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)

Thioredoxin reductase reduces thioredoxin, thereby contributing to multiple cellular events related to carcinogenesis including cell proliferation, apoptosis, and cell signaling. This selenium-containing oxidoreductase is over-expressed in many malignant cells and has been proposed as a target for cancer therapy. Ifosfamide is an oxazaphosphorine alkylating agent with a broad spectrum of antineoplastic activity. The purpose of this study is to test the hypothesis that anticancer efficacy of ifosfamide may rely on its ability to inhibit thioredoxin reductase in tumor. To inspect the consequence of thioredoxin reductase inhibition by ifosfamide on tumor cell proliferation, mice bearing hepatoma 22 (H22) cells in ascites were injected with 350 mg/kg ifosfamide. Thioredoxin reductase activity was maximally inhibited by half at 6 h, and a subsequent pronounced cellular proliferation inhibition due to cell cycle arrest in G(1) phase was found. Moreover, at 6 h, except thioredoxin reductase inhibition, ifosfamide did not affect cell cycle or other measured antioxidant enzymes activity in the tumor cells. Intriguingly, when these cells were injected into healthy mice, they totally lost the capacity of causing either ascitic or solid tumors. Thioredoxin reductase inhibition could also be found in solid H22 tumor by 62%, bladder by 74% and kidney by 37% at 6 h. Overall, these observations provide direct evidence that inhibition of thioredoxin reductase activity in malignant cells by ifosfamide is highly associated with its anticancer effect and the mechanism of ifosfamide systemic toxicity may be related to multi-organ inhibition of thioredoxin reductase activity.
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PMID:Thioredoxin reductase inactivation as a pivotal mechanism of ifosfamide in cancer therapy. 1802 6

An element/compound that acts as an antioxidant as well as, can increase the oxidative stress offers a new approach in differentiation therapy. Experiments were carried out to determine the effect of selenite on DNA damage and glutathione peroxidase (GPx) activity in N-nitrosodiethylamine (DEN) induced, phenobarbital promoted rat hepatoma. Supra-nutritional level of selenite (4 ppm) was supplemented at either, before-initiation/after-initiation and/or during entire period of the study. At the end of experiment period (20 weeks), extent of DNA damage (alkaline comet assay), selenium concentration, and GPx activity were assessed on nodular tissue (NL) cells, surrounding liver (SL) cells, and whole liver tissue (control) cells. Hepatic selenium level and GPx activity were decreased in DEN and PB-administered animals, whereas the DNA damage was found to be increased in both NL and SL cells compared with control group. However, the DNA damage is more in SL cells than in NL cells. Pre-supplementation of selenite did not show any difference in DNA (strand breaks) damage, selenium, and GPx activity. Increased hepatic selenium concentration and GPx activity were observed in both NL and SL cells in post-supplementation and entire period of selenite supplemented animals compared to DEN + PB treated animals. However, DNA damage was increased in NL but decreased in SL cells. Supplementation of selenite alone for 16 or 20 weeks had shown increased DNA damage, selenium concentration, and GPx activity compared to normal control animals. In summary, cancer bearing animals increased DNA damage and decreased Se level and GPx activity in NL and SL cells and other organs in cancer bearing animals, supplementation of Se further provoked DNA damage (no change in pretreatment) in NL cells, however it decreased DNA damage SL cells and other organs (kidney, lungs, and spleen). On the other hand Se levels and GPx activity were increased in NL and SL cells and other organs of Se-supplemented rats (no difference in group 3 animals). These results demonstrate that, in addition to chemopreventive and chemotherapeutic role of selenite, it also prevents cellular DNA damage induced in cancerous condition.
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PMID:Sodium selenite enhances glutathione peroxidase activity and DNA strand breaks in hepatoma induced by N-nitrosodiethylamine and promoted by phenobarbital. 1815 6

