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)

Chemo-therapeutic drugs act on cancerous and normal cells non-selectively and often cause organ impairments during treatment. Improving safety or reducing toxicity becomes an important challenge for developing better anticancer drugs. In the present study, effects of selected anticancer drugs (camptothecin, doxorubicin, colchicine, paclitaxel, cisplatin, and carboplatin) on cell viability and proliferation was investigated. The anti-proliferative activity of each drug on cancer cells (human hepatoma HepG2) and human primary renal proximal tubule cells (hRPTECs and LLC-PK1) was determined with the [(3)H]thymidine incorporation assay. Results indicated all six drugs blocked cell proliferation in cancer and normal cells. When the anti-proliferation potency was ranked in hRPTECs based on EC50 values, camptothecin is the most potent, followed by doxorubicin, paclitaxel, colchicine, cisplatin and carboplatin. Cytotoxicity of drugs to hRPTECs was assessed with the ATP bioluminescence assay. Doxorubicin and cisplatin were known to induce nephrotoxicity in vivo and they were indeed cytotoxic to hRPTECs in our study with EC50 values at 11.2 and 39.6 microM. All other drugs are not cytotoxic in the concentrations tested. These drugs typically displayed separation of EC50s between potency (anti-proliferation) and cytotoxicity. The dose separation provides a concentration range for each drug to act on cell proliferation without induction of significant cytotoxicity. Our results suggest that hRPTEC system can serve as an in vitro model for assessing potential nephrotoxicity of chemo-therapeutic drugs.
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PMID:Human primary renal cells as a model for toxicity assessment of chemo-therapeutic drugs. 1628 93

The recent achievements of microfluidic chip and its applications, based on the works mainly carried out in the authors' lab are reviewed. The chip fabrication capabilities have been extended into design and fabricate chips with higher degree of complexity in different materials, such as quartz, glass, polymethyl methacrylate (PMMA), and polydimethyl siloxane (PDMS). A set of methods for surface modification of micro-channels on such materials have been developed, which results in better reproducibility and higher efficiency in protein and peptide analysis. The use of novel materials for chip fabrication is also under investigation. A series of microfluidic workstations with integrated chip manipulation as well as laser induced fluorescence (LIF), ultraviolet (UV), electrochemical and chemiluminescence detection modules have been developed to attain the abilities of complex microfluidic control and data acquisition schemes. A single cell/single molecule imagining system was built up for dynamic analysis of molecular or cellular events too. Based on the work mentioned above, different functional units, such as membrane, monolithic, isotachophoresis (ITP) etc were set up and integrated. Glycoform separation of turkey ovalbumin in a lectin monolithic column and an electrophoresis channel was performed on an integrated microchip. And a novel technique has been developed that allows for the coupling of ITP and non-gel sieving electrophoresis for protein analysis in a single microchip and resulting in - 50 fold increase of the sensitivity in comparison with the use of gel electrophoresis only. A single molecule detection (SMD) based technique was developed for simultaneously measuring both bulk flow and near-wall flow velocity in the microchannels. And more recently, an SMD based technology was developed for observing molecular interactions at single molecule level. An ultra-rapid microchip electrophoresis method was established for simultaneous determination intracellular reactive oxygen species (ROS) and reduced glutathione (GSH) related to apoptosis and oxidative stress. In an effort to develop a novel microfluidic based drug screening platform, systematic studies on the interaction between granulocyte colony-stimulating factor (G-CSF) and sulfated oligosaccharides were carried out at both molecular and cellular levels. Doxorubicin induced apoptosis of human hepatocellular carcinoma (HepG2) was studied using the integrated microfluidic device with concentration generator. In the application phase, severe acute respiratory syndrome (SARS) diagnosis based on reverse transcription-polymerase chain reaction (RT-PCR) and microfluidic chip electrophoresis (MCE) with 18 cases, methylation analysis of the P16 gene in 159 samples of patients and references for cancer diagnosis and polymorphism analysis of angiotenigen gene in 226 patients and references with essential hypertension are described. Forty-three up to date references are
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PMID:[Laboratory on a microfluidic chip]. 1635 Jul 86

