Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular mechanisms behind the anti-neoplastic effects of non-steroidal anti-inflammatory drugs (NSAIDs) are not completely understood and cannot be explained by the inhibition of the cyclooxygenase (COX) enzymes COX-1 and COX-2 alone. We previously reported that both the selective COX-1 inhibitor SC-560 and the selective COX-2 inhibitor CAY10404 exhibit anti-tumor effects in human hepatoma cells. NSAID inhibitors have many COX-independent actions and, among others, the mitogen-activated protein kinase (MAPK) pathways are targets for NSAIDs. Here, we examined the role of MEK/ERK1/2 signaling in the anti-neoplastic effects of both selective COX-1 and COX-2 inhibitors in two human hepatoma cell lines. Treatment of hepatoma cells with the selective COX-1 inhibitor SC-560, as well as with the selective COX-2 inhibitor CAY10404, was associated with activation of ERK1/2 in a time- and dose-dependent manner. Treatment with COX-1 and COX-2 inhibitors in the presence of the selective MEK1/2 inhibitor U0126 effectively suppressed ERK1/2 activation and combinations of either SC-560 or CAY10404 with U0126 resulted in synergistic effects on cell growth inhibition and induction of apoptosis. In HuH-6 hepatoma cells the combination-induced apoptosis was associated with caspase-9 and -3 activation, PARP cleavage, release of cytochrome c from the mitochondria into the cytosol and down-regulation of survivin and beta-catenin levels. In conclusion, our study showed that growth inhibitory concentrations of selective COX-1 and COX-2 inhibitors increased ERK1/2 phosphorylation in hepatoma cells, and that inhibition of the MEK/ERK signaling pathway potentiates the antitumor activity of both types of inhibitors. Therefore, our results provide preclinical support for a combined chemotherapeutic approach with selective NSAIDs and MEK inhibitors for the treatment of hepatocellular carcinoma.
 ...
PMID:Potentiation of the antitumor effects of both selective cyclooxygenase-1 and cyclooxygenase-2 inhibitors in human hepatic cancer cells by inhibition of the MEK/ERK pathway. 1842 14

Cyclooxygenase (COX)-2 appears to play an important role in gastrointestinal carcinogenesis, and COX-2 overexpression has been demonstrated both in esophageal adenocarcinomas and lymph nodes metastasis. The aim of our study was to investigate the mechanism of growth inhibitory effect of selective inhibition of COX-2 by NS-398 on human cancer cells. The esophageal cancer cell lines (EC9706) that express COX-2 permanently and hepatocellular carcinoma cell lines (SMMC7721) while no expression of COX-2 were studied. Two kinds of cell lines were treated with various concentrations of NS-398 (selective for COX-2 inhibition) at 0.01-0.1 mM for 24 h, 48 h and 72 h. Antiproliferation effect was measured by 3H-TdR incorporation. The cell apoptosis were determined by flow cytometry (FCM) and DNA fragmentation analysis. Survivin was detected by immunocytochemical technique. The growth inhibition could be induced by NS398 in a dose- and time-dependent manner in two kinds of cell lines. FCM analysis revealed a high sub-G1 cell peak in EC9706 group. Agarose electrophroesis showed marked apoptosis ladder pattern, but no apoptosis by NS-398 in SMMC7721. The difference of apoptosis percentage in EC9706 and SMMC7721 was (45.23 +/- 1.08)% and (3.05 +/- 0.15)% (p < 0.001). After 24 h incubation with NS-398 at concentration of 0.1 dmM, the expression of survivin was markedly reduced in EC9706, but not in SMMC7721. We conclude that the administration of a selective inhibitor of COX-2 significantly decreases cell growth in cancer cell lines by different mechanism. NS-398 could inhibit cell proliferation in cancer cells whether or no COX-2 expression. Nevertheless, apoptosis in the cancer cells expressing COX-2 protein increase more than those lacking COX-2.
 ...
PMID:Mechanism of growth inhibitory effects of cyclooxygenase-2 inhibitor-NS398 on cancer cells. 1844 52

