Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ras activation occurs through stimulation of an upstream growth factor receptor such as epidermal growth factor receptor (EGFR). The ultimate effect of Ras is to induce nuclear transcription via a signaling pathway sequentially involving Raf, MAP kinase kinase (MEK), and mitogen-activated protein kinase (MAPK). To transform cells, Ras oncoproteins must be posttranslationally modified with a farnesyl group in a reaction catalyzed by farnesyl protein transferase. Farnesyltransferase inhibitors, therefore, have been proposed as potent anticancer agents. This study demonstrates the growth-inhibitory effects of farnesyltransferase inhibitor SCH66336 on human glioblastoma cell lines U-251 MG, U-251/E4 MG (a stably transfected cell line with elevated EGFR expression), and U-87 MG. As determined by (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) (MTS) and viability assays, the concentration required to achieve 50% inhibition (IC50) ranged from 30 microM (single 24-h treatment) to 10 microM (5-day treatment). U-251/E4 MG with overexpression of EGFR were more sensitive than U-251 MG parental cells. These observations were also supported by soft agar analysis. Cells treated with SCH66336 underwent G2 arrest. Western blot analysis revealed a decrease in phospho-MAPK levels upon treatment with 10 microM SCH66336, whereas MAPK levels were unaffected by the drug. Interestingly, increased expression of EGFR was observed in U-251 MG and U-251/E4 MG but not in U-87 MG in the presence of the inhibitor. These results demonstrate that SCH66336 inhibits viability and anchorage-independent growth in a time- and dose-dependent manner in glioblastoma cell lines U-251 MG, U-251/E4 MG, and U-87 MG via a signal transduction pathway involving the down-regulation of phospho-MAPK. Overexpression of EGFR appears to alter cellular sensitivity to farnesyltransferase inhibitors. This may have a particularly important implication in glioblastoma, where over 50% of tumors have amplification and overexpression of EGFR.
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PMID:Inhibition of cell growth in human glioblastoma cell lines by farnesyltransferase inhibitor SCH66336. 1130 35

We have previously reported that prostaglandin F2 alpha (PGF2 alpha) activates p44/p42 mitogen-activated protein kinase (MAPK) through protein kinase C (PKC) in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the mechanism of vascular endothelial growth factor (VEGF) synthesis induced by PGF2 alpha and the effect of incadronate on the VEGF synthesis in these cells. PGF2 alpha significantly stimulated the VEGF synthesis in a dose-dependent manner between 1 pm and 10 microm. Cycloheximide reduced the PGF2 alpha effect. PGF2 alpha increased the levels of mRNA for VEGF. Cloprostenol, a PGF2 alpha-sensitive receptor agonist, potently induced the VEGF synthesis. Indomethacin, an inhibitor of cyclooxygenase, significantly reduced the PGF2 alpha-induced VEGF synthesis. Bisindolylmaleimide, an inhibitor of PKC, reduced the PGF2 alpha-induced VEGF synthesis. The VEGF synthesis induced by PGF2 alpha was significantly attenuated in the PKC down-regulated cells. PGF2 alpha elicited the translocation of PKC beta I from cytosol to membrane fraction. PD98059 or U0126, inhibitors of MEK, suppressed the VEGF synthesis induced by PGF2 alpha. Farnesyltransferase inhibitor failed to affect the PGF2 alpha-induced VEGF synthesis. Incadronate enhanced the synthesis of VEGF induced by PGF2 alpha. NaF-induced VEGF synthesis was also amplified by incadronate. PD98059 suppressed the enhancement by incadronate of PGF2 alpha-induced VEGF synthesis. Incadronate markedly enhanced the phosphorylation of Raf-1, MEK1/2, and p44/p42 MAPK induced by PGF2 alpha or 12-O-tetradecanoylphorbol-13-acetate, a PKC activator. Incadronate significantly enhanced the cloprostenol-increased level of VEGF concentration in mouse plasma in vivo. These results strongly suggest that PGF2 alpha stimulates VEGF synthesis through the PKC-dependent activation of p44/p42 MAPK in osteoblasts and that the incadronate enhances the VEGF synthesis at the point between PKC and Raf-1.
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PMID:Incadronate amplifies prostaglandin F2 alpha-induced vascular endothelial growth factor synthesis in osteoblasts. Enhancement of MAPK activity. 1264 77

