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)

Conjugated linoleic acid (CLA) is a powerful anti-carcinogenic fatty acid. Previously, we showed that 10trans 12cis (10t, 12c) CLA induced apoptotic cell death in rat hepatoma. Here, we demonstrated significant cytotoxic effects of 1 muM 10t, 12c-CLA, but not 9c, 11t-CLA, on dRLh-84 rat hepatoma cells. 9t, 11t and 9c, 11c-CLA also showed low levels of cytotoxic activity. 10t, 12c-CLA activated caspase-3, 9 followed by cytochrome c release from mitochondria into the cytosol. Inhibitors of caspase-3, 9 blocked the cytotoxicity of 10t, 12c-CLA. 10t, 12c-CLA also induced translocation of Bax protein into the mitochondrial membrane and cleavage of Bid protein. Lysosomal destabilization induced by 10t, 12c-CLA was observed by monitoring the re-localization of Acridine Orange and the leakage of beta-hexosaminidase from lysosomes. 10t, 12c-CLA directly degraded the isolated lysosomes from the rat liver. Our observations indicate that 10t, 12c-CLA induces mitochondria-related apoptosis accompanied by lysosomal destabilization in rat hepatoma cells.
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PMID:Trans10, cis12-conjugated linoleic acid induces mitochondria-related apoptosis and lysosomal destabilization in rat hepatoma cells. 1600 59

Phenylethyl isothiocyanate (PEITC) is a well recognized potential chemopreventive compound against human cancers. In this study, the molecular mechanism of PEITC-induced apoptosis was examined with two antioxidants (N-acetyl-cysteine and vitamin E) and a caspase-3 inhibitor (z-DEVD-fmk). Results demonstrated that PEITC significantly induced human hepatoma PLC/PRF/5 (CD95-negative) cells undergoing apoptosis. Treatment with 0 approximately 10 microM PEITC-triggered cell apoptosis as revealed by the externalization of annexin V-targeted phosphatidylserine and the subsequent appearance of sub-G1 population. Results also displayed that PEITC-induced apoptosis involves the up-regulation of p53 and Bax protein, down-regulation of the XIAP, Bcl-2, Bcl-(XL) and Mcl-1 proteins, cleavage of Bid, and the release of cytochrome c and Smac/Diablo, which were accompanied by the activation of caspases -9, -3 and -8. PEITC-induced the generation of reactive oxygen species and the decrease of mitochondrial membrane potential (Deltapsim) in a time-dependent pattern. N-acetyl-cysteine and vitamin E at 100 microM, and z-DEVD-fmk at 50 microM markedly blocked PEITC-induced apoptosis, which was demonstrated by a decline in the reactive oxygen species generation and the release of the cytochrome c and Smac/Diablo from mitochondria to the cytosol. N-acetyl-cysteine, vitamin E and z-DEVD-fmk also prevented the PEITC in inducing the loss of Deltapsim. They also affected the activity of XIAP and Bax proteins. Taken together, these studies suggest that PEITC is an apoptotic inducer that acts on the mitochondria and the feedback amplification loop of caspase-8/Bid pathways in PLC/PRF/5 cells.
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PMID:Effects of antioxidants and caspase-3 inhibitor on the phenylethyl isothiocyanate-induced apoptotic signaling pathways in human PLC/PRF/5 cells. 1605 26

Arachidonic acid and, to a smaller extent, oleic acid at micromolar concentrations decreased the mitochondrial membrane potential within AS-30D rat hepatoma cells cultivated in vitro and increased cell respiration. The uncoupling effect of both fatty acids on cell respiration was partly prevented by cyclosporin A, blocker of the mitochondrial permeability transition pore. Arachidonic acid increased the rate of reactive oxygen species (ROS) production, while oleic acid decreased it. Both fatty acids induced apoptotic cell death of AS-30D cells, accompanied by the release of cytochrome c from mitochondria to the cytosol, activation of caspase-3 and association of proapoptotic Bax protein with mitochondria; arachidonic acid being a more potent inducer than oleic acid. Trolox, a potent antioxidant, prevented ROS increase induced by arachidonic acid and protected the cells against apoptosis produced by this fatty acid. It is concluded that arachidonic and oleic acids induce apoptosis of AS-30D hepatoma cells by the mitochondrial pathway but differ in the mechanism of their action: Arachidonic acid induces apoptosis mainly by stimulating ROS production, whereas oleic acid may contribute to programmed cell death by activation of the mitochondrial permeability transition pore.
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PMID:Short-term and long-term effects of fatty acids in rat hepatoma AS-30D cells: the way to apoptosis. 1661 Jan 2