1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enylfuran-2-caroxylate (SH-7), a new naphthoquinone compound, derived from shikonin, exhibited obvious inhibitory actions on topoisomerase II (Topo II) and topoisomerase I (Topo I), which were stronger than its mother compound shikonin. Notably, the SH-7's inhibitory potency on Topo II was much stronger than that on Topo I. In addition, SH-7 significantly stabilized Topo II-DNA cleavable complex and elevated the expression of phosphorylated-H2AX. The in vitro cell-based investigation demonstrated that SH-7 displayed wide cytotoxicity in diversified cancer cell lines with the mean IC(50) value of 7.75 microM. One important finding is SH-7 displayed significant cytotoxicity in the 3 MDR cell lines, with an average IC(50) value nearly equivalent to that of the corresponding parental cell lines. The average resistance factor (RF) of SH-7 was 1.74, which was much lower than those of reference drugs VP-16 (RF 145.92), ADR (RF 105.97) and VCR (RF 197.39). Further studies illustrated that SH-7 had the marked apoptosis-inducing function on leukemia HL-60 cells, which was validated to be of mitochondria-dependence. The in vivo experiments showed that SH-7 had inhibitory effects on S-180 sarcoma implanted to mice, SMMC-7721, BEL-7402 human hepatocellular carcinoma and PC-3 human prostate cancer implanted to nude mice. Taken together, these results suggest that SH-7 induces DSBs as a Topo II inhibitor, which was crucial to activate the apoptotic process, and subsequently accounts for its both in vitro and in vivo antitumor activities. The well-defined Topo II inhibitory activity, antitumor effects particularly with its obvious anti-MDR action, better solubility and less toxicity make SH-7 as a potential antitumor drug candidate for further research and development.
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PMID:SH-7, a new synthesized shikonin derivative, exerting its potent antitumor activities as a topoisomerase inhibitor. 1657 Feb 88

Microtubules are crucial targets for cancer chemotherapeutic drugs, and new microtubule-directed agents are of continued interest in drug development. A novel microtubule-directed agent, ethyl-2-[N-rho-chlorobenzyl-(2'-methoxy)]-anilino-4-oxo -4, 5-dihydro-furan-3-carboxylate, was identified. The compound, designated K2154, inhibited cell proliferation, with IC(50) values of 10.3, 15.3, 9.6, 11.2, 12.8 and 12.1 muM in prostate cancer PC-3, hepatocellular carcinoma Hep3B, non-small cell lung cancer A549, colorectal cancer HT29 and HCT116, and P-glycoprotein-rich breast cancer NCI/ADR-RES cells, respectively. Because NCI/ADR-RES cells were susceptible to inhibition by K2154, it indicated that this compound is a poor substrate for P-glycoprotein. In this study, PC-3 cells were used to identify the anticancer mechanisms of K2154. K2154 induced an arrest of the cell cycle at G2/M phase and a subsequent increase of hypodiploid phase in PC-3 cells, whereas it only induced a moderate level of G2/M arrest with little increase of hypodiploid phase in normal prostate cells. K2154 inhibited microtubule assembly in both in vitro turbidity assay and in vivo microtubule spin-down experiment. Immunochemical examination showed that K2154 caused formation of abnormal mitotic characteristics with bipolar spindles, particularly, in beta(II)- and beta(III)-tubulin staining. It also induced several pathways, including cyclin B1 up-regulation, dephosphorylation on Tyr(15) and phosphorylation on Thr(161) of Cdk1 and Cdc25C phosphorylation, and roscovitine (a Cdk1 inhibitor) significantly inhibited K2154-induced apoptosis, suggesting a pro-apoptotic role of Cdk1. Phosphorylation of Bcl-2 and Bcl-xL and cleavage of Mcl-1, together with activation of caspase-9 and -3, indicated that mitochondrial pathway played a central role in K2154-mediated apoptotic cell death. Additionally, AIF contributed to a late phase of K2154-induced apoptotic pathway. In conclusion, it is suggested that K2154 displays an anticancer activity through a target on microtubules and a subsequent signaling cascade on cell cycle regulation and apoptotic machinery.
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PMID:Investigation of anti-tumor mechanisms of K2154: characterization of tubulin isotypes, mitotic arrest and apoptotic machinery. 1710 38

Hepatocellular Carcinoma (HCC) is one of the most frequent cancers worldwide, however, prognosis remains poor following its discovery. We investigate the Thioredoxin superfamily of proteins as diagnostic markers for HCC. Furthermore, we delineate possible roles of the endoplasmic reticulum member of the superfamily, ERdj5, in carcinogenesis. Using antibodies against Thioredoxin 1, Thioredoxin Reductase 1 and ERdj5, we performed immunohistochemistry on paraffin embedded liver biopsy sections from HCC patients. All three redox proteins exhibited elevated expression levels in tumor tissue compared to internal control, with ERdj5 showing a remarkable 3-fold increase. In vitro cell viability experiments using Hepatocellular Carcinoma HuH7 cells treated with ERdj5 small interfering RNA showed that ERdj5 knockdown cells exhibited less resistance to Doxorubicin (chemotherapy drug), but more resistance to Tunicamycin (Endoplasmic Stress inducer), compared to control cells. In conclusion, we introduce members of the Thioredoxin superfamily as possible immunohistochemical markers in the diagnostics of hepatocellular carcinoma and indicate a potential defensive role for ERdj5 in chemotherapeutic drug resistance.
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PMID:Increased expression of specific thioredoxin family proteins; a pilot immunohistochemical study on human hepatocellular carcinoma. 1734 24

