Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A group of unnatural 1-(2-deoxy-beta-D-ribofuranosyl)isocarbostyrils having a variety of C-7 substituents [H, 4,7-(NO2)2, I, CF3, CN, (E)-CH=CH-I, -C triple bond CH, -C triple bond C-I, -C triple bond C-Br, -C=C-Me], designed as nucleoside mimics, were synthesized for evaluation as anticancer and antiviral agents. This class of compounds exhibited weak cytotoxicity in a MTT assay (CC50 = 10(-3) to 10(-5) M range) with the 4,7-dinitro derivative being the most cytotoxic, relative to thymidine (CC50 = 10(-3) to 10(-5) M range), against a variety of cancer cell lines. The 4,7-dinitro, 7-I and 7-C triple bond CH compounds exhibited similar cytotoxicity against non-transfected (KBALB, 143B), and HSV-1 TK+ gene transfected (KBALB-STK, 143B-LTK) cancer cell lines possessing the herpes simplex virus type 1 (HSV-1) thymidine kinase gene (TK+). This observation indicates that these compounds are not substrates for HSV type-1 TK, and are therefore unlikely to be useful in gene therapy based on the HSV gene therapy paradigm.
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PMID:Synthesis of unnatural 7-substituted-1-(2-deoxy-beta-D-ribofuranosyl)isocarbostyrils: "thymine replacement" analogs of deoxythymidine for evaluation as antiviral and anticancer agents. 1155 44

Human milk contains a variety of growth factors. Recently, it was reported that vascular endothelial growth factor (VEGF) was one of them. We investigated milk VEGF isoforms, their functions, and VEGF receptors on mammary gland epithelial cells (MEC). The VEGF concentration in human milk was 74.3+/-34.9ng/ml on the first day after delivery, and rapidly decreased in a couple of days to 6.2+/-2.3ng/ml on the fifth day, and matured milk maintained about 4ng/ml. In an MTT assay, human milk accelerated HUVEC proliferation and MV303, a neutralizing antibody of VEGF, blocked 17.3 % of the effect. Immunoprecipitation and Western blotting showed that VEGF121 and VEGF165 were contained in human colostrums, and RT-PCR of human MEC confirmed that VEGF121, VEGF165 and VEGF189 were present. By immunostaining of human breast tissues, RT-PCR of MEC from human colostrum and measurement of the VEGF concentrations of conditioned media of cultured human MEC, it was confirmed that VEGF was produced by MEC. MEC was also expressed VEGF receptors, flt-1 and Flk-1/KDR. These results speculate us that the existence of autocrine or paracrine system within breast tissue via VEGF receptors on MEC and have a role in lactation.
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PMID:Human lactiferous mammary gland cells produce vascular endothelial growth factor (VEGF) and express the VEGF receptors, Flt-1 AND KDR/Flk-1. 1212 41

The antigenic extract Hot Saline from Brucella ovis was microencapsulated by the spray-drying technique with different polyesters (poly-lactide-co-glycolide RG502H [PLGA], and blends with poly- epsilon -caprolactone [PEC]) in order to obtain microparticles smaller than 5 microm. Microparticles were tested for encapsulation efficiency, release studies, acidification of the in vitro release medium, and in vitro J744-macrophage experiments (phagocytosis and toxicity of the preparations) to determine the optimal formulation for vaccination purposes. Formulation containing no PCL showed the highest encapsulation efficiency, although the differences were not significant. The in vitro release kinetics were characterized by a high burst effect after 1 h of incubation, followed by a slow and continuous release. For the formulation based on PLGA, the pH of the medium during release dropped from 7.4 to 3.5 while the presence of PEC attenuated the pH drop. All formulations showed light toxicity by the MTT assay, but differences were observed in terms of phagocytosis, as particles prepared with PEC showed the higher uptake by J744-macrophages and cell respiratory burst, determined by oxygen peroxide release. All these characteristics suggest that the microparticulated antigenic formulation containing the higher ratio of PEC is susceptible to be used in animal vaccination studies.
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PMID:Development of microparticles prepared by spray-drying as a vaccine delivery system against brucellosis. 1217 75

