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)

Thioalkyl K vitamin derivatives, like 2-(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone (Cpd 5), have been shown to inhibit both hepatoma cell growth and DNA synthesis in rat hepatocytes in vitro. We have here examined the tissue distribution, in vivo tolerance and growth inhibitory effects of a single injected dose of Cpd 5 in rats. Cpd 5 administered i.p. was sufficient to cause a 90% inhibition of the peak in DNA synthesis in rat liver 24 h after two-thirds partial hepatectomy (PH). However, DNA synthesis in post-PH, Cpd 5-treated rat livers did occur, but with a delay of 36 h. Dual phosphorylation of ERK2 was induced in rat liver dose-dependently as early as 0.5 h, but gradually returned to almost basal levels by 6 h after Cpd 5 treatment. The MEK1/2 inhibitor PD098059, administered in vivo 1 h prior to Cpd 5 treatment, antagonized both induction of ERK2 phosphorylation and inhibition of DNA synthesis in rat liver. Liver protein lysates post-PH exhibited protein phosphatase activity for phospho-ERK2, which was inhibited by Cpd 5. These results show that induction of ERK2 phosphorylation is likely involved in the mechanism by which Cpd 5 inhibits PH-induced DNA synthesis, probably as a result of its ability to inhibit the activity of ERK phosphatase(s).
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PMID:Inhibition of rat liver regeneration after partial hepatectomy and induction of ERK phosphorylation by Cpd 5, a K vitamin-based anticancer compound. 1531 98

An increasing number of patients with hepatocellular carcinoma (HCC) are undergoing evaluation for listing for liver transplantation. Criteria for selection require ongoing review for suitability. A consecutive series of 40 patients with HCC within the standard Milan criteria (single tumors n = 19 < 5 cm, or up to 3 tumors < 3 cm) and beyond (Extended Criteria; single tumors n = 21 < 7.5 cm, multiple tumors < 5 cm) underwent liver transplant with a sirolimus-based immunosuppressive protocol designed to minimize exposure to calcineurin inhibitors and steroids. At 44.3 +/- 19.3 months (mean +/- standard deviation) follow-up, 1- and 4-year survivals (Kaplan-Meier) are 94.1 +/- 5.7% and 87.4 +/- 9.3%, in the Milan group, respectively, and 90.5 +/- 6.4% and 82.9 +/- 9.3% in the Extended Criteria group, respectively. Five patients died during follow-up, only 1 from recurrent HCC. Five tumor recurrences have occurred at median 17 (mean 22 +/- 17) months posttransplant, 1 in the Milan group and 4 in the Extended Criteria group. Median survival in the patients with recurrent tumor is 42 months (mean 45 +/- 25), and the median postrecurrence survival is 15.5 months (mean 23 +/- 16). The rate of patients who were alive and free of tumor at 1 and 4 years is 94.1 +/- 5.7% and 81.1 +/- 9.9%, respectively, in the Milan group and is 90.5 +/- 6.4% and 76.8 +/- 10.5%, respectively, in the Extended Criteria group. Five patients had sirolimus discontinued for toxicity, while 24 of 35 surviving patients have sirolimus monotherapy immunosuppression. In conclusion, the Milan criteria for liver transplantation in the presence of HCC can be carefully extended without compromising outcomes. This sirolimus based immunosuppression protocol appears to have beneficial effects on tumor recurrence and survival with an acceptable rate of rejection and toxicity.
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PMID:Sirolimus-based immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma. 1537 37