We previously reported that HS-1200, a synthetic chenodeoxycholic acid derivative, has apoptosis-inducing activity in various human cancer cells. The present study was undertaken to examine whether HS-1200 had an anticancer effect on HepG2 (wild-type p53) and Hep3B (p53 deleted) human hepatoma cells. Treatment of both cells with HS-1200 resulted in growth inhibition and induction of apoptosis as measured by MTT assay, nuclear staining, DNA fragmentation and flow cytometry analysis. The increase in apoptosis was associated with the alteration in the ratio of Bcl-2/Bax protein expression. In addition, flow cytometry analysis indicated that HS-1200 induced G1 phase arrest in both cells. When analyzing the expression of cell cycle-related proteins, we found that HS-1200 reduced the expression levels of cyclin D1, cyclin A, and Cdk2. HS-1200 treatment also caused an increase in the expression levels of p21 WAF1/CIP1 in HepG2 cells in a p53-dependent manner and in Hep3B cells in a p53-independent manner. Moreover, the expression level of p27 KIP1 was increased in both cell lines. We also observed that HS-1200 decreased the levels of cyclooxygenase (COX)-2 mRNA and protein expression. Furthermore, HS-1200 treatment markedly induced the Egr-1 expression at an early time point, and the increased expression levels of p53, p21 WAF1/CIP1, p27 KIP1, and COX-2 after treatment with HS-1200 were completely inhibited in HepG2 cells and partially inhibited in Hep3B cells by silencing of Egr-1, respectively. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anticancer activity of the synthetic bile acid derivative, HS-1200, through Egr-1 regulation.
 ...
PMID:A chenodeoxycholic derivative, HS-1200, induces apoptosis and cell cycle modulation via Egr-1 gene expression control on human hepatoma cells. 1855 81

The oncogenic hepatitis B virus X protein (HBx) and cyclooxygenase (COX)-2 are highly co-expressed in chronic hepatitis, cirrhosis and well-differentiated hepatocellular carcinoma (HCC). Although HBx is shown to activate COX-2, the functional consequences of this interaction in hepatocarcinogenesis remain unknown. Using an engineered hepatoma cell system in which the expression of wild-type p53 can be chemically modulated, we show here that COX-2 mediates HBx actions in opposing p53. Enforced expression of HBx sequestrates p53 in the cytoplasm and significantly abolishes p53-induced apoptosis. The anti-apoptotic Mcl-1 protein is suppressed by p53 but reactivated by HBx. The abrogation of apoptosis is completely reversed by specific COX-2 inhibition, suggesting that HBx blocks p53-induced apoptosis via activation of COX-2/PGE(2) pathway. We further show that COX-2 inhibition blocks HBx reactivation of Mcl-1, linking this protein to the anti-apoptotic function of COX-2. These results demonstrate that COX-2 is an important survival factor mediating the oncogenic actions of HBx. Over-expression of HBx and COX-2 may provide a selective clonal advantage for preneoplastic or neoplastic hepatocytes and contribute to the initiation and progression of HCC.
 ...
PMID:COX-2 mediates hepatitis B virus X protein abrogation of p53-induced apoptosis. 1860 5

The aim of this study was to investigate the expression of prostaglandin E(2) receptors (EP(1-4)), cyclooxygenase-1 (COX-1), and COX-2 in nontumor and tumor human liver tissues, and also to evaluate the antitumor activity of selective EP(1) receptor antagonist used alone or in combination with COX-1 and COX-2 selective inhibitors. Semiquantitative PCR analyses revealed that EP(1-4), COX-1, and COX-2 mRNA expression was detected in nearly all the tissue samples assayed, although with a high variability between nontumor and tumor tissues. In vitro EP(1) receptor antagonist inhibited anchorage-independent cell growth and reduced the viability of hepatocellular carcinoma (HCC) cells in a dose-dependent manner. Moreover, treatment with the combination of EP(1) receptor antagonist and COX inhibitors produced a significantly greater cell growth inhibition than the single agent alone. These findings suggest that the EP(1) receptor may represent an important target for HCC treatment, and in addition they could provide preclinical support for a combined chemotherapeutic approach with EP(1) antagonists and COX inhibitors in the treatment of liver cancer.
 ...
PMID:Prostaglandin E2 receptors and COX enzymes in human hepatocellular carcinoma: role in the regulation of cell growth. 1925 Feb 21

