Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Upregulation of expression and activation of epidermal growth factor receptor (EGFR) is involved in the development and progression of a wide range of human cancers. The present study aims at determining gene-silencing effects of vector-based short hairpin RNA (shRNA) targeting EGFR on receptor expression and cell growth and evaluating its modulation of responsiveness to drugs in human lung adenocarcinoma cells (HLAC). A vector-based polymerase 3-promotor system was used to express shRNA targeting EGFR in HLAC lines (A549 and SPC-A1). EGFR was detected by immunofluorescence staining and quantified by Western blot. The effect of shRNA targeting EGFR on tumor cell growth was assessed by colony formation assay, cell cycle and apoptosis by flow cytometry, and the responsiveness of HLAC lines to cytotoxic drugs by 3-[4,5-dimethylthiozol-2yl]-2,5-diphenyltetrazolium bromide [MTT] assay. Vectors expressing shRNA against EGFR significantly downregulated receptor expression by 74 and 85% and the colony number by 63 and 69% in A549 and SPC-A1, respectively. Vector-based shRNA against EGFR caused G1 arrest, induced apoptosis, and subsequently increased the sensitivity to cisplatin, doxorubicin and paclitaxel by about four- to seven-fold in both HLAC lines. Our data suggest that vector-based shRNA could be considered as an alternative to effectively inhibit EGFR expression in HLACs, probably with the higher efficacy in combination therapies with conventional chemotherapeutic drugs.
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PMID:Potential role of short hairpin RNA targeting epidermal growth factor receptor in growth and sensitivity to drugs of human lung adenocarcinoma cells. 1644 3

In clinical oncology, many trials with superoxide dismutase (SOD) have failed to demonstrate antitumor ability and in many cases even caused deleterious effects because of low tumor-targeting ability. In the current research, the Nostoc commune Fe-SOD coding sequence was amplified from genomic DNA. In addition, the single chain variable fragment (ScFv) was constructed from the cDNA of an LC-1 hybridoma cell line secreting anti-lung adenocarcinoma monoclonal antibody. After modification, the SOD and ScFv were fused and co-expressed, and the resulting fusion protein produced SOD and LC-1 antibody activity. Tracing SOD-ScFv by fluorescein isothiocyanate and superoxide anions (O2*-) in SPC-A-1 cells showed that the fusion protein could recognize and enter SPC-A-1 cells to eliminate O2*-. The lower oxidative stress resulting from the decrease in cellular O2*- delayed the cell cycle at G1 and significantly slowed SPC-A-1 cell growth in association with the dephosphorylation of the serine-threonine protein kinase Akt and expression of p27kip1. The tumor-targeting fusion protein resulting from this research overcomes two disadvantages of SODs previously used in the clinical setting, the inability to target tumor cells or permeate the cell membrane. These findings lay the groundwork for development of an efficient antitumor drug targeted by the ScFv.
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PMID:Molecular cloning and functional characterization of a cell-permeable superoxide dismutase targeted to lung adenocarcinoma cells. Inhibition cell proliferation through the Akt/p27kip1 pathway. 1655 17

In lung cancers the Notch signaling may function as an oncogene or a tumor suppressor depending on the tumor cell types. In this study we examined the expression of Notch receptors in the human lung adenocarcinoma cell lines A549 and SPC-A-1. We over-expressed the active form of Notch1 (NIC) in A549 cells by constitutive transfection to evaluate the effects of the Notch signaling on lung adenocarcinoma cells. Our results showed that over-expression of NIC in A549 cells inhibited the growth of A549 cells through induction of cell cycle arrest. Moreover, over-expression of NIC inhibited the colony-forming activity of A549 cells when cultured in methylcellulose medium, and their ability to form tumors in nude mice. These data suggest that the Notch signaling may function as a tumor inhibitor in human lung adenocarcinoma cells.
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PMID:Notch signaling inhibits growth of the human lung adenocarcinoma cell line A549. 1734 26

A series of novel cisplatin-type platinum complexes were designed, characteristic of epoxysuccinates as leaving groups. The pertinent compounds were prepared and characterized by IR, (1)H NMR, and ESI-MS spectra with elementary analyses. The in vitro cytotoxic activities of compounds toward SPC-A1 human lung adenocarcinoma cell line and BGC823 human stomach adenocarcinoma cell line were determined. Biological tests have confirmed that complexes containing 4R,5R-DMID [abbreviation of (4R,5R)-4,5-bis (aminomethyl)-2-isopropyl-1,3-dioxolane] as carrier ligands have greater cytotoxicity toward tumor cells than the corresponding compounds with other carrier ligands. Most platinum complexes with trans-epoxysuccinates usually have higher cytotoxicity than those with cis-epoxysuccinates. Complex 4a shows the most effective among those tested platinum complexes in both cell lines, and its cytotoxicity approached that of cisplatin.
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PMID:In vitro cytotoxicity study on platinum (II) complexes with epoxysuccinates as leaving groups. 1753 24