The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) exert numerous cellular effects through the inhibition of cholesterol synthesis. The objectives of these experiments were to determine the following: (1) whether lovastatin (LOV) inhibits phenylephrine (PE)-induced growth of neonatal rat cardiac myocytes without inducing cytotoxicity and (2) whether growth-inhibiting effects of LOV are associated with reduced PE activation of extracellular signal regulated kinases 1 and 2 (ERK 1/2). After 48 h of exposure, LOV alone (0.1-10 microM) inhibited 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyl tetrazolium bromide (MTT) reduction without significant changes in propidium iodide staining, and 100 microM mevalonic acid prevented the effect of LOV on MTT reduction. PE (50 or 100-microM for 48 h) induced significant increases in protein-to-DNA ratios. PE (100 microM for 5 min) significantly increased the phosphorylated forms of ERK 1 and ERK 2 and activity of ERK. After 24 h pretreatment or 48 h cotreatment, LOV (10 microM) significantly inhibited PE-induced growth. In addition, LOV pretreatment significantly inhibited the stimulatory effect of PE on ERK 2 phosphorylation and ERK activity. These results demonstrate that LOV, at concentrations that do not alter membrane integrity, inhibits PE-induced growth of cardiac myocytes, potentially through reduced activation of ERK 1/2.
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PMID:Lovastatin inhibits phenylephrine-induced ERK activation and growth of cardiac. 1221 76

Arsenic trioxide (As(2)O(3)) was recently demonstrated to be an effective inducer of apoptosis in patients with relapsed acute promyelocytic leukemia (APL) as well as in patients with APL in whom all-trans-retinoic acid and conventional chemotherapy failed. Chronic myelogenous leukemia cells are highly resistant to chemotherapeutic drugs. To determine if As(2)O(3) might be useful for the treatment of chronic myelogenous leukemia, we examined the ability of As(2)O(3) to induce apoptosis in K562 cells. In vitro cytotoxicity of As(2)O(3) was evaluated in K562 cells by a MTT assay; the IC(50) value for As(2)O(3) was determined to be 10 microM. When analyzed by agarose gel electrophoresis, the DNA fragments became evident after incubation of the cells with 20 microM As(2)O(3) for 24 h. We also found morphological changes and chromatin condensation of the cells undergoing apoptosis. Activation of caspase-3 was observed 6 h after treatment with 20 microM As(2)O(3) by a Western blot analysis. Next, we examined the MAP kinase-signaling pathway of As(2)O(3)-induced apoptosis in K562 cells. As(2)O(3) at 10 microM strongly induced the activation of p38 and JNK 1/2, while ERK 1/2 was inhibited. In addition, pretreatment of SB203580, a specific inhibitor of p38, inhibited As(2)O(3) induced apoptotic cell death. These results suggest that As(2)O(3) is able to induce the apoptotic activity in K562 cells, and its apoptotic mechanism may be associated with the activation of p38.
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PMID:Arsenic trioxide induces apoptosis in chronic myelogenous leukemia K562 cells: possible involvement of p38 MAP kinase. 1229 96

Amphiphilic diblock polymeric nanospheres composed of methoxy poly(ethylene glycol) (MePEG) and poly(epsilon-caprolactone)(PCL) was prepared for application as a novel drug carrier. We could obtain the MePEG/PCL nanospheres that exhibited an average diameter of less than 200 nm with narrow size distribution and a relatively high drug-loading efficiency of about 41.98% and 20.8% for indomethacin and paclitaxel, respectively. To estimate the toxicity of nanospheres, we investigated cytotoxicity using the normal human fibroblast, the median lethal dose (LD(50)) and various organ toxicities using male ICR mice. The indomethacin-loaded nanosphere showed higher cell viability than indomethacin in the cytotoxicity test using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The LD(50) of MePEG/PCL nanospheres determined by Litchfield-Wilcoxon method was 1.47 g/kg. After the mice were intraperitoneally injected with MePEG/PCL nanospheres as a half-dose level of LD(50) for 7 days, no significant histopathologic changes were observed in MePEG/PCL nanospheres-treated mice compared with normal mice in the light and electron microscopic observations of various organs such as heart, lung, liver and kidney. It was suggested that MePEG/PCL nanospheres might be useful candidate as a novel injectable drug carrier for hydrophobic drugs such as indomethacin and paclitaxel.
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PMID:Toxic characteristics of methoxy poly(ethylene glycol)/poly(epsilon-caprolactone) nanospheres; in vitro and in vivo studies in the normal mice. 1241 78