Morin--a bioflavonoid is a naturally available dietary agent believed to impede cancer promotion and progression. The present study was conducted to decipher, in vivo, the role of morin on the expression of matrix metalloproteinases, cyclooxygenase (COX)-2 and nuclear factor kappa B (NF-kappaB)-p65 during diethylnitrosamine (DEN)-induced hepatocarcinogenesis in Wistar albino rats. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed that administration of DEN (200 mg/kg bodyweight in drinking water) to experimental animals caused inflammation of the liver due to up-regulation of NF-kappaB-p65 and COX-2. RT-PCR and immunoblot analysis also revealed that the oral supplementation of morin (500 ppm in diet) to DEN-induced hepatocellular carcinoma rats down-regulated the expression of COX-2 and NF-kappaB-p65, thereby preventing inflammation and angiogenesis mediated hepatocellular carcinogenesis. Further, immunohistological analysis for NF-kappaB-p65 nuclear localization confirms the above observations. Gelatin zymography was performed for matrix metalloproteinase MMP-2 and MMP-9 expression to confirm their role in angiogenesis in DEN induced hepatocellular carcinoma and its modulation by morin. Both MMP-2 and MMP-9 levels were found to be increased in DEN-induced animals when compared to control. MMP-2 and MMP-9 levels were down-regulated in morin post-treated animals when compared to DEN-induced animals favouring prevention of angiogenesis. In conclusion, our findings indicate that morin possessed anti-inflammatory and anti-cancer properties favouring suppression of DEN-induced hepatocellular carcinoma.
 ...
PMID:Morin regulates the expression of NF-kappaB-p65, COX-2 and matrix metalloproteinases in diethylnitrosamine induced rat hepatocellular carcinoma. 1953 2

Antrodia camphorata, unique fungal specie, has been used as a folk medicine in Taiwan for many years. The purpose of this study was to compare the extracts from the solid-state culture of A. camphorata co-fermented with Chinese medicinal herb (AC-CF) with two other extracts from fruiting bodies (AC-FB) or solid-state culture (AC-SS), for their anti-tumor effects in human hepatoma HepG2 cells. We measured in vitro cell proliferation, percentage of apoptosis, population distribution of cell cycles, Western blot analysis of multiple drugs resistance-1 (MDR-1), and apoptosis-related proteins in HepG2 cells treated with three different preparations of A. camphorate extracts. Our results showed that AC-CF had better anti-proliferation effect on human hepatoma HepG2 cells than AC-FB or AC-SS dose-dependently. In addition, AC-CF in combination with anti-tumor agents (mitomycin C or methotrexate) showed better adjuvant anti-tumor effects than AC-FB or AC-SS. We further demonstrated the augmented adjuvant anti-tumor effects of AC-CF not only through down regulation of MDR-1 expression but also through a COX-2 dependent apoptosis pathway, involving down-regulation of COX-2 and p-AKT and up-regulation of PARP-1. In conclusion, in this study, we have demonstrated a novel strategy of fermenting A. camphorata with Chinese medicinal herb (AC-CF), which augmented their anti-tumor effects in human hepatoma HepG2 cells as compared to the traditional ones (AC-FB or AC-SS).
 ...
PMID:The augmented anti-tumor effects of Antrodia camphorata co-fermented with Chinese medicinal herb in human hepatoma cells. 1965 14

The role of COX-2 in the regulation of the expression of MDR1, a P-glycoprotein involved in hepatocellular carcinoma cell line, HepG2, was studied in the present investigation. Celecoxib, a selective inhibitor of COX-2, at 25 microM concentration increased the accumulation of doxorubicin in HepG2 cells and enhanced the sensitivity of the cells to doxorubicin by tenfold. The induction of MDR1 expression by PGE2 and its downregulation by celecoxib or by COX-2 knockdown suggests that the enhanced sensitivity of HepG2 cells to doxorubicin by celecoxib is mediated by the downregulation of MDR1 expression, through COX-2-dependent mechanism. Further studies revealed the involvement of AP-1 in the celecoxib-induced downregulation of MDR1 expression. These experimental studies correlated well with in silico predictions and further suggested the inactivation of the signal transduction pathways involving ERK, JNK and p38. The present study thus demonstrates the usefulness of COX-2 intervention in overcoming the drug resistance in HepG2 cells.
 ...
PMID:Celecoxib inhibits MDR1 expression through COX-2-dependent mechanism in human hepatocellular carcinoma (HepG2) cell line. 1968 55