4-1BB, a member of the tumor necrosis factor receptor (TNFR) superfamily, is a costimulatory receptor that is primarily expressed on activated T cells and professional antigen-presenting cells. In this study, the expression pattern of 4-1BB on immunology cells and tumor cells was explored by flow cytometry using newly generated three anti-4-1BB monoclonal antibodies (mAbs; 6F9, 7D6, and 1G11), which bind to distinct 4-1BB epitopes. Compared with the available 4-1BB mAb 4B4-1 that recognized 4-1BB on activated T cells and monocytes, the novel mAbs also could recognize 4-1BB on some cancer cell lines, particularly on lung cancer cell lines such as SPC-A-1, H446, H460, and H1299 by flow cytometry analysis, western blot, and RT-PCR. Immunohistochemistry staining showed the 4-1BB was expressed on lung tumor tissue (33/35) but not on normal lung tissue (3/3). It was determined that 4-1BB was strictly expressed on lung cancer cells, which may provide information on the 4-1BB signal in tumor immunology mechanism.
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PMID:Characterization and application of three novel monoclonal antibodies against human 4-1BB: distinct epitopes of human 4-1BB on lung tumor cells and immune cells. 1799 Sep 86

In our program to synthesize a series of novel derivatives as potential analogs of honokiol for anti-tumor treatment, we have found that at least three of the derivatives of honokiol showed more potency to inhibit the proliferation of K562 leukemia cells and SPC-A1 adenocarcinoma cells. As a critical step to our further series synthesis of derivatives of honokiol, three derivatives of honokiol composed of two isomers and one compound with two formyl groups, which were hardly separated by common purification methods, needed to be rapidly separated and purified. The present work describes analytical and preparative high-speed counter-current chromatography (HSCCC) for the isolation and purification of these three C-formylation derivatives of honokiol, named 3'-formylhonokiol, 5-formylhonokiol and 3',5-diformylhonokiol, respectively. The solvent system for HSCCC separation was composed of hexane-ethyl acetate-methanol-water with the ratio of 1:0.4:1:0.4 (v/v). The one-step purification produced 157.8 mg, 121.6 mg and 21.2 mg of 3'-formylhonokiol, 5-formylhonokiol, 3',5-diformylhonokiol from crude sample of 400mg with purities of 98.6%, 99.2% and 99.6%, respectively, in an elution time of 2.5 h. The purities and structural identification were determined by HPLC, (1)H NMR, (13)C NMR and mass spectroscopy. Their anti-proliferation effects on K562, A549 and SPC-A1 cell lines were evaluated by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay.
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PMID:Preparative purification of anti-tumor derivatives of honokiol by high-speed counter-current chromatography. 1808 56

Endothelin-1 (ET-1), the most potent vasoconstrictor, has been shown to be mitogenic in many tumor cells as well as in vascular cells. It was previously reported that the mRNA of ET-1 and endothelin receptors (ETRs) are expressed in lung cancer cells. However, their biological role in lung cancer remains to be explored. The purpose of this study was to determine whether ET-1 stimulates proliferation of the human lung adenocarcinoma cell SPC-A1 and probe its cellular mechanism. Reverse-transcription polymerase chain reaction and Western blot analysis showed that both the mRNA and protein of ET-1, ET A R and ET B R are expressed in SPC-A1 cells. Application of ET-1 at 10(-15)-10(-8) M caused a dose-dependent cell proliferation and an increase in intracellular free Ca2+ concentration ([Ca2+]i). This ET-1-induced cell proliferation and [Ca2+]i increase were completely abolished by BQ123, a selective ET A R antagonist, but not by BQ788, a selective ET B R antagonist. Furthermore, it was significantly reduced by U73122, a specific inhibitor of phospholipase C (PLC), but not by U73433, the structural isomer of U73122. Chelating extracellular Ca2+ or blocking voltage dependent calcium channels by nifedipine also significantly reduced the mitogenic effect of ET-1 and [Ca2+]i increase in SPC-A1 cells. These results indicate that ET-1 acts as an autocrine growth factor and enhances proliferation of SPC-A1 cells via activation of ET A R. The phosphoinositol/Ca2+ pathway and Ca2+ influx through voltage dependent Ca2+ channels activated by ET A R contribute to this process.
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PMID:Endothelin-1 enhances proliferation of lung cancer cells by increasing intracellular free Ca2+. 1829 57