Cyclin D1 is essential for Neu-induced cell growth and is induced by growth factors through Ras-dependent and Ras-independent signaling pathways (1). Because flavopiridol, a novel flavanoid cyclin-cyclin-dependent kinase inhibitor, may function through Ras-dependent and/or -independent pathways, we hypothesized that treatment of breast cancer cells with inhibitors of Neu signaling and flavopiridol might synergize to inhibit proliferation. Human breast cancer cell lines, which express high levels of endogenous Neu receptor, were treated with the anti-Neu antibody, trastuzumab, together with flavopiridol and subject to MTT assay. Cell lines were assayed for alterations in cell cycle by fluorescence-activated cell sorter and signaling proteins by Western blot. Flavopiridol and trastuzumab synergistically inhibited DNA synthesis, cellular proliferation, and contact-dependent growth. Cytotoxic synergy was observed independent of the sequence of addition of the two drugs to cultured cells. In SKBR3 cells, a combination of trastuzumab and flavopiridol inhibited the Ras-MAPK-Akt pathway, decreased cyclin D1 abundance, and kinase activity to a greater extent than either drug alone. Compared with single-agent treatment, combination treatment selectively inhibited Akt and pRB phosphorylation. Cytotoxic synergy was observed with flavopiridol plus LY294002 (selective phosphatidylinositol 3-kinase inhibitor) but not with PD98059 (selective mitogen-activated protein kinase kinase 1 inhibitor) suggesting that Akt inhibition may be important in synergy. Zinc-induced overexpression of cyclin D1 in T-47D deltaMTcycD1 cells were more resistant to drug-induced cell death when compared with vector-transfected T-47D deltaMT cells. Cyclin D1 overexpression reverses drug treatment induced cell cycle arrest in SKBR3 cells. Flavopiridol and trastuzumab yield cytotoxic synergy in human breast cancer cells overexpressing Neu. Cyclin D1 overexpression results in combination drug resistance. In addition, inhibition of Akt may prove to be a useful therapeutic strategy in combination with flavopiridol.
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PMID:Flavopiridol and trastuzumab synergistically inhibit proliferation of breast cancer cells: association with selective cooperative inhibition of cyclin D1-dependent kinase and Akt signaling pathways. 1247 66

Celsior, a new preservation solution in thoracic organ transplantation was evaluated for efficacy in cold preservation of human hepatocytes and compared with University of Wisconsin solution (UW) and histidine-tryptophan-ketoglutarate solution (HTK, Custodiol). Human hepatocyte cultures were preserved at 4 degrees C in Celsior, UW and HTK for 2, 6, 12, 24 and 48 h with 6 h of reperfusion. Levels of lactate dehydrogenase (LDH; cell necrosis), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT; mitochondrial function), and adenosine 5'-triphosphate (ATP; loss of intracellular energy) were measured. Cell necrosis, mitochondrial dysfunction, and loss of ATP were significantly ( P<0.001, P<0.001, P<0.002, respectively) lower in Celsior than in HTK. The amount of cell necrosis and mitochondrial dysfunction in Celsior solution (CS) and UW was equal ( P=n.s.) up to 24 h and significantly lower in UW after 48 h ( P<0.001). Additionally, the intracellular level of ATP was significantly higher after ischemia ( P<0.001) and reperfusion from long-term ischemia (24, 48 h) ( P<0.002). We can conclude that Celsior was superior to HTK and equal to UW in the protection of human hepatocytes against cold preservation injury from ischemia and reperfusion. Furthermore, Celsior was effective in long-term preservation of human hepatocytes.
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PMID:Celsior solution compared with University of Wisconsin solution (UW) and histidine-tryptophan-ketoglutarate solution (HTK) in the protection of human hepatocytes against ischemia-reperfusion injury. 1269 41

