Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Justicia procumbens is a traditional Taiwanese herbal remedy used to treat fever, pain, and cancer. Justicidin A, isolated from Justicia procumbens, has been reported to suppress in vitro growth of several tumor cell lines as well as hepatoma cells. In this study, justicidin A activated caspase-8 to increase tBid, disrupted mitochondrial membrane potential (Delta psi(m)), and caused the release of cytochrome c and Smac/DIABLO in Hep 3B and Hep G2 cells. Justicidin A also reduced Bcl-x(L) and increased Bax and Bak in mitochondria. Caspase-8 inhibitor (Z-IETD) attenuated the justicidin A-induced disruption of Delta psi(m). Growth of Hep 3B implanted in NOD-SCID mice was suppressed significantly by oral justicidin A (20 mg/kg/day). These results indicate that justicidin A-induced apoptosis in these cells proceeds via caspase-8 and is followed by mitochondrial disruption.
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PMID:Caspase-8 acts as a key upstream executor of mitochondria during justicidin A-induced apoptosis in human hepatoma cells. 1668 33

The present paper demonstrates that the proteasome inhibitor bortezomib, which behaves as an apoptotic agent in hepatoma HepG2 cells, caused in these cells a decrease in IkappaBalpha level and a consequent increase in NF-kappaB activity. The effect already appeared at 4 h of treatment and preceded the onset of apoptosis which was observed at 24 h. Our results demonstrate that bortezomib-induced IkappaBalpha degradation occurred in conjunction with the activation of caspase-8; moreover, the decrease in IkappaBalpha level was prevented in a dose-dependent manner by the addition of z-IETD, a specific inhibitor of caspase-8. Bortezomib caused the same effects in non-tumor Chang liver cells, which were not susceptible to the apoptotic effect of the drug. Our results also show that other proteases, such as caspase-3 and calpains, exerted only a limited effect on IkappaBalpha degradation. These findings suggest that caspase-8 can be involved in the control of IkappaBalpha level. In addition, the activation of caspase-8 can exert, at least in the first phase of treatment with bortezomib, a protective effect in both HepG2 and Chang liver cells, favouring the activation of the survival factor NF-kappaB.
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PMID:Bortezomib induces in HepG2 cells IkappaBalpha degradation mediated by caspase-8. 1673 6

Caspase-8 belongs to the cysteine protease family and is known to be activated at the initial step in the cascade of TRAIL-induced apoptosis. The activation of procaspase-8 can be blocked by a relatively large amount of c-FLIP, which renders resistance to death receptor-mediated apoptosis in many types of cancer cells. To ask if extrinsic over-expression of caspase-8 contributes to the induction of apoptosis, we introduced the caspase-8 gene into HCC cells using an adenoviral (Adv) vector (Adv-Casp8). We demonstrated that Adv-Casp8 increased expression of active forms of caspase-8 in MOI-dependent manner. A large amount of Adv-Casp8 (MOI of 50) induced apoptosis significantly in HCC cells and resulted in downregulation of c-FLIP (in SK-Hep1, HLE, and HepG2 cells), XIAP, survivin, and Bcl-xL (in HLE cells) and dynamic release of cytochrome c and Smac from the mitochondria into the cytosol. On the other hand, a small amount of Adv-Casp8 (MOI of 10) causes a slight but detectable increase in the level of apoptosis with only a small effect on anti-apoptotic proteins and mitochondrial activation. However, small amounts of Adv-Casp8 augmented TRAIL- or chemotherapeutic agent-induced cell death (with an MOI of 10 or 20, respectively). These results suggest both that exogenous over-expression of caspase-8 by Adv-Casp8 may be essential for induction of HCC cell death and that the combination of Adv-Casp8 and TRAIL or chemotherapeutic agents could provide a useful strategy for treatment of HCC.
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PMID:Adenovirus-mediated transfection of caspase-8 sensitizes hepatocellular carcinoma to TRAIL- and chemotherapeutic agent-induced cell death. 1675 Feb 75