Farnesyltransferase inhibitors (FTIs) are small-molecule inhibitors that selectivly inhibit farnesylation of a number of intracellular substrate proteins such as Ras. Preclinical work has revealed their ability to effectively inhibit tumor growth in vitro and in vivo in animal models across a wide range of malignant phenotypes. Acute myeloid leukemias (AMLs) are appropriate disease targets in that they express relevant biologic targets such as Ras, MEK, AKT, and others that may depend upon farnesyl protein transferase activity to promote cell proliferation and survival. Indeed, different intracellular proteins are substrates for prenylation. Interruption of prenylation may prevent substrates from undergoing maturation which may result in the inhibition of cellular events that depend on the function of those substrates. Phase I trials in AML and myelodysplasia have demonstrated biologic and clinical activities as determined by target enzyme inhibition, low toxicity, and both complete and partial responses. As a result, phase II trials have been initiated in order to further validate clinical activity and to identify downstream signal transduction targets that may be modified by these agents. It is anticipated that these studies will serve to define the optimal roles of FTIs in patients with these hematologic malignancies and provide insight into effective methods by which to combine FTIs with other agents.
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PMID:[Farnesyltransferase inhibitors: preliminary results in acute myeloid leukemia]. 1582 Sep 17

Farnesyltransferase inhibitors (FTI) are a class of therapeutic agents designed to target tumors with mutations of the ras oncogene. However, the biological effect of FTIs is often independent of ras mutation status, which suggests the existence of additional mechanisms. In this study, we investigated the molecular effects of SCH66336, an FTI, in head and neck squamous cell carcinoma cells using proteomic approaches. We showed that SCH66336 induced phosphorylation (inactivation) of eukaryotic translation elongation factor 2 (eEF2), an important molecule for protein synthesis, as early as 3 hours after SCH66336 administration. Protein synthesis was subsequently reduced in the cells. Paradoxically, activation of eEF2 kinase (eEF2K), the only known kinase that regulates eEF2, was observed only at 12 hours after SCH66336 treatment. Consistent with this observation, the inhibition of phosphorylated-MEK and phosphorylated-p70S6K, the two key signaling molecules responsible for activation of eEF2K, also occurred at least 12 hours after SCH66336 administration. Our data suggest that inhibition of protein synthesis through inactivation of eEF2 is a novel mechanism of SCH66336-mediated growth inhibition and that this effect is independent of ras-MEK/p70S6K-eEF2K signaling cascades.
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PMID:Farnesyltransferase inhibitor SCH66336 induces rapid phosphorylation of eukaryotic translation elongation factor 2 in head and neck squamous cell carcinoma cells. 1599 61

Besides being used as a spice, ginger has been applied in oriental medicine to ameliorate symptoms such as inflammatory, rheumatic disorders, and gastrointestinal discomforts. The effects of ginger on neuronal cells, however, have not been explored. We investigate the effect of 1-(3,4-dimethoxyphenyl)-3,5-dodecenedione (I(6)), a derivative of gingerdione, on cultured cortical neurons. After a 5-day maturation period in vitro, cortical neurons were treated with I(6) for 24 hr and cell viability was assessed using MTT assay. I(6) induced neuronal death in a concentration-dependent manner. Hoechst 33342, propidium iodide (PI), and TUNEL staining confirmed that the reduced cell viability by I(6) was due to apoptosis. Pre-treatment of cell with N-acetylcysteine (NAC) prevented cell death in a concentration-dependent manner. N-acetylcysteine increased phosphorylated levels of p42 and p44 extracellular signal-regulated kinases (ERKs). In parallel, farnesyltransferase and MEK inhibitors blocked ERK phosphorylation and neuroprotective effect of NAC. Unexpectedly, NAC also increased phosphorylated level of p38 mitogen-activated protein kinase (MAPK) and p38 specific inhibitors dose-dependently attenuated the effect of NAC. Farnesyltransferase and MEK inhibitors completely abolished NAC-induced p38 phosphorylation whereas p38 inhibitor did not influence NAC-induced ERK phosphorylation. These results show that NAC serially activates ERKs and p38 MAPK, and ERKs and p38 work together to mediate the neuroprotective effect of NAC.
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PMID:Neuroprotective effect of N-acetylcysteine on neuronal apoptosis induced by a synthetic gingerdione compound: involvement of ERK and p38 phosphorylation. 1698 58