IGF-II and type I-IGF receptor (IGF-IR) gene expression is increased in primary liver tumors, and transgenic mice overexpressing IGF-II in the liver develop hepatocellular carcinoma (HCC) spontaneously, suggesting that alterations of IGF-IR signaling in vivo may play a role in the auto/paracrine control of hepatocarcinogenesis. We have addressed the contribution of PI-3'K/Akt signaling on the proliferation of HepG2 human hepatoma cells and on their protection against doxorubicin-induced apoptosis. Both basal HepG2 cell DNA replication and that stimulated by IGF-IR signaling were inhibited by the specific PI-3'K inhibitor Ly294002 (Ly). In the former case, PI-3'K signaling overcame cell cycle arrest in G1 via increased cyclin D1 protein and decreased p27kip1 gene expression. Doxorubicin treatment induced apoptosis in HepG2 cells and was concomitant with the proteolytic cleavage of Akt-1 and -2. Drug-induced apoptosis was reversed by IGF-I and this effect was (i) dependent on Akt-1 and -2 phosphorylation and (ii) accompanied by the inhibition of initiator caspase-9 activity, suggesting that IGF-IR signaling interferes with mitochondria-dependent apoptosis. Accordingly, Ly enhanced doxorubicin-induced apoptosis and suppressed its reversal by IGF-I. Altogether, the data emphasize the crucial role of PI-3'K/Akt signaling (i) in basal as well as IGF-IR-stimulated HepG2 cell proliferation and (ii) in controlling both doxorubicin-induced apoptosis (e.g., drug-induced cleavage of Akt) and its reversal by IGF-I (protection against apoptosis parallels the extent of Akt phosphorylation). They suggest that targeting Akt activity or downstream Akt effectors (e.g., GSK3-beta, FOXO transcription factors) may help define novel therapeutic strategies of increased efficacy in the treatment of HCC-bearing patients.
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PMID:Pleiotropic effects of PI-3' kinase/Akt signaling in human hepatoma cell proliferation and drug-induced apoptosis. 1738 42

Cancer chemotherapeutic agents that interfere with tubulin/microtubule function are in extensive use. Quinolone is a common structure in alkaloids and its related components exhibit several pharmacological activities. In this study, we have identified the anticancer mechanisms of 2-phenyl-4-quinolone. 2-Phenyl-4-quinolone displayed anti-proliferative effect in several cancer types, including hormone-resistant prostate cancer PC-3, hepatocellular carcinoma Hep3B and HepG2, non-small cell lung cancer A549 and P-glycoprotein-rich breast cancer NCI/ADR-RES cells. The IC(50) values were 0.85, 1.81, 3.32, 0.90 and 1.53 microM, respectively. 2-Phenyl-4-quinolone caused G2/M arrest of the cell-cycle and a subsequent apoptosis. The turbidity assay showed an inhibitory effect on tubulin polymerization. After immunochemical examination, the data demonstrated that the microtubules were arranged irregularly into dipolarity showing prometaphase-like states. Furthermore, 2-Phenyl-4-quinolone induced the Mcl-1 cleavage, the phosphorylation of Bcl-2 and Bcl-xL (12-h treatment), and the caspase activation including caspase-8, -2 and -3 (24-h treatment). The exposure of cells to 2-phenyl-4-quinolone caused Cdk1 activation by several observations, namely (i) elevation of cyclin B1 expression, (ii) dephosphorylation on inhibitory Tyr-15 of Cdk1, and (iii) dephosphorylation on Ser-216 of Cdc25c. Moreover, a long-term treatment (36h) caused the release reaction and subsequent nuclear translocation of AIF. In summary, it is suggested that 2-phenyl-4-quinolone displays anticancer effect through the dysregulation of mitotic spindles and induction of mitotic arrest. Furthermore, participation of cell-cycle regulators, Bcl-2 family of proteins, activation of caspases and release of AIF may mutually cross-regulate the apoptotic signaling cascades induced by 2-phenyl-4-quinolone.
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PMID:Quinolone analogue inhibits tubulin polymerization and induces apoptosis via Cdk1-involved signaling pathways. 1747 21