Hepatitis C virus (HCV) recurs in nearly all patients after liver transplantation. This recurrence is associated with progressive fibrosis and graft loss. It remains unclear whether the natural course of HCV recurrence is altered in patients who undergo living donor liver transplantation (LDLT). We conducted a prospective, controlled trial using protocol liver biopsies to evaluate the histologic outcome of recurrent HCV in 23 patients who underwent LDLT and 53 patients who underwent transplantation with a deceased donor liver (DDLT) during the same period of time. Patients who did not survive at least 6 months after transplantation or who had hepatocellular carcinoma or any other coexistent liver disease were excluded from analysis. All patients underwent protocol liver biopsy at 6 months and at 12 months and at yearly intervals thereafter. The mean age, sex, racial distribution, and serum HCV RNA and the percentage of patients with genotype 1 were similar in the 2 groups of patients. The model for end-stage liver disease score at the time of transplantation was slightly lower in patients who underwent LDLT, but this difference was not significant. The distribution of immunosuppression agents used, the mean doses of calcineurin agents, the use of mycophenolate mofetil, and the dose and tapering schedule for prednisone were similar in both groups of patients. The mean duration of follow-up was 40 months. No significant difference in either graft or patient survival or the percentage of patients who developed acute rejection was noted in the 2 groups of patients. At 48 months, graft and patient survival were 82% and 82% and 75% and 79% for patients who underwent DDLT and LDLT, respectively. The degree of hepatic inflammation increased stepwise over 3 years but was not significantly different in the 2 patient groups. In contrast, the mean fibrosis score and the percentage of patients with fibrosis increased stepwise after DDLT but appeared to plateau 12 months after LDLT. At 36 months, fibrosis was present in 78% of DDLT patients, and mean fibrosis score was 1.9, compared with 59% with fibrosis and a mean score of.9 after LDLT. In conclusion, these data strongly suggest that fibrosis progression from recurrent HCV is not more severe in patients after LDLT.
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PMID:Histologic recurrence of chronic hepatitis C virus in patients after living donor and deceased donor liver transplantation. 1537 36

We have previously shown that Compound 5 (Cpd 5), an inhibitor of protein phosphatase Cdc25A, inhibits Hep3B human hepatoma cell growth. We now show that hepatocyte growth factor (HGF), a hepatocyte growth stimulant, can strongly enhance Cpd 5-induced growth inhibition in Hep3B cells, and this enhancement in cell growth inhibition is correlated with a much stronger ERK phosphorylation when compared to cells treated with Cpd 5 or HGF separately. We found that HGF/Cpd 5-induced ERK phosphorylation and cell growth inhibition were mediated by Akt (protein kinase B) pathway, since combination HGF/Cpd 5 treatment of Hep3B cells inhibited Akt phosphorylation at Ser-473 and its kinase activity, which led to the suppression of Raf-1 phosphorylation at Ser-259. The suppression of Raf-1 Ser-259 phosphorylation caused the induction of Raf-1 kinase activity, as well as hyper-ERK phosphorylation. Transient transfection of Hep3B cells with dominant negative Akt c-DNA further enhanced both Cpd 5- and HGF/Cpd 5-induced ERK phosphorylation, while over-expression of wild-type Akt c-DNA diminished their effects. In contrast, HGF antagonized the growth inhibitory actions of Cpd 5 on normal rat hepatocytes, thus showing a selective effect on tumor cells compared to normal cells. Our data suggest that Akt kinase negatively regulates MAPK activity at the Akt-Raf level. Suppression of Akt activity by either combination HGF/Cpd 5 treatment or by dominant negative Akt c-DNA transfection antagonizes the Akt inhibitory effect on Raf-1, resulting in an enhancement of Cpd 5-induced MAPK activation and cell growth inhibition.
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PMID:Hepatocyte growth factor enhances protein phosphatase Cdc25A inhibitor compound 5-induced hepatoma cell growth inhibition via Akt-mediated MAPK pathway. 1553 60

Extracellular signal-regulated kinase (ERK) plays a central role in regulating cell growth, differentiation, and apoptosis. We previously found that 2-(2-mercaptoethanol)-3-methyl-1,4-napthoquinone or Compound 5 (Cpd 5), is a Cdc25A protein phosphatase inhibitor and causes prolonged, strong ERK phosphorylation which is triggered by epidermal growth factor receptor (EGFR) activation. We now report that Cpd 5 can directly cause ERK phosphorylation by inhibiting Cdc25A activity independently of the EGFR pathway. We found that Cdc25A physically interacted with and de-phosphorylated phospho-ERK both in vitro and in cell culture. Inhibition of Cdc25A activity by Cpd 5 resulted in ERK hyper-phosphorylation. Transfection of Hep3B human hepatoma cells with inactive Cdc25A mutant enhanced Cpd 5 action on ERK phosphorylation, whereas over-expression of Cdc25A attenuated this Cpd 5 action. Furthermore, endogenous Cdc25A knock-down by Cdc25A siRNA resulted in a constitutive-like ERK phosphorylation and Cpd 5 treatment further enhanced it. In EGFR-devoid NR6 fibroblasts and MEK (ERK kinase) mutated MCF7 cells, Cpd 5 treatment also resulted in ERK phosphorylation, providing support for the idea that Cpd 5 can directly act on ERK phosphorylation by inhibiting Cdc25A activity. These data suggest that phospho-ERK is likely another Cdc25A substrate, and Cpd 5-caused ERK phosphorylation is probably regulated by both EGFR-dependent and EGFR-independent pathways.
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PMID:Cdc25A and ERK interaction: EGFR-independent ERK activation by a protein phosphatase Cdc25A inhibitor, compound 5. 1567 48

