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 earlier demonstrated that hsp68 is deficiently induced upon stress in the glucocorticoid-resistant, dedifferentiated Reuber rat hepatoma clone 2 cells, but is strongly activated in the differentiated, glucocorticoid-sensitive Faza 967 cells from which clone 2 was derived. We used the two cell types to address the questions whether hsp68 is specifically involved in the development of thermotolerance and/or thermoresistance or drug resistance. Our experiments show that clone 2 cells were not protected from the killing effect of heat by pre-treatment with sodium arsenite, whereas Faza 967 cells were. These results strongly suggest a role of hsp68 in the development of thermotolerance in hepatoma cells. Stable heat-resistant variants of clone 2 cells were also isolated, where an increased basal expression of several hsps was observed together with the (at least partial) restoration of the heat-inducibility of hsp68. These results suggest that several hsps are needed to protect the critical biological processes at high temperature. The heat-resistant hepatoma cells also became resistant to several anticancer drugs. The multidrug resistance of the hepatoma variants correlates with the overexpression of the plasma membrane P-glycoprotein. Our results showing that severely stressed hepatoma cells overexpressed the mdr gene(s) raise the possibility that the P-gp may participate in protection against environmental stress such as heat.
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PMID:The function of heat-shock proteins in stress tolerance. 791 98

The cytotoxic mechanism of a conjugate of doxorubicin (DXR) and glutathione (GSH) via glutaraldehyde (GSH-DXR) was investigated using DXR-sensitive (AH66P) and -resistant (AH66DR) rat hepatoma cells. GSH-DXR accumulated in AH66DR cells as well as in AH66P cells without efflux by P-gp and exhibited the potent cytocidal activity against both cells compared with DXR. To examine whether thiol from GSH-DXR affected the expression of cytotoxicity, two conjugates of DXR, with modified peptides containing alanine or serine substituted for cysteine in GSH were prepared and their cytotoxicities determined. Substitution of these amino acids for cysteine resulted in an approximately two- to fourfold reduction in cytotoxic activity against both cell lines compared with the effect of GSH-DXR. Depletion of intracellular GSH by treatment of both cells with buthionine sulphoximine did not change the cytotoxic activity of DXR, BSA-DXR or GSH-DXR. By co-treating the cells with tributyltin acetate, an inhibitor of glutathione S-transferase (GST), and either DXR, BSA-DXR or GSH-DXR, the cytotoxicity was markedly increased. Interestingly, GSH-DXR showed non-competitive inhibition of GST activity and its IC50 value was 1.3 microM. These results suggested that the inhibition of GST activity by GSH-DXR must be an important contribution to the expression of potent cytotoxicity of the drug.
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PMID:Glutathione-doxorubicin conjugate expresses potent cytotoxicity by suppression of glutathione S-transferase activity: comparison between doxorubicin-sensitive and -resistant rat hepatoma cells. 937 80

P-gp (Pgp) is a cell surface ATPase which confers resistance to many of the most active chemotherapy drugs, including taxol, doxorubicin, and vinca alkaloids. Pgp can be detected in human cancers by immunohistochemistry, RNA probes, or by functional assays utilizing transported fluorescent dyes such as rhodamine. The expression of Pgp in untreated human cancers is highly variable, being almost universal in colon, hepatocellular carcinoma, and renal cell cancers, less common in breast, ovarian, and lymphoid malignancies. At least part of the heterogeneity is attributable to different definitions of positivity even with a given method of detection. In chemotherapy naive cancers, resistant cells may not occur very frequently. Whilst the Goldie-Coldman hypothesis predicts treatment failure if 1 cell in 10(6) expresses a resistance mechanism, no method of detection yet described can reliably achieve this. The field has reached a stage in which it may be possible to detect Pgp accurately in advanced cancers which have failed chemotherapy allowing phase II clinical trials to be performed in Pgp-positive tumors. In terms of which Pgp inhibitors are selected for clinical study it is likely that selection of Pgp inhibitors with nM potency to bind to Pgp will be important. Such drugs should undergo extensive phase I trial evaluation to assess pharmacokinetic interactions with a range of cytotoxic drugs before entering randomized trials. In randomized clinical trials Pgp detection may be less important, as disease-free survival and overall survival would be the key end-points, but the Pgp positivity of relapsed disease would indicate if treatment with inhibitors of Pgp-eliminated Pgp-expressing clones. The accurate detection of Pgp in human cancers is being refined and will be an essential component of future Pgp inhibitor clinical trials. Finally, these trails must be of sufficient size (> 500 patients per arm) to reliably detect clinically meaningful differences.
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PMID:Testing the role of P-glycoprotein expression in clinical trials: applying pharmacological principles and best methods for detection together with good clinical trials methodology. 947 46

