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)

After successful clinical application, arginine deiminase (ADI) has been proposed to be a new cancer therapeutic. In the present study, we examined the effect of ADI in combination with ionizing radiation (IR) on MCF-7 cell growth and clonogenic cell death. Cell growth was inhibited by IR in a dose-dependent manner and ADI enhanced the radiosensitivity. ADI itself did not suppress the growth of MCF-7 cells due to the high level of expression of argininosuccinate synthetase (ASS), which convert citrulline, a product of arginine degradation by ADI, to arginine. Previously, it was suggested that ammonia, another product of arginine degradation by ADI, is the main cause of the growth inhibition of irradiated hepatoma cells contaminated with ADI-expressing mycoplasma [van Rijn et al. (2003)]. However, we found that ammonia is not the only factor that enhances radiosensitivity, as enhancement was also observed in the absence of ammonia. In order to identify the enhancing effect, levels of ASS and proteins related to the cell cycle were examined. ASS was unchanged by ADI plus IR, but p21 (a CDK inhibitor) was upregulated and c-Myc downregulated. These findings indicate that changes in the expressions of cell cycle proteins are involved in the enhancement of radiosensitivity by ADI. We suggest that ADI is a potential adjunct to cancer therapy.
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PMID:Arginine deiminase enhances MCF-7 cell radiosensitivity by inducing changes in the expression of cell cycle-related proteins. 1841 6

Certain cancers may be auxotrophic for a particular amino acid, and amino acid deprivation is one method to treat these tumors. Arginine deprivation is a novel approach to target tumors which lack argininosuccinate synthetase (ASS) expression. ASS is a key enzyme which converts citrulline to arginine. Tumors which usually do not express ASS include melanoma, hepatocellular carcinoma, some mesotheliomas and some renal cell cancers. Arginine can be degraded by several enzymes including arginine deiminase (ADI). Although ADI is a microbial enzyme from mycoplasma, it has high affinity to arginine and catalyzes arginine to citrulline and ammonia. Citrulline can be recycled back to arginine in normal cells which express ASS, whereas ASS(-) tumor cells cannot. A pegylated form of ADI (ADI-PEG20) has been formulated and has shown in vitro and in vivo activity against melanoma and hepatocellular carcinoma. ADI-PEG20 induces apoptosis in melanoma cell lines. However, arginine deprivation can also induce ASS expression in certain melanoma cell lines which can lead to in vitro drug resistance. Phase I and II clinical trials with ADI-PEG20 have been conducted in patients with melanoma and hepatocellular carcinoma, and antitumor activity has been demonstrated in both cancers. This article reviews our laboratory and clinical experience as well as that from others with ADI-PEG20 as an antineoplastic agent. Future direction in utilizing this agent is also discussed.
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PMID:Arginine deprivation as a targeted therapy for cancer. 1847 54

PEGylation which is reversed after the therapeutic agent reaches the target cell presents an attractive feature for drug, protein or nucleic acid delivery. Amine-reactive, endosomal pH cleavable polyethylene glycol aldehyde-carboxypyridylhydrazone, N-hydroxysuccinimide esters (PEG-HZN-NHS) were synthesized and applied for bioreversible surface shielding of DNA polyplexes. Monofunctional mPEG-HZN-NHS was synthesized by reacting succinimidyl hydraziniumnicotinate with mPEG-butyraldehyde (20 kDa). Bifunctional OPSS-PEG-HZN-NHS was synthesized analogously via a omega-2-pyridyldithio-PEG (10 kDa) propionaldehyde intermediate. Polyethylenimine (PEI) polyplexes were reacted with the pH-sensitive (mPEG-HZN-NHS) or the corresponding stable (mPEG-NHS) reagent. Both types of polyplexes remained shielded at pH 7.4 as demonstrated by particle size and zeta potential measurements after 4h of incubation at 37 degrees C. Polyplex deshielding at endosomal pH 5 was observed only with the mPEG-HZN-NHS shielded particles. This was confirmed by fluorescence correlation spectroscopy using the analogous Alexa-488 fluorescently labeled bifunctional PEGylation reagents. Luciferase gene transfections with epidermal growth factor (EGF) containing polyplexes using EGF-receptor overexpressing hepatoma HUH7 cells showed an up to 16-fold enhancement in gene expression with the reversibly shielded polyplexes as compared to stably shielded polyplexes. Consistently, the reversibly shielded polyplexes mediated also an enhanced tumor specific in vivo transgene expression after intravenous administration in a subcutaneous HUH7 tumor model in SCID mice.
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PMID:Amine-reactive pyridylhydrazone-based PEG reagents for pH-reversible PEI polyplex shielding. 1858 70