The molecular mechanisms of wogonin-induced apoptosis of human hepatoma SMMC-7721 cells are reported. Wogonin treatment resulted in significant inhibition of SMMC-7721 cells in a time-dependent and concentration-dependent manner. Typical morphological changes and apoptotic blebbing in SMMC-7721 cells were observed after treatment with 1x10(-4) mol/l wogonin for a period of 0-48 h. Flow cytometry and Annexin-V/propidium iodide double-staining experiments revealed a dramatic increase in the number of apoptotic and G0/G1 phase cells after wogonin treatment. The proapoptotic activity of wogonin is attributed to its ability to modulate the expression of bcl-2 and bax proteins. It is observed that the expression of bax protein is dramatically increased whereas the synthesis of bc1-2 protein is significantly decreased when cells are treated with wogonin. The results presented in this paper suggested an important relationship between gene regulation and wogonin-induced apoptosis, and indicated the possibility of developing naturally occurring monoflavonoids as novel anticancer agents for better management of human cancers.
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PMID:Involvement of bax/bcl-2 in wogonin-induced apoptosis of human hepatoma cell line SMMC-7721. 1692 29

Hepatitis B virus (HBV) infection afflicts >300 million people worldwide and is a leading cause of hepatocyte death, cirrhosis, and hepatocellular carcinoma. While the morphological characteristics of dying hepatocytes are well documented, the molecular mechanisms leading to the death of hepatocytes during HBV infection are not well understood. TRAIL, the TNF-related apoptosis-inducing ligand, has recently been implicated in the death of hepatocytes under certain inflammatory but not normal conditions. To determine the potential roles of TRAIL in HBV-induced hepatitis, we examined the effects of HBV and its X protein (HBx) on TRAIL-induced hepatocyte apoptosis both in vivo and in vitro. We found that hepatitis and hepatic cell death in HBV transgenic mice were significantly inhibited by a soluble TRAIL receptor that blocks TRAIL function. We also found that HBV or HBx transfection of a hepatoma cell line significantly increased its sensitivity to TRAIL-induced apoptosis. The increase in TRAIL sensitivity were associated with a dramatic up-regulation of Bax protein expression. Knocking down Bax expression using Bax-specific small interference RNA blocked HBV-induced hepatitis and hepatocyte apoptosis. The degradation of caspases 3 and 9, but not that of Bid or caspase-8, was preferentially affected by Bax knockdown. These results establish that HBV sensitizes hepatocytes to TRAIL-induced apoptosis through Bax and that Bax-specific small interference RNA can be used to inhibit HBV-induced hepatic cell death.
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PMID:Hepatitis B virus sensitizes hepatocytes to TRAIL-induced apoptosis through Bax. 1718 90

The tumor suppressor protein p53 restricts proliferation in response to DNA damage or the deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence. Consequently, p53 mutations increase cell proliferation and survival and in some settings promote genomic instability and resistance to certain anti-cancer drugs. It is very important to identify chemotherapeutic agents that activate in a p53-independent manner for the development of treatments for p53-deficient tumors. Pectenotoxin-2 (PTX-2), isolated from marine sponges has been reported to display significant cytotoxicity to p53-deficient cancer cell lines. In this study, we compared the anti-cancer activity of PTX-2 in order to further test the status of p53 using two well-known hepatocarcinoma cell lines, p53-deficient Hep3B and p53-wild-type HepG2. MTT assay indicated that Hep3B cells were highly susceptible, whereas HepG2 cells were more resistant to this compound which was connected with the induction of apoptotic cell death in p53-deficient Hep3B cells, though not in HepG2 cells. The apoptosis induced by PTX-2 in Hep3B cells was associated with the down-regulation of anti-apoptotic Bcl-2 members (Bcl-2 and Bcl-xL) and IAP family proteins, the up-regulation of pro-apoptotic Bax protein and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-receptor 1/receptor 2 (DR4/DR5) and mitochondrial dysfunction. PTX-2 activated caspases (caspase-3, -8 and -9) and the blockade of caspase-3 activity by the caspase-3 inhibitor prevented the PTX-2-induced apoptosis in Hep3B cells. Additionally, the transcription factor early growth response-1 (Egr-1) gene was transcriptionally activated and the levels of non-steroidal anti-inflammatory drugs (NSAID)-activated gene-1 (NAG-1) protein were also elevated in PTX-2-treated Hep3B cells. Although further studies are needed to prove that an increased expression of Egr-1 by PTX-2 directly leads to NAG-1 induction and then apoptosis induction in p53-deficient Hep3B cells, the results of this study suggest that PTX-2 may be a good candidate for the development of a potential anti-tumorigenic agent in p53-deficient tumors.
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PMID:Induction of apoptosis by pectenotoxin-2 is mediated with the induction of DR4/DR5, Egr-1 and NAG-1, activation of caspases and modulation of the Bcl-2 family in p53-deficient Hep3B hepatocellular carcinoma cells. 1820 2

