percentage of bcl-2 positive tumor cells in C group at 20 weeks was 1.88+/-2.59%. However, it dramatically increased to 34.00+/-13.67% in CA group (p<0.0001). It was also higher in CA group than in C group at 15 and 25 weeks (p<0.05 and p<0.01). In addition, the bax-positive cells were higher in CA group than in C group at 20 weeks (p<0.05). These data suggest that oral administration of cholic acid promotes liver tumorigenesis initiated by DEN through reducing apoptosis mediated by overexpression of bcl-2.
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PMID:Oral administration of cholic acid promotes growth of liver tumors initiated by diethylnitrosamine in rats. 1040 35

Hepatocyte growth factor (HGF) exerts a cytostatic effect on HepG2 and B16-F1 cell lines. To evaluate the possible involvement of the apoptotic process in this effect, we performed studies at cellular and molecular levels. HGF induced apoptosis only in HepG2 hepatoma cells at day 3 in about 20% of the cells undergoing growth inhibition, while hallmarks of apoptosis did not occur in B16-F1 melanoma cells. During the first 24 h after HGF treatment, enhanced expression of the pro-apoptotic genes bax and c-Myc was observed at level of mRNA and protein. Concomitant induction of antizyme (AZ) might lower ornithine decarboxylase (ODC) protein level though a huge increase in ODC mRNA level took place. This was suggested as a signal for apoptosis decisional phase. The levels of the proteins examined except that of AZ fell down thereafter when HepG2 cells underwent apoptosis. In B16-F1 cells, only ODC and AZ protein levels were elevated probably in relation to the initial elevated growth rate and the absence of apoptosis involvement in the following cytostatic effect of HGF in melanoma cells. Consistent with this hypothesis, bax mRNA and protein levels were unchanged or even lower relative to control values.
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PMID:Hepatocyte growth factor induces pro-apoptotic genes in HepG2 hepatoma but not in B16-F1 melanoma cells. 1116 78

Chemotherapy does not have a prominent role in the treatment of hepatoma. However, an acyclic retinoid prevented tumor recurrence post-hepatectomy, and tamoxifen (TAM) induced apoptosis in tumor cells. Combination therapy of these agents on proliferation and apoptosis of hepatoma cells has not been explored. HepG2, Hep1B, Hepa1-6 and MH1C1 hepatoma cells were incubated with TAM, 9-cis- and all-trans retinoic acid (CRA, ATRA, respectively) alone or in combination. Proliferation rate was assessed and apoptosis was analyzed by flow cytometry, immunostaining, caspase activity assays and the expression of apoptosis- and/or cell cycle-related molecules. CRA and TAM, but not ATRA monotherapy were moderately effective. Apoptosis was accompanied by upregulation of caspase 3 and 8 activity, and increased p27, bax, caspase 3 expression, while the levels of p21cip/waf and bcl-2 were unchanged or decreased. Combination therapy enhanced apoptosis from a maximum of 60% after monotherapy to more than 90% after 96 h in all cell types. Pro-apoptotic effects were paralleled by inhibition of proliferation. Combination of TAM and CRA, but not ATRA, have an additive to synergistic anti-proliferative and pro-apoptotic effect on HCC cells. This justifies trials for HCC using combinations of these biological response modifiers.
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PMID:Combined in vitro anti-tumoral action of tamoxifen and retinoic acid derivatives in hepatoma cells. 1174 47

Patients with tumors expressing promoters of apoptosis (bax) versus inhibitors of apoptosis (bcl-2, bcl-x) may have increased survival. The purpose of this study was to determine the frequency of expression of apoptotic markers in hepatocellular carcinoma (HCC) and their relationship with prognosis. Seventy HCC were immunostained for bcl-2, bax, and bcl-x. Staining intensity in tumor cells was graded 0 to 3+. Follow-up data were available for mean survival (57 cases) and death rates (58 cases). These values and clinical parameters were related to prognosis. Staining frequency for bcl-2, bax, and bcl-x was 20%, 66%, and 60%, respectively. Immunostaining intensity of bax correlated with overall survival and death rates: of 57 patients, the 37% with 0 to 1+ intensity had a median survival of 6.6 months, the 63% with 2 to 3+ intensity had a median survival of 31.9 months (P = 0.05); 86% of 19 patients with 0 to 1+ intensity died, and 50% of 36 patients with 2 to 3+ intensity died (P < 0.05). Intensity of bcl-x staining tended to correlate with survival: of the 57 patients with 0 to 1+, 42% had a median survival of 32.7 months compared with 5.8 months in the 58% with 2 to 3+ intensity (P = 0.06). By multivariate analysis, this relationship held for bax (P = 0.011) and bcl-x (P = 0.048). There was no correlation between bcl-2 expression, stage, or gender and prognosis. Patients with bax-expressing HCC experience improved survival compared with those with no or low bax expression, in uni- and multivariate models. Patients with no or low bcl-x tended toward improved survival compared with patients with more bcl-x in their HCC. bcl-2 expression did not correlate with prognosis.
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PMID:Hepatocellular carcinoma and markers of apoptosis (bcl-2, bax, bcl-x): prognostic significance. 1237 45