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that have promoting activity in the liver. PCBs induce oxidative stress, which may influence carcinogenesis. Epidemiological studies strongly suggest an inverse relationship between dietary selenium (Se) and cancer. Despite evidence linking Se deficiency to hepatocellular carcinoma and liver necrosis, the underlying mechanisms for Se cancer protection in the liver remain to be determined. We examined the effect of dietary Se on the tumor promoting activities of two PCBs congeners, 3,3', 4,4'-tetrachlorobiphenyl (PCB-77) and 2,2', 4,4', 5,5'-hexachlorobiphenyl (PCB-153) using a 2-stage carcinogenesis model. An AIN-93 torula yeast-based purified diet containing 0.02 (deficient), 0.2 (adequate), or 2.0 mg (supplemental) selenium/kg diet was fed to Sprague-Dawley female rats starting ten days after administering a single dose of diethylnitrosamine (150 mg/kg). After being fed the selenium diets for 3 weeks, rats received four i.p. injections of either PCB-77 or PCB-153 (150 micromol/kg) administered every 14 days. The number of placental glutathione S-transferase (PGST)-positive foci per cm(3) and per liver among the PCB-77-treated rats was increased as the Se dietary level increased. Unlike PCB-77, rats receiving PCB-153 did not show the same Se dose-response effect; nevertheless, Se supplementation did not confer protection against foci development. However, the 2.0 ppm Se diet reduced the mean focal volume, indicating a possible protective effect by inhibiting progression of preneoplastic lesions into larger foci. Cell proliferation was not inhibited by Se in the liver of the PCB-treated groups. Se did not prevent the PCB-77-induced decrease of hepatic Se and associated reduction in glutathione peroxidase (GPx) activity. In contrast, thioredoxin reductase (TrxR) activity was not affected by the PCBs treatment or by Se supplementation. These findings indicate that Se does not inhibit the number of PGST-positive foci induced during promotion by PCBs, but that the size of the lesions may be inhibited. The effects of Se on altered hepatic foci do not correlate with its effects on GPx and TrxR.
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PMID:Effect of dietary selenium on the promotion of hepatocarcinogenesis by 3,3', 4,4'-tetrachlorobiphenyl and 2,2', 4,4', 5,5'-hexachlorobiphenyl. 1829 42

Selenium is an important trace element with anti-cancer properties. In the present study, the apoptosis-inducing effects of organic selenium derivatives, namely methyl-L-selenocysteine and selenomethionine, were evaluated in vitro on human tumour-derived cell lines from breast, liver, colon, brain, skin and a non-tumorigenic line of epithelial origin. Apoptosis was assessed by cell-death detection immunoassay on cytoplasmic cell lysates. Breast carcinoma cells were highly sensitive to the organic selenium compounds, manifesting apoptosis at concentrations as low as 0.113 microm (0.0205 microg/ml) selenium. By contrast, non-tumorigenic mammary epithelial cells displayed poor sensitivity to selenium, requiring a substantially high concentration of the trace element of 87.9 microm (16.0 microg/ml). The cell lines derived from hepatoma and neuroblastoma showed intermediate sensitivity, with colon carcinoma cells manifesting the lowest sensitivity to the trace element. These results indicate intrinsic differences in the sensitivity of human tumour derivatives to selenium-mediated apoptosis, providing experimental support for the development of organic selenium compounds as anti-neoplastic agents against solid tumours displaying selective apoptotic sensitivity to these compounds.
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PMID:Differential sensitivity of various human tumour-derived cell types to apoptosis by organic derivatives of selenium. 1854 10

Allylic hydroxylated derivatives of the C18 unsaturated fatty acids were prepared from linoleic acid (LA) and conjugated linoleic acids (CLAs). The reaction of LA methyl ester with selenium dioxide (SeO(2)) gave mono-hydroxylated derivatives, 13-hydroxy-9Z,11E-octadecadienoic acid, 13-hydroxy-9E,11E-octadecadienoic acid, 9-hydroxy-10E,12Z-octadecadienoic acid and 9-hydroxy-10E,12E-octadecadienoic acid methyl esters. In contrast, the reaction of CLA methyl ester with SeO(2) gave di-hydroxylated derivatives as novel products including, erythro-12,13-dihydroxy-10E-octadecenoic acid, erythro-11,12-dihydroxy-9E-octadecenoic acid, erythro-10,11-dihydroxy-12E-octadecenoic acid and erythro-9,10-dihydroxy-11E-octadecenoic acid methyl esters. These products were purified by normal-phase short column vacuum chromatography followed by high-performance liquid chromatography (HPLC). Their chemical structures were characterized by liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance spectroscopy (NMR). The allylic hydroxylated derivatives of LA and CLA exhibited moderate in vitro cytotoxicity against a panel of human cancer cell lines including chronic myelogenous leukemia K562, myeloma RPMI8226, hepatocellular carcinoma HepG2 and breast adenocarcinoma MCF-7 cells (IC(50) 10-75 microM). The allylic hydroxylated derivatives of LA and CLA also showed toxicity to brine shrimp with LD(50) values in the range of 2.30-13.8 microM. However these compounds showed insignificant toxicity to honeybee at doses up to 100 microg/bee.
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PMID:Synthesis and biological activity of hydroxylated derivatives of linoleic acid and conjugated linoleic acids. 1914 41

