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)

Cellular senescence is a process leading to terminal growth arrest with characteristic morphological features. This process is mediated by telomere-dependent, oncogene-induced and ROS-induced pathways, but persistent DNA damage is the most common cause. Senescence arrest is mediated by p16(INK4a)- and p21(Cip1)-dependent pathways both leading to retinoblastoma protein (pRb) activation. p53 plays a relay role between DNA damage sensing and p21(Cip1) activation. pRb arrests the cell cycle by recruiting proliferation genes to facultative heterochromatin for permanent silencing. Replicative senescence that occurs in hepatocytes in culture and in liver cirrhosis is associated with lack of telomerase activity and results in telomere shortening. Hepatocellular carcinoma (HCC) cells display inactivating mutations of p53 and epigenetic silencing of p16(INK4a). Moreover, they re-express telomerase reverse transcriptase required for telomere maintenance. Thus, senescence bypass and cellular immortality is likely to contribute significantly to HCC development. Oncogene-induced senescence in premalignant lesions and reversible immortality of cancer cells including HCC offer new potentials for tumor prevention and treatment.
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PMID:Senescence and immortality in hepatocellular carcinoma. 1907 Apr 23

Peroxisomes play an important role in bile acid biosynthesis because the last steps of the synthesis pathway are performed by the beta-oxidation system located inside peroxisomes. As a consequence, C(27)-bile acid intermediates accumulate in several peroxisomal disorders. It has been suggested that C(27)-bile acids are especially toxic and contribute to the liver disease associated with peroxisomal disorders. For this reason, we investigated the toxicity of C(27)-bile acids and the underlying mechanisms. We studied the effects of conjugated and unconjugated C(27)-bile acids on cell viability, mitochondrial respiratory chain function and production of oxygen radicals in the rat hepatoma cell line McA-RH7777. Cell viability decreased progressively after incubation with increasing concentrations of different bile acids with dihydroxycholestanoic acid (DHCA) being clearly the most cytotoxic bile acid. In addition, the different bile acids caused a dose-dependent decrease in ATP synthesis by isolated mitochondria oxidizing malate and glutamate. Finally, there was a dose-dependent stimulation of ROS generation in the presence of C(27)-bile acids. In conclusion, our studies showed that C(27)-bile acids are more cytotoxic than mature C(24)-bile acids. In addition, C(27)-bile acids are potent inhibitors of oxidative phosphorylation and enhance mitochondrial ROS production by inhibiting the respiratory chain.
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PMID:Toxicity of peroxisomal C27-bile acid intermediates. 1913 87

Luteolin has been shown to exhibit anti-cancer activity against several forms of cancers, including human hepatic cancers. Many in vitro studies have reported anti-oxidant effects of luteolin. Here, we demonstrate using ROS (reactive oxygen species) detection in the human hepatocellular carcinoma cell line, Huh-7, that anti-cancer action of luteolin are mediated through an increasing in intracellular ROS levels. To identify proteins potentially involved in this mechanism, a two-dimensional electrophoresis (2-DE)-based-proteomic approach was employed. Proteomic analysis revealed that several proteins were associated with the anti-cancer effects of luteolin. Interestingly, these proteins included peroxiredoxin 6 (PRDX6) and prohibitin (PHB), which are implicated in ROS metabolism and apoptosis. Western blot analyses confirmed the expression of these proteins in Huh-7 cells following luteolin application. On the basis of these results, we suggest that PRDX6 and PHB are key targets of luteolin that the mechanism of luteolin-induced apoptosis in Huh-7 cells is mediated through effects involving intracellular ROS.
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PMID:Proteomic identification of anti-cancer proteins in luteolin-treated human hepatoma Huh-7 cells. 1934 56

