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)

We examined the interaction between the multikinase inhibitor sorafenib and histone deacetylase inhibitors. Sorafenib and vorinostat synergized (sorafenib + vorinostat) to kill HCT116 and SW480 cells. In SW480 cells, sorafenib + vorinostat increased CD95 plasma membrane levels and promoted death-inducing signal complex (DISC) formation, and drug toxicity was blocked by knockdown of CD95 or overexpression of cellular FLICE-like inhibitory protein (c-FLIP-s). In SW620 cells that are patient-matched to SW480 cells, sorafenib + vorinostat toxicity was significantly lower, which correlated with a lack of CD95 activation and lower expression of ceramide synthase 6 (LASS6). Overexpression of LASS6 in SW620 cells enhanced drug-induced CD95 activation and enhanced tumor cell killing, whereas knockdown of LASS6 in SW480 cells suppressed CD95 activation. Knocking down LASS6 expression also suppressed CD95 activation in hepatoma, pancreatic, and ovarian cancer cells. In HCT116 cells, sorafenib + vorinostat treatment caused DISC formation without reducing c-FLIP-s expression and did not increase CD95 plasma membrane levels; sorafenib + vorinostat exposure killed HCT116 cells via an intrinsic pathway/caspase 9-dependent mechanism. In HCT116 cells, knockdown of CD95 enhanced sorafenib + vorinostat lethality, which correlated with less drug-induced CD95-dependent autophagy. Sorafenib + vorinostat treatment activated the c-Jun NH(2)-terminal kinase pathway, which was causal in promoting dissociation of Beclin1 from BCL-2, and in promoting autophagy. Knockdown of Beclin1 expression blocked autophagy and enhanced drug toxicity. Our data demonstrate that treatment of colon cancer cells with sorafenib + vorinostat activates CD95 via de novo ceramide synthesis that promotes viability via autophagy or degrades survival via either the extrinsic or intrinsic pathways.
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PMID:Sorafenib and vorinostat kill colon cancer cells by CD95-dependent and -independent mechanisms. 1948 4

Lgr5 (leucine-rich-repeat-containing G-protein-coupled receptor 5), a recently discovered intestinal stem cell marker, is expressed in premalignant lesions including Barrett's esophagus (BE) and cancers including colon cancer, ovarian cancer, and hepatocellular carcinoma. It was also recently found to be expressed in tumor spheres prepared from colon cancer, suggesting that it will likely serve as a cancer stem cell marker. We sought to examine Lgr5 as a biomarker in BE-associated neoplasia. Using standard immunohistochemistry, we performed immunostaining on 81 esophageal specimens (53 biopsy specimens and 28 surgical resections) representing BE, BE-associated dysplasia, and esophageal adenocarcinoma (EAC). Each immunostain was scored based on intensity of immunostaining and percentage of positive cells. For 24 EAC cases, survival analysis was performed with expression scores and other clinicopathological variables. We found that Lgr5 expression was detected in 70% of BE cases and between 90 and 100% of advanced dysplastic lesions and EAC. The intensity of expression was significantly higher in high-grade dysplasia and EAC than BE. In EAC, high Lgr5 expression scores (> or = 5) were associated with worse survival, independent of stage, age, and neoadjuvant/adjuvant therapy (P = 0.03). Our findings suggest that Lgr5 has potential utility as a biomarker for BE-associated dysplasia and EAC.
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PMID:Lgr5, an intestinal stem cell marker, is abnormally expressed in Barrett's esophagus and esophageal adenocarcinoma. 1954 12

VEGFR inhibitors are in broad use for the treatment of metastatic renal-cell carcinoma, gastrointestinal stromal tumors and hepatocellular carcinoma and in development in a number of other oncology indications, including colorectal cancer, non-small-cell lung cancer, pancreatic cancer, thyroid malignancies, ovarian cancer, breast cancer and sarcomas. This Review outlines the structure-activity relationships of the 44 VEGFR inhibitors currently in development. An overview of the pharmacokinetic profile of each molecule and its stage in development is provided. Phase III clinical trials being conducted for licensing of these agents for specific indications and phase III developmental efficacy trials are described in detailed tables that include the disease studied, trial design including combination therapy, study end points, and projected or final accrual. The relative frequency of on-target and off-target adverse events observed in 3,060 patients is described for a subset of agents in development in clinical trials sponsored by the National Cancer Institute. No interagent comparisons were undertaken and no data from pharmaceutical pharmacovigilance databases were used. The on-target effects seem to be mechanistically based and predicted by VEGFR inhibition. Small-molecule inhibitors of angiogenesis are active in a wide variety of malignancies and fill a unique niche for cancer therapeutics.
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PMID:An overview of small-molecule inhibitors of VEGFR signaling. 1973 52