Recent clinical trials have shown that interferon (IFN) is effective for chemoprevention against hepatocellular carcinoma (HCC). However, it remains controversial as to whether IFN exerts direct cytotoxicity against HCC. Cyclooxygenase (COX)-2 also plays a role in hepatocarcinogenesis and may mediate resistance to apoptosis in HCC. Therefore, we aimed to elucidate the combined effect of COX-2 inhibitor, NS-398, and IFN on in vitro growth suppression of HCC using 3 hepatoma cell lines (HepG2, PLC/PRF/5, and Huh7) and in vivo nude mouse xenotransplantation model using Huh7 cells. Only minimal growth inhibition was observed after treatment with IFN-beta alone in the 3 hepatoma cell lines. In contrast, treatment with NS-398 and IFN-beta synergistically inhibited cell proliferation in dose- and time-dependent manner. Apoptosis was identified by 4',6-diamidino-2-phenylindole dihydrochloride and fluorescent staining. IFN-beta up-regulated the expression of TRAIL, while NS-398 increased the expression of TRAIL receptors (especially of death receptor 5). Subsequently, activation of caspase-8 and caspase-3 was observed following the treatment with NS-398 and IFN-beta. Blockade of TRAIL with a specific antibody attenuated this apoptosis. Furthermore, we found that IFN-beta up-regulated COX-2 expression in Huh7 cells, and NS-398 might suppress the up-regulated COX-2 activity downstream of IFN signaling. In vivo experiment showed the combined regimen with NS-398 and IFN-beta reduced the growth of xenotransplated HCCs in nude mice. In conclusion, NS-398 is sufficient to overcome IFN resistance in hepatoma cells through the TRAIL/TRAIL receptor pathway, therefore, the combination would appear to be a new therapeutic regimen for HCC.
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PMID:Cyclooxygenase-2 inhibitor and interferon-beta synergistically induce apoptosis in human hepatoma cells in vitro and in vivo. 1686 78

Interferon (IFN) combined with 5-Fluorouracil (5-FU) treatment has recently been reported to show beneficial effects in patients with advanced hepatocellular carcinoma. IFNalpha is usually provided for this combination therapy. In this study, we investigated the molecular mechanisms of apoptosis induction in hepatoma cell lines with IFNalpha and 5-FU combination therapy from the view point of 5-FU's additive effect on interferon-related signaling pathways. Five hepatoma cell lines (Hep3B, Huh7, HLE, PLC/PRF/5, and HepG2) were tested for apoptosis inducibility by IFNalpha in the absence or presence of 5-FU. Hep3B was the most apoptosis sensitive to IFN plus 5-FU treatment. The JAK/STAT pathway transcriptional factor ISRE was activated more synergistically when 5-FU was added to IFNalpha treatments. Caspase-3, -9, and especially caspase-8 activity was higher with IFN alpha plus 5-FU than IFN or 5-FU alone. Inhibition of caspase-8, -9, c-Jun N-terminal kinase (JNK), phosphatidylinositide 3-kinase (PI3K), and p38 mitogen-activated protein kinase (p38 MAPK) revealed that caspase-8 inhibition was the most effective at decreasing the apoptotic effects of IFN and/or 5-FU. In JAK1 and ISGF3gamma-silenced Hep3B cells, the apoptosis induction and caspase-8 activation levels by IFN, even in combination with 5-FU, were abrogated. In conclusion, caspase-8 is the most important factor that controls IFN and 5-FU-induced apoptosis in hepatoma cell lines.
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PMID:Combination of 5-FU and IFNalpha enhances IFN signaling pathway and caspase-8 activity, resulting in marked apoptosis in hepatoma cell lines. 1701 59

Dietary polyphenols have been associated with the reduced risk of chronic diseases such as cancer, but the precise underlying mechanism of protection remains unclear. The aim of this study was to investigate the effect of quercetin on the activation of the apoptotic pathway in a human hepatoma cell line (HepG2). Treatment of cells for 18 h with quercetin induced cell death in a dose-dependent manner; however, a shorter treatment (4 h) had no effect on cell viability. Incubation of HepG2 cells with quercetin for 18 h induced apoptosis by the activation of caspase-3 and -9, but not caspase-8. Moreover, this flavonoid decreased the Bcl-xL:Bcl-xS ratio and increased translocation of Bax to the mitochondrial membrane. A sustained inhibition of the major survival signals, Akt and extracellular regulated kinase (ERK), also occurred in quercetin-treated cells. These data suggest that quercetin may induce apoptosis by direct activation of caspase cascade (mitochondrial pathway) and by inhibiting survival signaling in HepG2.
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PMID:Quercetin induces apoptosis via caspase activation, regulation of Bcl-2, and inhibition of PI-3-kinase/Akt and ERK pathways in a human hepatoma cell line (HepG2). 1705 90