Cadmium, mercury and rotenone are environmental pollutants whose neurotoxic mechanisms are not fully understood. We have shown previously that exposure of nerve cells to these agents produces oxidative stress which reversibly blocks growth factor and cytokine-mediated Janus kinase (Jak)/signal transducer and activator of transcription (STAT) signaling. Here we determined a critical role for mitochondrial dysfunction in inhibiting Jak/STAT activity in human BE(2)-C neuroblastoma cells. Exposure of BE(2)-C cells to the heavy metals CdCl(2) and HgCl(2) and to the mitochondrial complex I inhibitor rotenone inhibited interleukin-6, interferon-gamma and ciliary neurotrophic factor-mediated Jak/STAT signaling, reduced Jak1 and Jak2 auto-phosphorylation and induced Jak tyrosine nitration. However, identical exposure of HepG2 hepatoma cells produced no inhibition of these cytokine responses. In contrast, mitochondria in both BE(2)-C and HepG2 cells showed reduced mitochondrial membrane potential and increased superoxide production after exposure to CdCl(2), HgCl(2) and rotenone. Further, in an in vitro Jak auto-phosphorylation assay Jak2 isolated from either BE(2)-C or HepG2 cells was equally inhibited by mitochondria made dysfunctional by treatment with CdCl(2), HgCl(2) and rotenone. Each of these pro-oxidant effects was reversed by the mitochondrial antioxidant alpha-lipoic acid. The actions of cadmium were also blocked by the mitochondrial complex III bypass agent, 2,6-dichloroindophenol. Therefore, in BE(2)-C cells CdCl(2), HgCl(2) and rotenone disrupt mitochondria to increase intracellular ROS, which directly inhibits neuronal Jak tyrosine kinase activity. Non-neuronal cells such as HepG2 cells that are resistant to oxidative stress-mediated inhibition of cytokine signaling possess some as yet unknown mechanism that protects Jak kinases from oxidative insults. Pro-oxidant-induced mitochondrial dysfunction resulting in selective neuronal Jak inhibition provides a potential mechanism for environmental agents to promote neurodegeneration.
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PMID:Environmental toxicants inhibit neuronal Jak tyrosine kinase by mitochondrial disruption. 1963 91

Sorafenib (Nexavar, BAY43-9006), a bi-arylurea, is a newly established anti-cancer drug and its functional attribute of cytotoxicity is based on the multi-kinase inhibitory action. Here, we report yet another novel pathway in which sorafenib can induce apoptotic cell death preferentially and efficaciously on an experimentally proven drug- and radio-resistant human Hep G2 cells via a mitochondria-dependent oxidative stress mechanism. A real time confocal imaging assay revealed that sorafenib could rapidly provoke the production of ROS plethorically, mainly concentrating in the mitochondria, albeit substantial amounts of ROS could also be detected in cytosol and nucleus. The rapid production of ROS could simultaneously induce intracellular glutathione (iGSH) depletion. A nearly 90% of iGSH was found to be depleted in 1h period after the cells received the drug treatment. Besides mitochondria, iGSH depletion could also be detected in other cellular compartment including cytoplasm and nucleus. Interestingly, we also demonstrated that sorafenib could trigger mitochondrial Ca(2+) overload. All these events compoundedly serve as the final arbitrator to initiate lethal apoptotic process through the release of cytochrome c and caspase 3/7 activation. Collectively, we provide first evidence here that sorafenib can provoke an alternative pathway for apoptosis induction of Hep G2 cells through a mitochondria-dependent oxidative stress mechanism which is independent of original kinase inhibitory attribute of the drug action. Most importantly, we also demonstrate that sorafenib can effectively eradicate a highly drug- and radio-resistant HCC cells. Thus, our data can provide the basis for a potential applicability of sorafenib in a combined treatment modality.
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PMID:Sorafenib induces preferential apoptotic killing of a drug- and radio-resistant Hep G2 cells through a mitochondria-dependent oxidative stress mechanism. 1977 May 76

Fenretinide, a synthetic retinoid, is known to induce apoptosis in various cancer cells. However, the mechanism by which fenretinide induces apoptosis remains unclear. The current study examines the mechanisms of fenretinide-induced apoptosis in human hepatoma cells. The induction of Nur77 and the cytoplasmic distribution of Nur77 induced by fenretinide were positively correlated with the apoptotic effect of fenretinide in HCC cells. The sensitivity of Huh-7 cells was related to Nur77 translocation and targeting mitochondria, whereas the mechanism of resistance for HepG2 cells seemed due to Nur77 accumulating in the nucleus. The intracellular location of Nur77 was also associated with the differential capability of fenretinide-induced ROS generation in these two cell lines. In addition, the knockdown of Nur77 expression by siRNA greatly reduced fenretinide-induced apoptosis and cleaved caspase 3 in Huh-7 cells. Therefore, our findings demonstrate that fenretinide-induced apoptosis of HCC cells is Nur77 dependent and that the intracellular localization of Nur77 dictates the sensitivity of the HCC cells to fenretinide-induced apoptosis.
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PMID:Induction and intracellular localization of Nur77 dictate fenretinide-induced apoptosis of human liver cancer cells. 1991 93