The aim of this work was to study the effect of arsenic trioxide (As2O3) on rat hepatocellular carcinoma (HCC), and investgate on the mechanisms of its antitumor effect. HCC was induced by chemocarcinogen diethylnitrosamine (DEN) in Wistar rats, that were then treated with As2O3 intraperitoneally in three different concentrations once a day for two weeks, and twice a week for another two weeks. The histological and ultrastructural changes in liver tissue were observed under microscope and electronic microscope on the 7th, 14th and 28th day after drug administration. The apoptosis and cellular dynamic parameters of tumor cells were observed by flow cytometry. The expression of bcl-2, bax, and proliferation cell nuclear antigen (PCNA) of rat liver cancer cells on the 7th day after drug administration was determined by using immunohistochemical technique. Treatment with As2O3 caused HCC cells death via both apoptotic and non-apoptotic mechanisms when the dose was high (5 mg.kg(-1)), while necrosis was rare and apoptosis was common when the dose was appropriate (1 mg.kg(-1)). This effect was obviously accompanied with accumulation of cells in G2/M phases (G2/M restriction). Many apoptotic cells were also found in G2/M phases. The expression intensity of bcl-2 or bax varied depending on the dose administrated. Downregulation of bcl-2/bax was observed, accompanied with upregulation of apoptosis. However, the ratio of bcl-2/bax and the percentage of apoptosis were not the utmost when the dose administered was the highest. In conclusion, these data demonstrate that As2O3 induces apoptosis of rat HCC cells, and it is closely associated with G2/M restriction when apoptosis reaches the top. Apoptosis can be observed in all three phases of cell cycle, but it is more common in G2/M phase when the dose is appropriate. It is suggested that arsenic trioxide may be an atypical cell cycle specific agent. Apoptosis of tumor cells is closely associated with down-regulation of the ratio of bcl-2/bax, but that may not be the only dominant factor.
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PMID:Arsenic trioxide induces apoptosis of rat hepatocellular carcinoma cells in vivo. 1272 24

Effective therapy for advanced hepatocellular carcinoma (HCC) is lacking. Conventional chemotherapy was judged to be ineffective. We previously demonstrated that the histone deacetylase inhibitor Trichostatin A (TSA) blocks growth of HCC cells in vitro. The anti-tumoral effect of a combination of more than 2 classes of drugs remains unexplored. Four hepatoma cell lines were incubated with increasing concentrations of Tamoxifen (TAM), 9-cis retinoic acid (CRA), the methioninaminopeptidase inhibitor TNP-470 and TSA as single agents and in combination. Anti-proliferative and pro-apoptotic effects were assessed using BrdU-incorporation, FACS analysis and immunocytochemistry. Central pro- and anti-apoptotic proteins were measured by semi-quantitative Western blotting and substrate assays. All single substances inhibited proliferation and induced apoptosis in HCC cells only at high concentrations. The combination of TAM/CRA/TNP/TSA multiplied the anti-tumoral effects, reaching up to 93% inhibition of proliferation and 63% induction of apoptosis after 24 h in Hep1B cells. Pro-apoptotic factors bax and caspase 3 were highly increased with quadruple therapy, while anti-apoptotic bcl-2 decreased to undetectable levels. Fibroblasts remained largely unaffected. While the single substances were not effective on hepatoma cells in tolerable doses, their combination significantly increases anti-tumoral efficacy. Combination therapy with biomodulators is a promising treatment option for HCC.
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PMID:A quadruple therapy synergistically blocks proliferation and promotes apoptosis of hepatoma cells. 1506 30

Retinoids can block cell proliferation and induce apoptosis in tumor cells. The antitumoral effect of synthetic retinoids like Adapalene (ADA) on hepatoma cells (HepG2, Hep1B) was investigated. Cell proliferation was assessed by measuring DNA synthesis and apoptosis by flow cytometry and immunocytochemistry. Cell cycle- and apoptosis-associated proteins were semi-quantified by Western Blotting and breakdown of mitochondrial membrane potentials was detected by JC-1 staining. ADA at 10(-4)M efficiently induced apoptosis, reaching 61.7% in HepG2 and 79.1% in Hep1B after 72 h incubation. This was accompanied by up-regulation of pro-apoptotic bax and caspase 3, while bcl-2 was down-regulated, shifting the bax/bcl-2 ratio to >2.3 in hepatoma cells. ADA inhibits hepatoma cell growth in vitro and is a powerful inducer of hepatoma cell apoptosis.
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PMID:Potentiated anticancer effects on hepatoma cells by the retinoid adapalene. 1510 45


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