Hepatocellular carcinoma (HCC) is one of the most common cancer-related causes of death, and conventional treatments offer unsatisfactory response. We have previously reported that kallistatin gene therapy suppressed the growth of HCC tumors by its anti-angiogenic activity, and meloxicam, a selective COX-2 inhibitor, inhibited proliferation and induced apoptosis of human HCC cells in vitro. The aim of this study was to determine whether combining kallistatin gene therapy and meloxicam could offer a better therapeutic effect to combat HCC in mice. A kallistatin expression plasmid was constructed and its expression was detected after intratumoral gene transfer. Both kallistatin gene therapy and meloxicam suppressed the growth of subcutaneous human HepG2 tumors established in BALB/c nude mice, and the combinational therapy showed a stronger effect in suppressing tumor growth, tumor angiogenesis and cell proliferation, and increasing cell apoptosis, than the respective monotherapies. Gene transfer of kallistatin inhibited tumor angiogenesis, and slightly inhibited cell proliferation and increased cell apoptosis in situ, but had no effect on expression of vascular endothelial growth factor, basic fibroblast growth factor, proliferating cell nuclear antigen, Bcl-2, Bax, or activation of caspase-3. Meloxicam therapy inhibited cell proliferation, induced cell apoptosis, reduced expression of proliferating cell nuclear antigen, increased activation of caspase-3, and upregulated Bax. Meloxicam also slightly inhibited tumor angiogenesis with no effect on the expression of vascular endothelial growth factor or basic fibroblast growth factor. Combining two novel anticancer agents, kallistatin targeting tumoral vascularization and meloxicam targeting cell proliferation and apoptosis, warrants investigation as a therapeutic strategy to combat HCC.
 ...
PMID:Combining kallistatin gene therapy and meloxicam to treat hepatocellular carcinoma in mice. 1970 25

Hepatocellular carcinoma (HCC), one of the most lethal cancers, results in more than one million fatalities worldwide every year. In view of the limited therapeutic alternatives and poor prognosis of liver cancer, preventive control approaches, notably chemoprevention, have been considered to be the best strategy in lowering the present prevalence of the disease. Resveratrol, a naturally occurring antioxidant and antiinflammatory agent found in grapes and red wine, inhibits carcinogenesis with a pleiotropic mode of action. Recently, we have reported that dietary resveratrol significantly prevents chemically-induced liver tumorigenesis in rats. One of the mechanisms of resveratrol-mediated chemoprevention of hepatocarcinogenesis could be related to its antiinflammatory action through hepatic cyclooxygenase (COX-2) inhibition. Although several COX-2 inhibitors are known to exert chemopreventive efficacy, not all are considered ideal candidates for chemoprevention due to the risk of adverse cardiovascular events. Accordingly, the objective of the present study was to evaluate the role of resveratrol on cardiac performance during experimental hepatocarcinogenesis initiated with diethylnitrosamine and promoted by phenobarbital. Rats had free access to diet supplemented with resveratrol four weeks before the carcinogen injection and 14 weeks thereafter. The cardiotoxicity of resveratrol was assessed by monitoring the cardiac function using transthoracic echocardiography as well as Western blot analysis of cardiac tissue. Long-term dietary administration of resveratrol dose-dependently suppressed hepatic tumor multiplicity, the principal endpoint for evaluating the chemopreventive potential of a candidate agent. The chemopreventive effects of resveratrol were also reflected in histopathological assessment of hepatic tissues. Resveratrol did not exhibit any cardiotoxicity but rather improved the cardiac function in a dose-responsive fashion. Our results indicate that resveratrol-mediated chemoprevention of rat liver carcinogenesis is devoid of any adverse cardiovascular events. Resveratrol may be developed as a chemopreventive as well as therapeutic drug for human HCC.
 ...
PMID:Chemopreventive doses of resveratrol do not produce cardiotoxicity in a rodent model of hepatocellular carcinoma. 1981 93


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>