Regucalcin was discovered in 1978 as a Ca(2+)-binding protein that does not contain EF-hand motif of Ca(2+)-binding domain. The name regucalcin was proposed for this Ca2(2+)binding protein, which can regulate liver cell functions related to Ca(2+). The regucalcin gene is localized on chromosome X, and the organization of the regucalcin gene consists of seven exons and six introns. AP-1 and NFI-A1 can bind to the promoter region of the rat regucalcin gene to mediate the Ca(2+) response for transcriptional activation. Regucalcin plays a pivotal role in maintaining intracellular Ca(2+) homeostasis due to activating Ca(2+) pump enzymes in the plasma membrane (basolateral membrane), microsomes (endoplasmic reticulum) and mitochondria of many cell types. Regucalcin has a suppressive effect on Ca(2+) signaling from the cytoplasm to the nucleus in the proliferative cells. Also, regucalcin has been demonstrated to transport to nucleus, and it can inhibit nuclear protein kinase, protein phosphatase, and deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis. Regucalcin can control enhancement of cell proliferation due to hormonal stimulation. Moreover, overexpression of regucalcin suppresses cell death and apoptosis in the cloned rat hepatoma cells induced by various signaling factors. Regucalcin plays a multifunctional role in the regulation of cellular function in liver, kidney cortex, heart and brain. Moreover, regucalcin-overexpressing rat has been shown to induce bone loss and hyperlipidemia with increasing age, indicating a pathophysiologic role. Regucalcin transgenic rat may be useful as an animal model in osteoporosis and hyperlipidemia. Thus, regucalcin plays a pivotal role in maintaining cell homeostasis and function. Regucalcin gene expression-related diseases may be found in human.
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PMID:Role of regucalcin in maintaining cell homeostasis and function (review). 1570 26

We present evidence that increases in intracellular calcium, induced by treatment with calcium ionophore A23187 or the endoplasmic reticulum calcium-ATPase inhibitor thapsigargin, dephosphorylated histone H3 at serine10 (histone H3-Ser10) in a dose-dependent manner in human hepatoma HepG2 cells. Inhibition of p42/44MAPK, pp90RSK, or p38MAPK did not affect the ability of A23187 to dephosphorylate histone H3-Ser10. This response is significantly blocked by okadaic acid, indicating a requirement for protein phosphatase 2A (PP2A). A23187 increased the activity of PP2A towards phosphorylated histone H3-Ser10. Furthermore, pretreatment with calphostin C, a selective protein kinase C (PKC) inhibitor, blocked A23187-dependent dephosphorylation of histone H3-Ser10, and coimmunoprecipitation analysis showed PP2A association with the PKCbetaII isoform. Unlike untreated cells, coimmunoprecipitated complex from A23187-treated cells showed greater dephosphorylation of histone H3-Ser10 in a PP2A-dependent manner. Inhibition of PP2A increased phosphorylation at Ser660 that determines calcium sensitivity and activity of PKCbetaII isoform, thus supporting a role for intracomplex regulation. Finally, chromatin immunoprecipitation assays following exposure to A23187 and okadaic acid revealed regulatory role of histone H3-Ser10 phosphorylation in selective gene induction. Altogether, our findings suggest a novel role for calcium in modulating histone H3-Ser10 phosphorylation level and led us to propose a model emphasizing PP2A activation, occurring downstream following perturbations in calcium homeostasis, as key event in dephosphorylating histone H3-Ser10 in mammalian cells.
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PMID:Increases in intracellular calcium dephosphorylate histone H3 at serine 10 in human hepatoma cells: potential role of protein phosphatase 2A-protein kinase CbetaII complex. 1588 Apr 62