In previous studies, rhein, one of the major bioactive constituents in the rhizome of rhubarb, inhibited the proliferation of various human cancer cells. However, because of its water insolubility, the anti-tumor efficacy of rhein was limited in vivo. In this study, we observed the anti-tumor activity of rhein lysinate (the salt of rhein and lysine easily dissolves in water) in vivo and investigated its mechanism. Inhibition of ovarian cancer SKOV-3 cell proliferation was determined by MTT assay and the mechanism of action of rhein lysinate was investigated by Western blot analysis. The therapeutic efficacy of rhein lysinate was evaluated by intragastric and intraperitoneal administrations in H22 hepatocellular carcinoma mice. Rhein lysinate inhibited the proliferation of SKOV-3 cells and the IC50 value was 80 microM. Rhein lysinate inhibited the phosphorylation of MEK and ERK and increased the anti-tumor activity of Taxol in vitro. It inhibited tumor growth by both intragastric and intraperitoneal administrations and improved the therapeutic effect of Taxol in H22 hepatocellular carcinoma mice. In conclusion, rhein lysinate offers an anti-tumor activity in vivo and is hopeful to be a chemotherapeutic drug.
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PMID:Rhein lysinate suppresses the growth of tumor cells and increases the anti-tumor activity of Taxol in mice. 1988 52

Arginine, a semi-essential amino acid in humans, is critical for the growth of human cancers, particularly those marked by de novo chemoresistance and a poor clinical outcome. In addition to protein synthesis, arginine is involved in diverse aspects of tumour metabolism, including the synthesis of nitric oxide, polyamines, nucleotides, proline and glutamate. Tumoural downregulation of the enzyme argininosuccinate synthetase (ASS1), a recognised rate-limiting step in arginine synthesis, results in an intrinsic dependence on extracellular arginine due to an inability to synthesise arginine for growth. This dependence on extracellular arginine is known as arginine auxotrophy. Several tumours are arginine auxotrophic, due to variable loss of ASS1, including hepatocellular carcinoma, malignant melanoma, malignant pleural mesothelioma, prostate and renal cancer. Importantly, targeting extracellular arginine for degradation in the absence of ASS1 triggers apoptosis in arginine auxotrophs. Several phase I/II clinical trials of the arginine-lowering drug, pegylated arginine deiminase, have shown encouraging evidence of clinical benefit and low toxicity in patients with ASS1-negative tumours. In part, ASS1 loss is due to epigenetic silencing of the ASS1 promoter in various human cancer cell lines and tumours, and it is this silencing that confers arginine auxotrophy. In relapsed ovarian cancer, this is associated with platinum refractoriness. In contrast, several platinum sensitive tumours, including primary ovarian, stomach and colorectal cancer, are characterised by ASS1 overexpression, which is regulated by proinflammatory cytokines. This review examines the prospects for novel approaches in the prevention, diagnosis and treatment of malignant disease based on ASS1 pathophysiology and its rate-limiting product, arginine.
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PMID:Arginine deprivation and argininosuccinate synthetase expression in the treatment of cancer. 2010 27

ERC/mesothelin is highly expressed in malignant mesothelioma, pancreatic cancer, and ovarian cancer. It is cleaved to a 30 kDa N-terminal secretory form (N-ERC) and a 40 kDa C-terminal membranous form (C-ERC). Several functions have been reported for full-length ERC (full-ERC) and C-ERC/mesothelin, such as in cell adhesion and invasion, stimulation of cell proliferation, and the suppression of cell death. However, there have been no studies to date on the function of secretory N-ERC, despite the fact that it is abundantly secreted into the sera of mesothelioma patients. In this study, we investigated whether N-ERC could function as a secretory factor to stimulate tumor progression. Full-, N, or C-ERC was overexpressed in the human hepatocellular carcinoma cell line Huh7 that lacks endogenous expression of ERC/mesothelin. Changes in the rates of cell proliferation and cell death were determined, and the state of signal transducers was examined using various endpoints: total cell counts, trypan blue exclusion rate, BrdU incorporation rate, TUNEL assay, and the phosphorylation of ERK1/2 and Stat3. In cells overexpressing N-ERC, phosphorylation of ERK1/2 was enhanced and the rate of cell death decreased, leading to the increase of cell number. The culture medium containing the secretory N-ERC also had the activity to increase the number of cells. Our data suggested that one of the full-ERC functions reported previously was mediated by the secretory N-ERC.
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PMID:Suppression of cell death by the secretory form of N-terminal ERC/mesothelin. 2059 97