One hundred and ninety-three Sprague-Dawley (SD) rats (average body weight being 100-120 g) were randomly divided into 5 groups (I-V). Animals in group I and group II served as the negative control and positive control, respectively, and both received 0.1 mg/kg selenium (Se) from sodium selenite. Animals in groups III-V were fed with Se from Se-enriched malt (SEM) supplemented diets (0.3, 1 and 3 mg/kg, respectively). Simultaneously, hepatocarcinoma were induced in groups II-V by diethylnitrosamine (DEN) solution (100 mg/L) at the dosage of 10 mg/kg body weight every day as drinking water for 16 weeks, then sterilized water for a further two weeks. Rats of group I drank sterilized water during the whole experimental time. At 4th, 8th, 12th, 16th week, five rats in each group were then sacrificed by cervical decapitation. At the termination of the study, at 18th week, the surplus rats were sacrificed by cervical decapitation. Feed was withheld from the rats for 12h before sampling. The values of plasma glucose at different sampling times were measured. The values of the hormones in plasma related to plasma glucose metabolism, including insulin, glucagon, insulin-like growth factors-II (IGF-II), and the ratios of insulin/glucose (IGR(1)), insulin/glucagon (IGR(2)) and glucagon/glucose (GGR) were determined. At the same time, the correlation of plasma glucose concentrations related to hormones was statistically analyzed. The results indicated that the values of plasma glucose, insulin, glucagon and GGR in the groups treated with DEN were decreased significantly as compared with that of the negative control group, however, the values of IGF-II and IGR(2) were increased significantly. SEM showed a significant effect in suppressing the decreased of plasma glucose and glucagons, and delaying the increased of IGF-II and IGR(2) in the DEN-induced hepatocarcinoma rats. The plasma glucose concentrations revealed a significant relation to the hormones. In conclusion, SEM could reduce the development of hypoglycemia in the DEN-induced hepatocarcinoma rats by regulating the relative levels and balances or proportions of hormones.
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PMID:Effect of selenium-enriched malt on hypoglycemia and regulatory hormones in diethylnitrosamine-induced hepatocarcinoma SD rats. 1952 Apr 6

Selenium-containing thioredoxin reductase (TrxR) is an important target of cancer therapy. Many useful anticancer agents including bis-alkylating agents, cisplatin, and arsenic trioxide are known to interact with the selenocysteine dipeptide in the carboxy terminal region of thioredoxin reductase and inactivate its ability to reduce thioredoxin. Some investigators have postulated that the inactivation of TrxR may add to the cytotoxic potential of these anticancer agents. TH-302 is a newly developed antineoplastic drug which represents a potential new class of tumor selective hypoxia-activated prodrugs (HAPs). TH-302 is an inactive prodrug created by the covalent conjugation of 2-nitroimidazole as an oxygen sensor to bromo-isophosphoramide (Br-IPM). In the presence of severe hypoxia and near anoxia, the two imidazole sensor moiety undergoes reduction and the Br-IPM is released in situ. Bromo-IPM is a more potential analog of Chloro-IPM, the active alkylating moiety that is derived by activation of ifosfamide (IFO). We previously demonstrated that IFO could inhibit tumor TrxR activity and chloro-IPM is known to bind covalently to the seleno-cysteine dipeptide in thioredoxin reductase. The present study assessed the ability of TH-302 to activate in the tumors of mice-bearing hepatoma 22 (H22) and inactivate the tumor TrxR. In mice-bearing hepatoma 22 (H22) solid tumors, intraperitoneal (i.p.) injection with TH-302 at the dose of 200 mg/kg administered twice, a regimen which was well tolerated by the mice, significantly inhibited tumor growth. Also in this mice model, i.p. TH-302 at the dose of 300 mg/kg, which would be the maximum single i.p. administration dose tolerated by mice, and which induced only 2% body weight loss, significantly inhibited both TrxR and glutathione reductase (GR) activities by 46% (P < 0.001) and 60% (P < 0.001) as compared with the controls, respectively, at 3 h after the injection. Since TrxR is a key player in thioredoxin system and GR is the major reductase for the reduction of oxidized glutathione in glutathione system, the present results imply the anticancer effect of TH-302 is associated concurrently with modulation of TrxR and GR. These findings suggest that the anticancer activity of TH-302 in this model system may associate with both DNA alkylation and the modulation of TrxR and GR. In addition, they suggest that, by inhibition of these two critical reductases, with less glutathione available to intercept the reactive intermediates involved in DNA alkylation, the antitumor effects of the chemotherapy would be enhanced.
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PMID:Inhibition of both thioredoxin reductase and glutathione reductase may contribute to the anticancer mechanism of TH-302. 1983 42