A 63-year-old man with liver cirrhosis and hepatocellular carcinoma presented with abrupt encephalopathy with markedly elevated blood ammonia levels. He was found lying down in front of the hospital 2 days after treatment of right hypochondrial pain with sustained-release oral morphine sulfate. He tended to be constipated before receiving morphine sulfate. The excess production of ammonia due to his constitutional constipation exacerbated by the use of oral morphine was thought to be the causal association with transient hepatic encephalopathy. He regained consciousness by receiving aminoleban intravenously and anticonstipating suppository. We realized that much care should be taken to avoid such opioid-related constipation at the time of pain management for quality of life improvement in patients with cancer pain.
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PMID:[A case of hepatic encephalopathy induced by adverse effect of morphine sulfate]. 1863 39

Nutritional support may play an important role in management of liver cirrhosis (LC) associated with unresectable hepatocellular carcinoma (HCC). Total protein and albumin deteriorate in patients with LC undergoing trans-arterial chemoembolization (TACE). Therefore, in this study, we examined the hypothesis that short-term administration of branched-chain amino acids (BCAA) will prevent a fall in total protein and albumin in the perioperative period. The subjects were 56 patients who underwent TACE for HCC between 2004 and 2005 at Nagasaki University Hospital. The patients were randomly placed in the BCAA group (n = 28) or a control group (n = 28). The patients in the BCAA group consumed a snack containing 50 g of BCAA once a day at 10:00 pm starting 1 day before TACE and continuing until 2 weeks after TACE. A comparison of baseline and end point data showed greater decreases in the concentrations of total protein, albumin, cholinesterase, and total cholesterol and in the red blood cell count in the control group compared to the BCAA group. Ammonia levels decreased in the BCAA group and increased in the control group. Our findings indicate that a BCAA supplement taken orally as a late evening snack prevents suppression of liver function by TACE in patients with LC complicated with HCC during the 2-week period after TACE.
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PMID:A snack enriched with oral branched-chain amino acids prevents a fall in albumin in patients with liver cirrhosis undergoing chemoembolization for hepatocellular carcinoma. 1928 98

The genus Acanthostrongylophora is famous for producing a wide array of manzamine alkaloids as natural hydrochloride salts. An examination of A. ingens has now yielded two tertiary bases, (+)-8-hydroxymanzamine A (1) and (+)-manzamine A (2), by chromatography over alumina using CHCl3-MeOH-NH3.H2O as solvent. In addition, (+)-8-hydroxymanzamine A hydrochloride (3) and (+)-manzamine A hydrochloride (4) were isolated under the same conditions from the same source by silica gel chromatography. The structures of 1-4 were determined from 1D- and 2D-NMR spectra and by circular dichroism experiments, and the spectral features of the bases 1 and 2 were found to be different from those of the salts 3 and 4. Compounds 3 and 4 were deprotonated by both A12O3 and strong base to afford 1 and 2, which were converted again to their respective salts 3 and 4. Both the compounds 1 and 3 showed equally potent in vitro antimalarial activity against chloroquine-sensitive (D6) and -resistant (W2) strains of P. falciparum (IC50 = 19.5 and 22.0 ng/mL vs. 27.0 and 36.5 ng/mL, respectively), while 2 was >3-fold less potent than 4 (IC50 = 20.8 and 25.8 ng/mL vs. 6.1 and 7.3 ng/mL, respectively). Compounds 1, 3 and 4 showed good antimicrobial activities against methicillin-resistant Staphylococcus aureus and Mycobacterium intracellulare and antileishmanial activity against Leishmania donovani promastigotes. In contrast, manzamine A base (2) showed relatively weaker antimicrobial, antileishmanial and cytotoxic activities [towards cancer (HepG2: Human hepatocellular carcinoma or hepatoma), and non-cancer cells (VERO: Monkey kidney fibroblast; LLC-PK11: Pig kidney epithelial)], compared with salt 4.
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PMID:Bioactive (+)-manzamine A and (+)-8-hydroxymanzamine A tertiary bases and salts from Acanthostrongylophora ingens and their preparations. 1937 Sep 20

Cirrhosis leads to an inability of the liver to perform its biochemical functions. It can also lead to hepatocellular carcinoma in which, as we showed lately, arginase isoenzyme pattern changes. The present work presents our results on arginase isoenzymes and their possible role in liver cirrhosis. The study was performed on tissues obtained during liver transplantation from 60 patients with liver cirrhosis, and on samples of histologically normal liver (control) from 40 patients with benign or colorectal cancer liver metastases removed during surgery, 6-7 cm from the tumor border. Arginase isoenzymes AI (so-called liver-type arginase) and AII (called extrahepatic arginase) were identified by Western blotting and isolated by ion-exchange chromatography. Their expression on mRNA level was studied by RT-PCR. A significant decrease in arginase activity, dependent of the liver clinical stage, was observed in cirrhotic tissue. Arginase AI activity and its mRNA level were significantly decreased in cirrhotic liver, whereas the activity and expression of arginase AII were concurrently raised, as compared to normal liver. Since arginase AI is a key enzyme of the urea cycle, whereas arginase AII most probably takes part in the biosynthesis of ornithine and polyamines, the defective ammonia inactivation and increased collagen biosynthesis observed in cirrhotic liver may be related to the changes in arginase AI and AII levels, respectively.
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PMID:Arginase isoenzymes in human cirrhotic liver. 1963 40