We have investigated the antiproliferative effects of TBIDOM (N-(4-(2,2,2-trifluoroethyl) benzylidene) (7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl) meth-anamine) and have explored its possible mechanisms on human hepatocellular carcinoma SMMC-7721 cells. The proliferative status of cells treated with TBIDOM was measured by the colorimetric MTT assay. Cellular apoptosis was analysed using Hoechst 33342 staining and flow cytometry. Reduction of mitochondrial membrane potential (Delta psi(m)) was also detected by flow cytometry. Western blotting assay was used to evaluate the release of cytochrome c and expression of p53, Bcl-2 and Bax proteins. It was shown that TBIDOM displayed a significant inhibitory effect on growth of SMMC-7721 cells in a dose- and time-dependent manner. Hoechst 33342 staining and flow cytometry analysis showed an increase of apoptosis rate and decrease of mitochondrial membrane potential after SMMC-7721 cells were exposed to TBIDOM for 24 h. Pretreatment of SMMC-7721 cells with TBIDOM significantly induced a decrease of Bcl-2 protein expression and an increase of caspase-3 activity and Bax protein expression. The results indicated that TBIDOM could effectively inhibit proliferation by induction of apoptosis and could be a promising candidate in the development of a novel class of antitumour agent.
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PMID:Cytotoxic effects and pro-apoptotic mechanism of TBIDOM, a novel dehydroabietylamine derivative, on human hepatocellular carcinoma SMMC-7721 cells. 1823 68

Retinoids play an important role in the regulation of cell growth and death. Synthetic retinoid CD437 reportedly induces apoptosis in various cancer cell lines. However, the mechanism of inducing apoptosis in hepatocellular carcinoma (HCC) cells by this agent remains to be clarified. In this study, we investigated the signaling pathway by which CD437 induces apoptosis in HCC cell lines. Apoptosis of six human HCC cell lines was induced by treatment with CD437. Caspase-3 and -9 were activated by CD437, suggesting that the apoptosis is mediated by mitochondrial pathways. Consistent with these findings, the treatment with CD437 upregulated Bax protein, downregulated Bcl-2 protein and released cytochrome c into the cytoplasm. Moreover, rhodamine123 staining revealed mitochondrial depolarization in the cells treated with CD437. These data of the present study suggest that CD437 induces apoptosis in HCC cells via mitochondrial pathways.
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PMID:Synthetic retinoid CD437 induces mitochondria-mediated apoptosis in hepatocellular carcinoma cells. 1840 43

We previously reported that HS-1200, a synthetic chenodeoxycholic acid derivative, has apoptosis-inducing activity in various human cancer cells. The present study was undertaken to examine whether HS-1200 had an anticancer effect on HepG2 (wild-type p53) and Hep3B (p53 deleted) human hepatoma cells. Treatment of both cells with HS-1200 resulted in growth inhibition and induction of apoptosis as measured by MTT assay, nuclear staining, DNA fragmentation and flow cytometry analysis. The increase in apoptosis was associated with the alteration in the ratio of Bcl-2/Bax protein expression. In addition, flow cytometry analysis indicated that HS-1200 induced G1 phase arrest in both cells. When analyzing the expression of cell cycle-related proteins, we found that HS-1200 reduced the expression levels of cyclin D1, cyclin A, and Cdk2. HS-1200 treatment also caused an increase in the expression levels of p21 WAF1/CIP1 in HepG2 cells in a p53-dependent manner and in Hep3B cells in a p53-independent manner. Moreover, the expression level of p27 KIP1 was increased in both cell lines. We also observed that HS-1200 decreased the levels of cyclooxygenase (COX)-2 mRNA and protein expression. Furthermore, HS-1200 treatment markedly induced the Egr-1 expression at an early time point, and the increased expression levels of p53, p21 WAF1/CIP1, p27 KIP1, and COX-2 after treatment with HS-1200 were completely inhibited in HepG2 cells and partially inhibited in Hep3B cells by silencing of Egr-1, respectively. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anticancer activity of the synthetic bile acid derivative, HS-1200, through Egr-1 regulation.
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PMID:A chenodeoxycholic derivative, HS-1200, induces apoptosis and cell cycle modulation via Egr-1 gene expression control on human hepatoma cells. 1855 81

The effect of targeted magnetic nanoparticles on hepatoma and the underlying mechanism were examined. Nude mice transplanted with a human hepatoma cell line (HepG2 cells) were randomized into 5 groups, including: (1) group A, receiving normal saline, (2) group B, receiving 5-fluorouracil (5-Fu), (3) group C, receiving magnetic nanoparticles containing 5-Fu, (4) group D, consisting of treatment with magnetic nanoparticles containing 5-Fu and inside magnetic field and (5) group E, receiving pure magnetic nanoparticles and inside magnetic field. Morphological features of transplanted tumors in mice in each group were observed under transmission electron microscope (TEM). The expression of bcl-2/bax protein was immunohistochemically detected by SABC method. The results showed that a large number of apoptotic tumor cells were found in group B and group D under TEM. The expression of bcl-2 protein was significantly decreased and the expression of bax protein increased significantly in both group B and D as compared with those in group A, C and E (P<0.01 for all). The decrease in bcl-2 and the increase in bax were more in group D as compared with group B (P<0.01). It is concluded that the targeted magnetic nanoparticles containing 5-Fu can improve the chemotherapeutic effect of 5-Fu by decreasing bcl-2 expression, increasing bax expression and inducing apoptosis of the liver cancer cells.
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PMID:The effect of targeted magnetic nanopaticles on hepatoma and the expression of bcl-2/bax protein. 1870 8


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