Peroxiredoxins are thiol-specific antioxidants that catalyze the reduction of cellular peroxides and protect cells from ROS-mediated damage and death. Peroxiredoxin gene expression is up-regulated in a number of cancers, suggesting a possible role in cancer cell maintenance. Prdx6, a cytoplasmic protein elevated in certain cancers, is highly expressed in liver and transcriptionally regulated by various oxidative stresses. In the present study, we found that the cancerous Hepa1-6 hepatoma cell line is significantly more resistant to peroxide-induced cytotoxicity than the non-cancerous H2.35 cell line. We also demonstrated that Hepa1-6 cells express approximately 3-fold more Prdx6 mRNA and 2.5-fold more Prdx6 protein than H2.35 cells. Treatment with mithramycin A resulted in a nearly 20% reduction in Prdx6 mRNA in Hepa1-6 cells, suggesting a possible role for Sp1 in Prdx6 up-regulation. We hypothesized that suppression of Prdx6 in Hepa1-6 cells would increase susceptibility to peroxide-induced cell death. Transient transfection of Hepa1-6 cells with Prdx6 siRNA led to a marked reduction in Prdx6 expression, and an increase in peroxide-induced cytotoxicity by apoptosis. Together, these data demonstrate an important anti-apoptotic function for Prdx6 in cancerous liver cells, and suggest that its up-regulation may be a tumor-supportive adaptation in cancerous states.
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PMID:Overexpression of Prdx6 and resistance to peroxide-induced death in Hepa1-6 cells: Prdx suppression increases apoptosis. 2000 13

3-(4-(Benzo[d]thiazol-2-yl)-1-phenyl-1H-pyrazol-3-yl) phenyl acetate (DPB-5) is a synthetic benzothiazole derivative. In the present study, we revealed that DPB-5 had strong cytotoxicity to induce cell apoptosis, which was mediated by ROS. And DPB-5 was more cytotoxic toward hepatoma cells than toward normal hepatic cells, which was resulted from the greater susceptibility of the malignant cells to ROS. DBP-5 caused massive ROS accumulation and GSH decrease, which lead to MMP disruption, caspase activation and finally induced cell apoptosis. Additionally, rotenone, an inhibitor of mitochondria electron transport system, effectively blocked the ROS elevated effect of DPB-5, which suggested that DPB-5-induced ROS generated from the mitochondria. Further studies showed that DPB-5-induced cell apoptosis through caspases-cascade, but failed to activate caspase-9. Hence, we concluded that DPB-5-induced Hep G2 cells apoptosis via a ROS-mediated pathway which was caspase-dependent but did not rely on caspase-9.
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PMID:3-(4-(Benzo[d]thiazol-2-yl)-1-phenyl-1H-pyrazol-3-yl) phenyl acetate induced Hep G2 cell apoptosis through a ROS-mediated pathway. 2001 82

Using Seidel ascites hepatoma as a model, we studied in detail changes in cell population size and in the level of reactive oxygen species in the tumor growth zone and in the blood plasma of tumor carrier. It was found that reduction-oxidation conditions in the blood plasma and in the tumor growth zone were different. Thus, because of hyperactivity and increase in the number of leukocytes, the blood plasma exhibited strong oxidative stress inducing damage to healthy cells, whereas the tumor growth zone showed the decrease in macrophage concentration, as well as in oxygen and ROS levels. These conditions favor intensive growth of tumor cells.
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PMID:[Variations in cell population size and reactive oxygen species level in the blood and the ascites liquid of tumor carrier]. 2035 95

Isoniazid (INH) is a first-line antibiotic used in the treatment of infections caused by Mycobacterium tuberculosis. However it has a serious limitation of being hepatotoxic. Delineating the mechanism underlying INH-induced hepatotoxicity may be beneficial in devising ways to counteract its toxic manifestations. Studies in human hepatoma HepG2 cells have indicated that INH exposure causes induction of apoptosis. This study was aimed at identifying the key components/pathways of the INH-induced apoptotic pathway using HepG2 cells. HepG2 cells were exposed to increasing concentrations of INH (6.5, 13, 26, and 52 mM). Hydrogen peroxide (0.3 mM) served as positive control. After incubating for specific time intervals cells were harvested and evidences of cytotoxicity, oxidative stress, and apoptosis were sought. The findings indicated that INH exposure causes increased ROS generation along with alteration in levels of enzymatic antioxidants such as Superoxide dismutase, Catalase, and Glucose-6-Phosphate dehydrogenase. Altered Bcl-2/Bax content, cytochrome-c translocation, caspase activation, and DNA fragmentation emphasized involvement of apoptosis.
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PMID:Isoniazid-induced apoptosis in HepG2 cells: generation of oxidative stress and Bcl-2 down-regulation. 2043 47


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