Tyrosine kinase with immunoglobulin and epidermal growth factor homology domain-2 (Tie2) has been considered as a rational target for gene therapy in solid tumors. In order to identify a novel peptide ligand of Tie2 for targeted gene therapy, we screened a phage display peptide library and identified a candidate peptide ligand NSLSNASEFRAPY (designated GA5). Binding assays and Scatchard analysis revealed that GA5 could specifically bind to Tie2 with a dissociation constant of 2.1x10(-8)M. In addition, we showed that GA5 was internalized into tumor cells highly expressing Tie2. In the biodistribution assay, (125)I-GA5 was mainly accumulated in SPC-A1 xenograft tumors that express Tie2. In gene delivery studies, GA5-conjugated polyethylenimine vector could achieve greater transgene transduction than non-targeted vectors both in vitro and in vivo. Tumor growth inhibition was observed in SPC-A1 xenograft-bearing mice that received eight intratumoral injections of GA5-polyethylenimine/p53 complexes in 3 weeks. The difference in tumor volume between the experiment and control groups was significant (P<0.05). Our results showed that GA5 is a potentially efficient targeting element for cancer gene or molecular therapy.
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PMID:Identification and characterization of a novel peptide ligand of Tie2 for targeting gene therapy. 1833 Apr 76

This study developed an active loading method for encapsulating chloroquine diphosphate (CQ) into liposomes. The effects of different formulation factors on the encapsulation efficiency (EE) and the size of CQ liposomes were investigated. These factors included the internal phase of liposomes, the external phase of liposomes, the ratio of drug to soybean phosphatidylcholine (drug/SPC), the ratio of cholesterol to soybean phosphatidylcholine (Chol/SPC), and the incubation temperature and time. The EE (93%) was obtained when using drug/SPC (1:50 mass ratio), SPC/Chol (1:5 mass ratio) at 0.10 M citrate-sodium citrate buffer (pH 3.6). As 5 mol% methoxypoly(ethylene glycol)(2,000) cholesteryl succinate (CHS-PEG(2000)) or distearoyl phosphatidylethanolamine-poly (ethylene glycol)(2,000) (DSPE-PEG(2000)) was added, the size of particle was reduced and the EE was improved. Freeze-drying with 5% trehalose as a cryoprotectant was carried out to achieve long-term stability. The drug release studies were performed in vitro simulating the desired application conditions, such as physiological fluids (pH 7.4), tumor tissues (pH 6.5) and endosomal compartments (pH 5.5). The release of CQ from the liposomes prepared via remote loading showed the significant pH-sensitivity and retention properties, which favored the application of liposomal CQ at tumor tissues and endosomal compartments.
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PMID:Preparation and in vitro evaluation of liposomal chloroquine diphosphate loaded by a transmembrane pH-gradient method. 1857 26

Transmembrane TNF-alpha (tmTNF-alpha) contains a leader sequence (LS) that can be phosphorylated and cleaved at its cytoplasmic portion, inducing IL-12 production. We observed that the breast cancer cell line MDA-MB-231 expressing transmembrane TNF-alpha (tmTNF-alpha) at high level was resistant to soluble TNF-alpha (sTNF-alpha)-induced cytotoxicity, accompanied by constitutive NF-kappaB activation. In contrast, MCF-7 cells expressing tmTNF-alpha at very low level were sensitive to sTNF-alpha-induced cell death and had no detectable NF-kappaB activation. Consistently, siRNA-mediated tmTNF-alpha knockdown blocked NF-kappaB activation and rendered MDA-MB-231 sensitive. To test our hypothesis that TNF-LS may play an important role in determining the sensitivity of tumor cells to sTNF-alpha, we stably transfected MCF-7 cells with TNF-LS. We found that transfection of TNF-LS or wild-type TNF-alpha containing LS constitutively activated NF-kappaB and conferred the cytotoxic resistance of MCF-7 cells, while transfection of a mutant tmTNF-alpha lacking the cytoplasmic segment of LS neither activated NF-kappaB nor affected the sensitivity. However, NF-kappaB inhibitor PDTC suppressed NF-kappaB activation and reconstituted sensitivity of TNF-LS/MCF-7 cells. To check whether TNF-LS is required to be cleaved or internalized for NF-kappaB activation to occur, we used signal peptide peptidase inhibitor (Z-LL)(2)-ketone and receptor internalization inhibitor MDC to treat cells. Interestingly, both inhibitors increased TNF-LS expression on the cell surface and enhanced NF-kappaB activation. These results indicate that membrane-anchored TNF-LS contributes to constitutive activation of NF-kappaB and resistance to sTNF-alpha-induced cell death. Therefore, TNF-LS appears to be responsible for tmTNF-alpha-induced resistance in the breast cancer cells.
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PMID:Expression of TNF-alpha leader sequence renders MCF-7 tumor cells resistant to the cytotoxicity of soluble TNF-alpha. 1861 39


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