FLT3 is a receptor tyrosine kinase involved in the proliferation and differentiation of hematopoietic stem cells. FLT3 internal tandem duplications (FLT3/ITDs) are reported in acute myeloid leukemia (AML) and predict poor clinical outcome. We found FLT3/ITDs in 11.5% of 234 children with de novo AML. FLT3/ITD-positive patients were significantly older and had higher percentages of normal cytogenetic findings or French-American-British (FAB) classification M1/M2 and lower percentages of 11q23 abnormalities or FAB M5. FLT3/ITD-positive patients had lower remission induction rates (70% vs 88%; P =.01) and lower 5-year probability rates of event-free survival (pEF) (29% vs 46%; P =.0046) and overall survival (32% vs 58%; P =.037). Patients with high ratios (higher than the median) between mutant and wild-type FLT3 had significantly worse 2-year EFS rates than FLT3/ITD-negative patients (pEFS 20% vs 61%; P =.037), whereas patients with ratios lower than the median did not (pEFS 44% vs 61%; P =.26). FLT3/ITD was the strongest independent predictor for pEFS, with an increase in relative risk for an event of 1.92 (P =.01). Using an MTT (methyl-thiazol-tetrazolium)-based assay, we studied cellular drug resistance on 15 FLT3/ITD-positive and 125 FLT3/ITD-negative AML samples, but we found no differences in cellular drug resistance that could explain the poor outcomes in FLT3/ITD-positive patients. We conclude that FLT3/ITD is less common in pediatric than in adult AML. FLT3/ITD is a strong and independent adverse prognostic factor, and high ratios between mutant and WT-FLT3 further compromise prognosis. However, poor outcomes in FLT3/ITD-positive patients could not be attributed to increased in vitro cellular drug resistance.
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PMID:FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance. 1281 73

Despite therapeutic interventions including surgery, chemotherapy and radiotherapy, glioblastoma multiforme (GBM) has a very poor prognosis and novel therapies are required. MDA-7 (IL-24), when expressed via a recombinant replication defective adenovirus, Ad.mda-7, has profound anti-proliferative and cytotoxic effects in a variety of tumor cells, but not in non-transformed cells. The present studies examined the combined impact of Ad.mda-7 and ionizing radiation on the proliferation and survival of GBM cells. Ad.mda-7 reduced the proliferation of rodent and human glioma cells in MTT assays and in colony formation assays. The anti-proliferative effects of Admda-7 were enhanced by radiation in a greater than additive fashion. In vitro, this cellular change correlated with enhanced cell numbers in G1/G0 and G2/M phases of the cell cycle, implying Ad.mda-7 radiosensitizes tumor cells in a cell cycle-independent manner. The radiosensitizing effects were not observed in cultures of non-transformed primary astrocytes. The enhanced reduction in growth correlated with increased necrosis and DNA degradation. Ad.mda-7 enhanced p38 and ERK1/2 activity but did not alter JNK or Akt activity. Irradiation of cells expressing MDA-7 suppressed ERK1/2 activity and dramatically enhanced JNK1/2 activity without altering either Akt or p38 activity. Inhibition of JNK1/2, but not p38, signaling abolished the radiosensitizing properties of MDA-7. Inhibition of neither ERK1/2 nor PI3K signaling enhanced the anti-proliferative effects of Ad.mda-7, whereas combined inhibition of both pathways enhanced cell killing, suggesting that ERK and PI3K signaling can be protective against MDA-7 lethality.
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PMID:mda-7 (IL-24) Inhibits growth and enhances radiosensitivity of glioma cells in vitro via JNK signaling. 1450 3


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