The Wnt/beta-catenin signaling pathway has been increasingly implicated in liver development and physiology. Aberrant activation of this pathway is one of the major genetic events observed during the process of human HCC development. To gain insight into the mechanism underlying beta-catenin action in the liver, we conducted a quantitative differential proteomic analysis using 2-D DIGE combined with MS, in mice with liver-specific deletion of Apc resulting in acute activation of beta-catenin signaling (Apc(KOliv) mice). We identified 94 protein spots showing differential expression between mutant Apc(KOliv) and control mice, corresponding to 56 individual proteins. Most of the proteins identified were associated with metabolic pathways, such as ammonia and glucose metabolism. Our analysis showed an increase in lactate dehydrogenase activity together with a downregulation of two mitochondrial ATPase subunits (ATP5a1 and ATP5b). These observations indicate that beta-catenin signaling may induce a shift in the glucose metabolism from oxidative phosphorylation to glycolysis, known as the "Warburg effect". Imaging with (18)F-fluoro-2-deoxy-D-glucose-positron emission tomography suggests that the specific metabolic reprogramming induced by beta-catenin in the liver does not imply the first step of glycolysis. This observation may explain why some HCCs are difficult to assess by fluoro-2-deoxy-D-glucose-positron emission tomography imaging.
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PMID:Proteomic analysis of beta-catenin activation in mouse liver by DIGE analysis identifies glucose metabolism as a new target of the Wnt pathway. 1963 98

Hepatic encephalopathy (HE) is a common reversible neuropsychiatric syndrome associated with chronic and acute liver dysfunction and significant morbidity and mortality. Although a clear pathogenesis is yet to be determined, elevated ammonia in the serum and central nervous system are the mainstay for pathogenesis and treatment. Management includes early diagnosis and prompt treatment of precipitating factors (infection, gastrointestinal bleeding, electrolyte disturbances, hepatocellular carcinoma, dehydration, hypotension, and use of benzodiazepines, psychoactive drugs, and/or alcohol). Clinical trials have established the efficacy of lactulose and lactitol enemas in the treatment of acute hepatic encephalopathy. Extensive clinical experience has demonstrated the efficacy of oral lactulose and lactitol with the goal of two to three soft bowel movements a day for the treatment of chronic HE. However, lactulose and lactitol have significant gastrointestinal side effects. For patients unable to tolerate lactulose or lactitol or who still have persistent chronic HE with lactulose or lactitol, neomycin, metronidazole and rifaximin are second-line agents. More recent data supports the benefits of rifaximin used solely and as an additional agent with fewer side effects than neomycin or metronidazole. Newer therapies being investigated in humans with clinical promise include nitazoxanide, the molecular adsorbent recirculating system (MARS), L-ornithine phenylacetate, sodium benzoate, and/or sodium phenylacetate and Kremezin((R)) (AST-120).
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PMID:Current trends in the treatment of hepatic encephalopathy. 1970 77

HepG2, hepatocellular carcinoma cells, are used in drug toxicity studies and have also been explored for bioartificial livers. For these applications, the cells are under variable levels of nutrients and hormones, the effects of which on metabolism are poorly understood. In this study, HepG2-C3A cells were cultured under varying levels of glucose (high, low, and glucose-free) and insulin (without and with physiological levels of insulin) for 5 days. Cell growth was found to be comparable between high and low glucose media and lowest for glucose-free medium. Several features of central metabolism were affected profoundly by the medium glucose levels. Glucose consumption was greater for low glucose medium compared to high glucose medium, consistent with known glucose feedback regulation mechanisms. Urea productivity was highest in glucose-free medium. Further, it was seen that lactate acted as an alternative carbon source in the absence of glucose, whereas it acted as a sink for the high and low glucose media. Using a metabolic network flexibility analysis (MNFA) framework with stoichiometric and thermodynamic constraints, intracellular fluxes under varying levels of glucose and insulin were evaluated. The analysis indicates that urea production in HepG2-C3A cells arises via the arginase II pathway rather than from ammonia detoxification. Further, involvement of the putrescine metabolism with glutamine metabolism caused higher urea production in glucose-free medium consistent with higher glutamine uptake. MNFA indicated that in high and low glucose media, glycolysis, glutaminolysis, and oxidative phosphorylation were the main sources of energy (NADH, NADPH, and ATP). In the glucose-free medium, due to very low glycolytic flux, higher malate to pyruvate glutaminolytic flux and TCA cycle contributed more significantly to energy metabolism. The presence of insulin lowered glycerol uptake and corresponding fluxes involved in lipid metabolism for all glucose levels but otherwise exerted negligible effect on metabolism. HepG2-C3A cells thus show distinct differences from primary hepatocytes in terms of energy metabolism and urea production. This knowledge can be used to design media supplements and metabolically engineer cells to restore necessary hepatic functions to HepG2-C3A cells for a range of applications.
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PMID:Effects of glucose and insulin on HepG2-C3A cell metabolism. 2050 78


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