A novel series of TCM-platinum complexes [Pt(C8H8O5)(NH2R)2] 1-5, designed from incorporating demethylcantharidin, a modified component from a traditional Chinese medicine (TCM) with a platinum moiety was found to circumvent cisplatin resistance in mouse leukemia and human hepatocellular carcinoma. These properties are most likely due to the inclusion of the protein phosphatase 2A (PP2A)-inhibiting demethylcantharidin in the novel compounds. We have investigated the potential synergistic effect of combining demethylcantharidin with a platinum-based antitumor agent, such as cisplatin, carboplatin, or oxaliplatin in vitro against L1210 mouse leukemia and SK-Hep-1 human hepatocellular carcinoma, and in vivo against a SK-Hep-1 subcutaneous-inoculated xenograft in nude mice, using median effect analysis. Demethylcantharidin and the platinum antitumor agents were synergistic in all cell lines tested in vitro, and the most effective antiproliferative regimen was when demethylcantharidin was added 24 h before cisplatin. Synergistic antitumor activity was also demonstrated in vivo without undue toxicity; no excessive loss in mouse body weight or overt pathology were observed at the effective doses. The results support a new approach for augmenting cytotoxic effect of established Pt-based drugs with demethylcantharidin in treating human hepatocellular carcinoma and other solid tumors.
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PMID:Synergistic interaction between platinum-based antitumor agents and demethylcantharidin. 1589 57

Protein phosphatase 2A (PP2A) is a new target for platinum (Pt)-based cancer chemotherapeutic agents. A series of novel Pt complexes containing demethylcantharidin, a modified component of a traditional Chinese medicine (TCM), [Pt(C8H8O5)(NH2R)2] 1-5 have been shown to inhibit PP2A both in its purified form and in cell homogenates. In this study, the potential efficacy of compounds 1-5 in suppressing the growth of PP2A-highly expressed liver cancer was evaluated. The in vitro anti-proliferative activity of compounds 1-5 was investigated in human hepatocellular carcinoma (HCC) cell lines using the MTT assay. Compounds 1-5 were about 2-20 and 20-200 times more potent than cisplatin and carboplatin, respectively, in SK-Hep1 and HepG2 cells. The in vivo anti-tumor efficacies of 1-5 were evaluated in a s.c. inoculated SK-Hep1 xenograft model in nude mice. Compounds 1-5 demonstrated definite in vivo activity (giving rise to an optimal %T/C as low as 14.5%) without inducing undue toxicity, contrasting the lack of activity of cisplatin and carboplatin. In a cisplatin-resistant model established in vivo in human HCC, compounds 1-5 could still elicit the same level of tumor growth suppression as in the control tumors, demonstrating the circumvention of cisplatin cross-resistance. An acute toxicity study in ICR mice showed that compounds 1-5 are not nephrotoxic at LD10. The high potency of the novel TCM-Pt compounds against liver cancer and the minimal toxicity suggest that they have significant potential to be developed into useful Pt-based anti-tumor drugs.
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PMID:In vitro and in vivo suppression of growth of hepatocellular carcinoma cells by novel traditional Chinese medicine-platinum anti-cancer agents. 1609 30

Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide. HCV has a positive-strand RNA genome of about 9.4 kb in size, which serves as a template for replication and for translation of a polyprotein of about 3,000 amino acids. The polyprotein is cleaved co- and posttranslationally by cellular and viral proteases into at least 10 different mature proteins. One of these proteins, nonstructural protein 3 (NS3), has serine protease and NTPase/RNA helicase activity. Arginine 467 in the helicase domain of NS3 (arginine 1493 in the polyprotein) can be methylated by protein arginine methyltransferase 1 (PRMT1). Here we report that the methylation of NS3 inhibits the enzymatic activity of the helicase. Furthermore, we found that PRMT1 activity itself is regulated by protein phosphatase 2A (PP2A). PP2A inhibits PRMT1 enzymatic activity and therefore increases the helicase activity of NS3. This is important, because we found an increased expression of PP2A in cell lines with inducible HCV protein expression, in transgenic mice expressing HCV proteins in hepatocytes, and in liver biopsy samples from patients with chronic hepatitis C. Interestingly, up-regulation of PP2A not only modulates the enzymatic activity of an important viral protein, NS3 helicase, but also interferes with the cellular defense against viruses by inhibiting interferon-induced signaling through signal transducer and activator of transcription 1 (STAT1). We conclude that up-regulation of PP2A might be crucial for the efficient replication of HCV and propose PP2A as a potential target for anti-HCV treatment strategies.
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PMID:Upregulation of protein phosphatase 2Ac by hepatitis C virus modulates NS3 helicase activity through inhibition of protein arginine methyltransferase 1. 1630 5


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