The present study investigated the combined effect of Akt or extracellular signal-regulated kinase (ERK) inhibition in the presence of farnesyltransferase inhibitor against human cervix and uterus tumor cell line SiHa cells. Farnesyltransferase inhibitor may induce apoptosis through the mitochondria-mediated process and inhibition of the MEK, ERK, and Akt activity. Inhibitors of Akt and ERK at low concentrations seem to prevent the farnesyltransferase inhibitor-induced apoptosis in cervical SiHa cells by suppressing the mitochondrial membrane permeability change that leads to cytochrome c release and caspase-3 activation. These effects may be associated with inhibition of the reactive oxygen species formation and glutathione depletion. In contrast, at higher concentrations more than 1 microM, the Akt inhibitor and ERK inhibitor seem to exhibit an additive toxic effect against farnesyltransferase inhibitor-induced apoptosis by increasing mitochondrial membrane permeability change and oxidative stress, which may not involve inhibition of MEK, ERK, and Akt activity.
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PMID:Combined effect of protein kinase B inhibitor or extracellular signal-regulated kinase inhibitor against farnesyltransferase inhibition-induced apoptosis in SiHa cells. 1885 83

Farnesyltransferase (FTase) inhibitors induce growth arrest and apoptosis in various human cancer cells by inhibiting the post-translational activation of Ras. FTase inhibitors also function to suppress the release of vascular endothelial growth factor (VEGF) from tumor cells by inhibiting Ras activation; however, the effects of FTase inhibitors on VEGF-induced angiogenesis in endothelial cells have not been studied. We have investigated the antiangiogenic effect and molecular mechanism of 4-((1-((1-((4-bromophenyl)methyl)-1H-imidazol-5-yl)methyl)-4-(1-napthalenyl)-1H-pyrrol-3-yl)carbonyl)-(9C1)-morpholine (LB42708), a selective nonpeptidic FTase inhibitor, using in vitro and in vivo assay systems. LB42708 inhibited VEGF-induced Ras activation and subsequently suppressed angiogenesis in vitro and in vivo by blocking the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase/p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt/endothelial nitric-oxide synthase pathways in endothelial cells without altering FAK/Src activation. In addition, this inhibitor suppressed VEGF-induced endothelial cell cycle progression at the G(1) phase by suppressing cyclin D1 expression and retinoblastoma phosphorylation as well as up-regulating the cyclin-dependent kinase inhibitors p21 and p27. Knockdown of Ras by short interfering RNA revealed similar inhibitory effects on VEGF-induced angiogenic signal events compared with LB42708. Moreover, the inhibitory effects of LB42708 were significantly higher than those of 4-(2-(4-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo-(5,6)-cyclohepta(1,2-b)-pyridin-11(R)-yl)-1-piperidinyl)-2-oxo-ethyl)-1-piperidinecarboxamide (SCH66336), a well known FTase inhibitor. LB42708 suppressed tumor growth and tumor angiogenesis in both xenograft tumor models of Ras-mutated HCT116 cells and its wild-type Caco-2 cells, indicating its potential application in the treatment of both Ras-mutated and wild type tumors. These data indicate that the antitumor effect of LB42708 can be associated with direct inhibition of VEGF-induced tumor angiogenesis by blocking Ras-dependent MAPK and PI3K/Akt signal pathways in tumor-associated endothelial cells.
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PMID:The farnesyltransferase inhibitor LB42708 suppresses vascular endothelial growth factor-induced angiogenesis by inhibiting ras-dependent mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt signal pathways. 2040 54

KRAS genes are the most commonly mutated oncogenes in cancer. Unfortunately, effective therapeutic strategies for targeting KRAS mutant cancers have proven to be difficult to obtain. A key reason for this setback is due to the lack of success direct KRAS mutant inhibitors have received. Researchers have turned their efforts away from targeting the KRAS nucleotide-binding site directly and towards targeting other areas of the MAPK signaling pathway to block KRAS function. Researchers found that inhibiting enzymes and protein-protein interactions involved in the MAPK signaling pathway inhibit the activation of KRAS mutant therefore can lead to a potential therapeutic for KRAS mutated cancers. Throughout the past two decades, various indirect inhibitors have been designed and tested. EGFR and MEK inhibitors have presented with less success; however, significant advances have been made when targeting the plasma membrane localization process and the allosteric site of KRAS mutant. Farnesyltransferase and allosteric inhibitors have both advanced to human clinical trials. This comprehensive review presents the most recent developments of direct and indirect KRAS mutant inhibitors. This review summarizes published data on the inhibitory and anti-cancer activity of compounds that target KRAS activation as well as highlights the most promising strategies for targeting KRAS mutant cancers.
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PMID:Targeting KRAS mutant cancers by preventing signaling transduction in the MAPK pathway. 3322 76