Whether the phenotypes of drug resistance and metastatic activity in cancer are dependent on each other or not is controversial. We compared in vitro invasive properties of human hepatoma cells resistant to epirubicin and rich in P-glycoprotein (Pgp) (HB8065/R) with the parental epirubicin-sensitive, Pgp-poor cells (HB8065/S). The HB8065/R cells displayed elevated capacity to migrate in a transwell chamber assay (three- to fourfold compared to the HB8065/S cells), both in the absence and presence of a reconstituted basement membrane extract (Matrigel). In the presence of the P-gp inhibitor PSC 833 (1.5 micrograms/ml) the capacity of the HB8065/R cells to cross Matrigel-coated filters was attenuated by approximately 25%. Compared to the HB8065/S cells, the resistant cell line expressed higher level of plasminogen activator inhibitor (PAI)-1 mRNA (approximately threefold), which was reflected by a approximately fivefold increase in secreted PAI-1 immunoactivity (approximately 50 ng/10(6) HB8065/R cells). Furthermore, treatment with PSC 833 was associated with upregulation of PAI-1 mRNA (approximately 3.5-fold) and immunoactivity (approximately twofold) in the HB8065/R cells. Level of tissue inhibitor of metalloproteinases (TIMP)-1 was also significantly increased in the HB8065/R cells compared to the HB8065/S cells, whereas both cell lines showed low constitutive expression of TIMP-2. Levels of TIMPs were not altered by PSC 833. These data suggest that overexpression of Pgp in these hepatoma cells may covariate with the phenotypes of both enhanced in vitro invasiveness and high PAI-1 expression, whether randomly acquired or not.
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PMID:Human hepatoma cells rich in P-glycoprotein display enhanced in vitro invasive properties compared to P-glycoprotein-poor hepatoma cells. 980 60

The multidrug resistance protein 2 (MRP2, symbol ABCC2) transports anionic conjugates and certain amphiphilic anions across the apical membrane of polarized cells. Human hepatoma Hep G2 cells retain hepatic polarity and form apical vacuoles into which cholephilic substances are secreted. Immunofluorescence microscopy showed that human MRP2 was expressed in the apical vacuole membrane of polarized Hep G2 cells, whereas the isoform MRP3 was localized to the lateral membrane. Expression of both MRP2 and MRP3 was confirmed by immunoblotting and reverse transcription PCR. Fluo 3 secretion into the apical vacuoles was inhibited by cyclosporin A but not by selective inhibitors of multidrug resistance 1 P-glycoprotein. In addition, carboxyfluorescein, rhodamine 123, and the fluorescent bile salt derivatives ursodeoxycholyl-(Nepsilon-nitrobenzoxadiazolyl)-lysine and cholylglycylamido-fluorescein were secreted into the apical vacuoles; the latter two probably via the bile salt export pump. We conclude that MRP2 mediates fluo 3 secretion into the apical vacuoles of polarized Hep G2 cells. Thus the function of human MRP2 and the action of inhibitors can be analyzed by the secretion of fluorescent anions such as fluo 3.
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PMID:MRP2, a human conjugate export pump, is present and transports fluo 3 into apical vacuoles of Hep G2 cells. 1076 5

Cancer chemotherapy with taxol often fails due to acquired resistance of cancer cells, which is frequently associated with an overexpression of P-gp and alterations of beta-tubulin. A taxol-resistant cell line, QGY-TR50, derived from a human hepatocellular carcinoma (HCC) QGY-7703 cell line was used to investigate the mechanisms of taxol-resistance. QGY-TR50 cells showed more than 250-fold resistance to taxol and exhibited cross-resistance to other drugs including actinomycin D, doxorubicin, vinblastine, and vincristine. P-gp was highly expressed in QGY-TR50 cells. Expression levels of five human beta-tubulin isotypes (betaI-, betaII-,betaIII-, betaIva, and betaIvb-tubulin) were examined by real-time semi-quantitative PCR. Comparing with QGY-7703 cells, QGY-TR50 cells did not show any significant change in the expression levels of betaI-, betaIva, and betaIvb-tubulin. While a 1.2-fold increased in betaII-tubulin and a 0.5-fold decreased in betaIII-tubulin levels were observed. All results suggest that the P-glycoprotein could be one key factor involved in enhancing drug resistance in QGY-TR50 cells.
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PMID:Study of multi-drug resistant mechanisms in a taxol-resistant hepatocellular carcinoma QGY-TR 50 cell line. 1116 60

It has been proposed that ceramide mediates anthracyclin-induced apoptosis and that drug resistance may arise due to upregulated removal of this active lipid through glucosylation. We report that HepG2 hepatoma cells displayed only a modest apoptotic response to doxorubicin treatment, accompanied by a substantial elevation of ceramide levels only at toxic drug concentrations. D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) and D,L-threo-1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol (PPPP), used at concentrations causing a 90% inhibition of ceramide glucosylation, enhanced doxorubicin-elicited ceramide elevation, but only PDMP potentiated apoptosis. Exogenously administered ceramide had only a marginal apoptotic effect on HepG2 cells; moreover, even in this case, apoptosis was propagated by PDMP but not by PPPP. PDMP moderately inhibited P-glycoprotein activity only at the highest concentration tested, but its chemosensitizing effect was still outstanding at lower concentrations, at which P-gp inhibition was no longer observed. These results demonstrate that the chemosensitizing effect of PDMP is, at least partly, independent from its activity as a glucosylceramide synthase inhibitor. Moreover, P-glycoprotein inhibition is not central to the phenomenon.
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PMID:Differential chemosensitizing effect of two glucosylceramide synthase inhibitors in hepatoma cells. 1159 84