Hepatocellular carcinoma (HCC) happens to be one of the most lethal cancers in the world. Even though most cases occur in the developing world, reported cases in Western Europe as well as North America are on a steep rise. Human HCC etiology includes chronic liver disease, viral hepatitis, alcoholism, iron overload as well as dietary carcinogens such as aflatoxins and nitrosoamines. Surgical resection as well as liver transplants, which are currently used to treat HCC, is mostly ineffective. Consequently, there exists a decisive requirement to explore possible alternative chemopreventive and therapeutic strategies for HCC. Both oxidative stress and inflammatory mechanisms have been implicated in the pathophysiology of HCC. The use of dietary antioxidants and micronutrients has been proposed as an effective means for successful management of human HCC. Trace elements such as vanadium and selenium are involved in several major metabolic pathways as well as antioxidant defense systems. Selenium has been shown to be involved in the prevention of numerous chronic illnesses such as several specific cancers and neurodegenerative diseases. This review examines the potential role of selenium in the prevention and treatment of HCC. The in vivo and in vitro effects of selenium and the mechanisms involved in preclinical models of liver cancer are critically reviewed in this article. The chemopreventive and therapeutic effects of selenium are reviewed especially in relation to its antioxidant property. Future directions and potential challenges involved in the advance of selenium use in the prevention and treatment of liver cancer are also discussed.
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PMID:Selenium in the prevention and treatment of hepatocellular carcinoma. 2038 Jun 34

In this review, the role of dietary antioxidants in the prevention of hepatocarcinogenesis is examined. Both human and animal models are discussed. Vitamin C, vitamin E, and selenium are antioxidants that are essential in the human diet. A number of non-essential chemicals also contain antioxidant activity and are consumed in the human diet, mainly as plants or as supplements, including beta-carotene, ellagic acid, curcumin, lycopene, coenzyme Q(10), epigallocatechin gallate, N-acetyl cysteine, and resveratrol. Although some human and animal studies show protection against carcinogenesis with the consumption of higher amounts of antioxidants, many studies show no effect or an enhancement of carcinogenesis. Because of the conflicting results from these studies, it is difficult to make dietary recommendations as to whether consuming higher amounts of specific antioxidants will decrease the risk of developing hepatocellular carcinoma.
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PMID:Dietary antioxidants in the prevention of hepatocarcinogenesis: a review. 2051 89

Chronic B and C virus hepatitis (HBV and HCV) are the most important risk factors in the development of hepatocellular carcinoma (HCC). About 40-50% of HCC is induced by these two chronic viral infections. Prevalence of HCC is slowly increasing in the United States and in Western-Europe, whereas alcohol consumption is gradually decreasing in the majority of these countries. However, the most important environmental risk factor for HCC is still the heavy long-term alcohol use. The risk of cirrhosis and HCC increases linearly, wherever ethanol intake is greater than 60 g/day for men and women. Aflatoxin, which contaminates grains, mostly in China and Africa, is a well-known mycotoxin. Since geographical distribution of aflatoxin as well as HBV overlaps with each other, they have a synergistic effect on inducing HCC. Cigarette smoking has also hepatocarcinogenic effect, which is significantly enhanced by the concomitant alcohol use or chronic viral hepatitis. Obesity, non-alcoholic fatty liver and steatohepatitis as well as diabetes mellitus together also form a significant risk for HCC, due to the gradually increasing number of patients. Insulin resistance and oxidative stress are the major pathogenetic mechanisms leading to hepatic cell injury in these patients. Oral contraceptive drugs may also play a role in the development of HCC. The long-term exposure to organic solvents is also a risk factor for HCC. Dietary antioxidants, selenium, statins and coffee drinking have protective effect against HCC.
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PMID:[Role of environmental factors in the etiology of hepatocellular carcinoma]. 2057 Jul 93


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