Doxorubicin (DOX) is a widely used chemotherapeutic drug for human hepatocellular carcinoma (HCC). A major limitation to its effectiveness is the development of multidrug resistance of cancer cells. In clinical trials, patients with advanced HCC were treated with high-dose acetaminophen (HAAP) in an effort to improve the antitumor activity of chemotherapeutics. In this study, we investigated the effect of concomitant treatment of DOX and HAAP on hepatoma-derived HepG2 cells. Viability, cell cycle distribution, and ultrastructure were examined. Unexpectedly, HAAP, when added to DOX-exposed cells, increased cell viability, released cell cycle arrest, and decreased apoptosis. To elucidate the mechanisms by which HAAP reduces the DOX lethal effect to HepG2 cells, we investigated the multidrug resistance P-glycoprotein (P-gp) and p44/42-mitogen-activated protein kinase (MAPK) pathways. The P-gp function was enhanced by DOX and HAAP, and it was further stimulated during combined treatment, leading to decreased DOX retention. Verapamil (VRP), when added to DOX + HAAP exposure, increased DOX accumulation and restored DOX-induced toxicity. The increased phospho-p44/42-MAPK level in DOX-exposed cells was inhibited by HAAP. In addition, suppression of p44/42 activation by the p44/42-MAPK inhibitor 2'-amino-3'-methoxyflavone (PD98059) blocked DOX-induced apoptosis. These findings suggest that the antagonistic effect of concomitant DOX + HAAP treatment occurs as a result of interactive stimulation of P-gp, generating decreased intracellular drug concentrations. Furthermore, inhibition of the p44/42-MAPK phosphorylation by HAAP could abolish the DOX-induced cell death pathway. Thus, combined treatment by DOX + HAAP, intended to improve chemotherapeutic efficacy, could have an opposite effect facilitating cancer cell survival.
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PMID:High-dose acetaminophen inhibits the lethal effect of doxorubicin in HepG2 cells: the role of P-glycoprotein and mitogen-activated protein kinase p44/42 pathway. 1752 8

Many anthracyclines are currently in clinical development with the common aim of improving selectivity. This could be achieved by improving tumor drug delivery through the identification and development of molecules with new structure, prodrugs with low molecular weight for selective release and activation, prodrugs with high molecular weight conjugated to antibody with active targeting or macromolecules with enhanced permeability and retention. There are still interfering factors to be defined, in particular chemical, with degradation steps in tumor tissues, biological, related to tumor proteases, pharmacological, with inter-individual tumor differences in the extent of accumulation. Another way to improve selectivity is to activate the drug at the tumor site, a good example of which is provided by Nemorubicin (2\"-(S)-methoxymorpholinodoxorubicin hydrochloride) in hepatocellular carcinoma. The favorable characteristics of Nemorubicin in terms of broad spectrum of significant antitumor activity in liver malignancies models, lower cardiotoxicity than Doxorubicin, make Nemorubicin a promising third-generation anthracycline, suitable for intrahepatic administration.
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PMID:Ongoing phase I and II studies of novel anthracyclines. 1765 8

Anthracyclines and anthracenediones are well-known cancer chemotherapeutic agents but their uses are limited with cardiotoxicity and drug resistance. Several l- and d-form amino acids were introduced into the anthraquinone skeleton and numerous derivatives were synthesized for the evaluation of anticancer activity. The screening tests showed that WRC-213, an l-methionine conjugation, was the most effective derivative to inhibit proliferative effect of human androgen-independent prostate cancer PC-3 cells (IC50=50 nM). In an extension evaluation, WRC-213 displayed a potent anti-proliferative activity in various cancer cell lines, including non-small cell lung cancer A549, androgen-independent prostate cancer DU145, colorectal cancer HT-29, breast cancer MCF-7 and hepatocellular carcinoma Hep3B and HepG2. It induced cell-cycle arrest at S and G2, but not mitotic phase, in PC-3 cells. The comet assay revealed that induction of DNA damage and inhibition of topoisomerase II were the primary insults. After the checkpoint arrest of the cell-cycle, WRC-213 induced the mitochondria-mediated intrinsic apoptotic pathway, including Mcl-1 cleavage, Bcl-2 down-regulation and activation of caspase-9/caspase-3 cascades. Survivin degradation and caspase-2 activation also contributed to WRC-213-induced apoptosis. Moreover, the assessment of cytotoxicity in H9c2 cardiomyocytes and drug resistance in NCI/ADR-RES cells demonstrated that WRC-213 showed much lower cardiotoxicity and P-glycoprotein-related resistance than those of mitoxantrone, etoposide and doxorubicin. In conclusion, it is suggested that WRC-213 is a potential topoisomerase II inhibitor with reduced cardiotoxicity and drug resistance. It inhibits topoisomerase II activity and induces chromosomal DNA strand breaks, leading to S and G2 arrest of the cell-cycle and activation of mitochondria-mediated apoptotic pathways.
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PMID:WRC-213, an l-methionine-conjugated mitoxantrone derivative, displays anticancer activity with reduced cardiotoxicity and drug resistance: identification of topoisomerase II inhibition and apoptotic machinery in prostate cancers. 1803 33


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