Overexpression of mdr1-type P-glycoproteins (P-gps) is thought to contribute to primary chemotherapy resistance of untreated hepatocellular carcinoma. However, mechanisms of endogenous multidrug resistance 1 (mdr1) gene activation still remain unclear. Because recent studies have demonstrated overexpression of cyclooxygenase-2 (COX-2) in hepatocytes during early stages of hepatocarcinogenesis, we investigated whether the COX system, which catalyzes the rate-limiting step in prostaglandin synthesis, participates in mdr1 gene regulation. In the present study, primary rat hepatocyte cultures, exhibiting time-dependent mdr1b overexpression, demonstrated basal COX-2 and COX-1 mRNA expression and liberation of prostaglandin E(2) (PGE(2)), indicative of an active COX-dependent arachidonic acid metabolism. PGE(2) accumulation in culture supernatants was further enhanced by arachidonic acid (1mumol/L) and epidermal growth factor (EGF) (16 nmol/L). PGE(2) and prostaglandin F(2alpha) (PGF(2)alpha) (3-6mug/mL), added directly to the culture medium, significantly up-regulated intrinsic mdr1b mRNA overexpression and mdr1-dependent transport activity. Up-regulation was maximal after 3 days of culture. Like prostaglandins, the COX substrate, arachidonic acid, also induced mdr1b gene expression. Apart from this, structurally different COX inhibitors (indomethacin, meloxicam, NS-398) mediated significant inhibition of time-dependent and EGF-induced mdr1b mRNA overexpression, resulting in enhanced intracellular accumulation of the mdr1 substrate, rhodamine 123 (Rho123). Thus, the present data support the conclusion that the release of prostaglandins through activation of the COX system participates in endogenous mdr1b gene regulation. COX-2 inhibition might constitute a new strategy to counteract primary mdr1-dependent chemotherapy resistance.
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PMID:The cyclooxygenase system participates in functional mdr1b overexpression in primary rat hepatocyte cultures. 1214 66

To reverse multidrug resistance(MDR) of HepG2 by anti-MDR1 hammerhead ribozyme, an anti-MDR1 hammerhead ribozyme was developed and delivered to P-gp-overproducing human hepatocarcinoma cell line HepG2 by a retroviral vector containing RNA polymerase III promoter. The expression of mdr1/Pgp and Rz was detected in HepG2, HepG2 multidrug-resistant cell line and HepG2 Rz-transfected cells by semi-quantitative RT-PCR and Western blot methods. Moreover, MTT assay was employed to detect the sensitivity of these ribozyme-transfected cells, and Rhodamine123 (Rh123) was used to test the function of Pgp. The Rz- transfected HepG2 cells became doxorubicin-sensitive, which was concomitant with the decreased MDR1 expression. The study showed that the retrovirus vector encoding the anti-MDR1 ribozyme may be applicable to the treatment of MDR cells.
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PMID:Reversal of HCC drug resistance by using hammerhead ribozymes against multidrug resistance 1 gene. 1669 19

Hepatocellular carcinoma (HCC) is one of the most common malignant cancers closely associated with chronic infection by the hepatitis B virus (HBV) or the hepatitis C virus (HCV) throughout the world. In this study, the genetic associations of 20 known polymorphisms in eight candidate genes, including angiotensinogen (AGT), cadherin 1 (CDH1), cyclooxygenase 2 (COX2), monocyte chemotactic protein-1 (MCP1), multidrug resistance 1 (MDR1), chemokine ligand 5 (RANTES), thrombospondin 2 (THBS2), and thrombospondin 4 (THBS4), were analyzed in a large chronic hepatitis B cohort (n=1,095) recruited from the Korean population. In addition, three polymorphisms in chemokine receptor 4 (CXCR4) and vimentin (VIM) identified in this study were also genotyped. Using logistic regression analysis controlling possible confounding factors, one common (freq.=0.367) promoter polymorphism of MCP1 (MCP1-2518G>A) among analyzed polymorphisms was significantly associated with clearance of HBV infection. The frequency of homozygotes for the MCP1-2518A allele (MCP1-2518A/A) among chronic hepatitis B virus (HBV) carrier patients was significantly higher than that among spontaneously recovered (SR) subjects (17.7% vs. 10.4%)(OR=1.78, P=0.004). Our findings imply a plausible explanation for the contribution of host genetic determinants to the variable outcome of HBV infection, which might provide valuable information for future genetic study in this area.
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PMID:Association of common promoter polymorphisms of MCP1 with hepatitis B virus clearance. 1720 46


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