Homeobox genes encode transcription factors that are essential for normal development and are often dysregulated in cancers. The molecular mechanisms that cause their misregulation in cancers are largely unknown. In this study, we investigate the mechanism by which the Six1 homeobox protein, which has a crucial role during development, is frequently deregulated in several poor outcome, aggressive, metastatic adult human cancers, including breast cancer, ovarian cancer, hepatocellular carcinoma and pediatric malignancies such as rhabdomyosarcoma and Wilms' tumor. Our results reveal that miRNA-185 translationally represses Six1 by binding to its 3'-untranslated region. Analyses of ovarian cancers, pediatric renal tumors and multiple breast cancer cell lines showed decreased miR-185 expression, paralleling an increase in Six1 levels. Further investigation revealed that miR-185 impedes anchorage-independent growth and cell migration, in addition to suppressing tumor growth in vivo, implicating it to be a potent tumor suppressor. Our results indicate that miR-185 mediates its tumor suppressor function by regulating cell-cycle proteins and Six1 transcriptional targets c-myc and cyclin A1. Furthermore, we show that miR-185 sensitizes Six1-overexpressing resistant cancer cells to apoptosis in general and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in particular. Together, our findings suggest that the altered expression of the novel tumor suppressor miR-185 may be one of the central events that leads to dysregulation of oncogenic protein Six1 in human cancers.
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PMID:MicroRNA-185 suppresses tumor growth and progression by targeting the Six1 oncogene in human cancers. 2060 20

Bioassay-guided fractionation of an ethanol extract of the roots of the endemic Malagasy plant Pongamiopsis pervilleana led to the isolation of the three new compounds (2'R)-4'-hydroxyemoroidocarpan (1), pongavilleanine (3), and epipervilline (4) together with two known compounds, identified as emoroidocarpan (2) and rotenolone (5). The structures of all compounds were determined by physical, chemical, and spectroscopic evidence. The stereochemistry at C-2' of the previously reported compound emoroidocarpan was determined to be R by the observation of a negative Cotton effect at 474 nm in the CD spectrum of its osmate ester derivative. Compounds 2-5 displayed moderate antiproliferative activity against the A2780 human ovarian cancer cell line, and rotenolone also showed micromolar antiproliferative activity toward the breast cancer BT-549, prostate cancer DU 145, NSCLC NCI-H460, and colon cancer HCC-2998 cell lines.
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PMID:Antiproliferative compounds from Pongamiopsis pervilleana from the Madagascar Dry Forest. 2080 65

Thy1/CD90 is an important marker of many types of stem cells. It functions as a tumor suppressor in ovarian cancer and in nasopharyngeal carcinoma. In this study, the expression status of Thy1 in clinical hepatocellular carcinoma (HCC) tissue samples was investigated. Relationships of Thy1 expression with clinical parameters and patient survival rate were analyzed. The quantities of Thy1 mRNA were statistically higher in tumor tissues than those in the adjacent non-tumor tissues (p<0.001). Immunohistochemical data confirmed that Thy1 protein was increased in 73% of HCC samples. Thy1 expression was not influenced by chronic alcohol exposure or cirrhosis. Overexpression in Thy1 was correlated with age (p=0.006), hepatitis B virus (HBV) infection (p=0.044), and histological grade (p=0.014). Patients with the highest level of Thy1 expression showed the poorest prognosis (p=0.040). In conclusion, overexpression of Thy1 may not suppress the development of HCC. Thy1 could provide a clinical prognostic marker for HCC.
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PMID:Overexpression of Thy1/CD90 in human hepatocellular carcinoma is associated with HBV infection and poor prognosis. 2127 24

Cytochrome P450 proteins are the most important enzymes involved in metabolic activation or detoxification of various drugs used in clinical practice. However, some drug metabolism pathways may be responsible for their increased toxicity. New expression systems of cytochrome P450 proteins in mammalian cells, including human, are designed to explore the influence of metabolism on the cellular and molecular mechanisms of action of potential drugs and those used therapeutically. They can also be used to study the effect of tested compounds on activity and expression of metabolizing enzymes. Human tumor cell lines with overexpression of cytochrome P450 isoenzymes are of particular importance, especially in studies of potential chemotherapeutics. The HepG2 cell line, derived from human liver cancer, is the most commonly used in studies on drug metabolism and toxicity. However, due to the low level of metabolizing enzymes in these cells, the Hep3A4 cell line with overexpression of CYP3A4 isoenzyme was developed. The stable overexpression of cytochrome P450 isoenzymes was also obtained in other human cancer cell lines, including hepatoma HepaRG cells, ovarian cancer IGROV-1 cells, colon cancer Caco-2, and LS180 cells. This review describes currently developed bacterial, yeast, insect and mammalian (including human) cytochrome P450 protein expression systems, in terms of their advantages and disadvantages in the context of their suitability for basic research and use on a commercial scale.
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PMID:[Expression systems of cytochrome P450 proteins in studies of drug metabolism in vitro]. 2173 21


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