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

Extracellular adenosine induced apoptosis of HuH-7 cells, a Fas-deficient human hepatoma cell line. The adenosine action was inhibited by dipyridamole, an adenosine transporter inhibitor, or 5'-amino-5'-deoxyadenosine, an inhibitor of adenosine kinase to convert from adenosine to AMP, but it was not affected by inhibitors for adenosine A(1), A(2a), A(2b), and A(3) adenosine receptors. Adenosine activated caspase-3 and -8, but not caspase-9, in HuH-7 cells, and the activation was abolished by dipyridamole. In the real-time RT-PCR and Western blot analysis, extracellular adenosine downregulated mRNA and protein levels for c-FLIP, and the effect was suppressed by dipyridamole. Furthermore, overexpression of c-FLIP short in HuH-7 cells inhibited adenosine-induced caspase-8 activity. Taken together, these results suggest that intracellularly transported adenosine, perhaps converted AMP as the ensuing event, activates caspase-8 and the downstream effector caspase caspase-3 by neutralizing caspase-8 inhibition due to c-FLIP as a consequence of decreased c-FLIP expression, leading to apoptosis. This extends our understanding of adenosine-induced molecular apoptotic pathways.
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PMID:Intracellularly transported adenosine induces apoptosis in HuH-7 human hepatoma cells by downregulating c-FLIP expression causing caspase-3/-8 activation. 1730 86

Histone deacetylase (HDAC) inhibitors represent a promising group of anticancer agents. This paper shows that the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) stimulated at 5-10 microM apoptosis in human hepatoma HepG2 and Huh6 cells, but was ineffective in primary human hepatocytes (PHH). In HepG2 cells SAHA induced the extrinsic apoptotic pathway, increasing the expression of both FasL and FasL receptor and causing the activation of caspase-8. Moreover, SAHA enhanced the level of Bim proteins, stimulated alternative splicing of the Bcl-X transcript with the expression of the proapoptotic Bcl-Xs isoform, induced degradation of Bid into the apoptotic factor t-Bid and dephosphorylation and inactivation of the anti-apoptotic factor Akt. Consequently, SAHA caused loss of mitochondrial transmembrane potential, release of cytochrome c from mitochondria, activation of caspase-3 and degradation of PARP. Interestingly, a combination of suboptimal doses of SAHA (1 microM) and bortezomib (5-10 nM), a potent inhibitor of 26S proteasome, synergistically induced apoptosis in both HepG2 and Huh6 cells, but was ineffective in PHH. Combined treatment increased with synergistic effects the expression levels of c-Jun, phospho-c-Jun and FasL and the production of Bcl-Xs. These effects were accompanied by activation of Bid, caspase-8 and 3. In conclusion, SAHA stimulated apoptosis in hepatoma cells and exerted a synergistic apoptotic effect when combined with bortezomib. In contrast, these treatments were quite ineffective in inducing apoptosis in PHH. Thus, our results suggest the potential application of the SAHA/bortezomib combination in clinical trials for liver cancer.
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PMID:SAHA induces apoptosis in hepatoma cells and synergistically interacts with the proteasome inhibitor Bortezomib. 1735 39

The protein encoded by bcl-2 proto-oncogene plays an important role in the mitochondria-mediated apoptotic pathway. Although the general role of Bcl-2 is anti-apoptotic, previous work showed that Bcl-2 fragments cleaved by caspases could promote apoptotic process. We report herein that Bcl-2 protein was cleaved to produce two fragments of around 23 kDa in human hepatocarcinoma BEL-7404 cells or in Bcl-2 overexpressing CHO cells induced by cisplatin. Treating cells with the general caspase inhibitor z-VAD-fmk blocked the induced cleavage of Bcl-2. Mutagenesis analyses showed that Bcl-2 was cleaved by caspases at two adjacent recognition sites in the loop domain (YEWD(31) decrease AGD(34) decrease V), which could be inhibited by caspase-8 and -3 inhibitors, respectively. Overexpression of the carboxyl terminal 23 kDa fragments increased the sensitivity of CHO cells to cisplatin-induced apoptosis. These results indicate that Bcl-2 can be cleaved into two close fragments by different caspases during cisplatin-induced apoptosis, both of which contribute to the acceleration of apoptotic process.
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PMID:Bcl-2 cleavages at two adjacent sites by different caspases promote cisplatin-induced apoptosis. 1745 97


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