Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Des-gamma-carboxyl prothrombin (DCP) is a well recognized tumor marker for hepatocellular carcinoma. Previously, we have demonstrated that DCP stimulates cell proliferation in hepatocellular carcinoma cell lines through Met-Janus kinase 1 signal transducer and activator of transcription 3 signaling pathway. In the present study, we demonstrated that DCP induces both cell proliferation and migration in human umbilical vein endothelial cells. DCP was found to bind with the kinase insert domain receptor (KDR), alternatively referred to as vascular endothelial growth factor receptor-2. Furthermore, DCP induced autophosphorylation of KDR and its downstream effector phospholipase C-gamma and mitogen-activated protein kinase (MAPK). To support these results, we showed that DCP-induced cell proliferation and cell migration were inhibited by KDR short interfering RNA, KDR kinase inhibitor, or MAPK inhibitor. In conclusion, these results indicate that DCP is a novel type of vascular endothelial growth factor that possesses potent mitogenic and migrative activities.
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PMID:Des-gamma-carboxyl prothrombin-promoted vascular endothelial cell proliferation and migration. 1725 2

ZD6474 is a novel, orally available inhibitor of vascular endothelial growth factor receptor kinase insert domain receptor/flk-1 tyrosine kinase activity with additional activity against the epidermal growth factor receptor-1 tyrosine kinase. The aim of this study was to evaluate ZD6474, alone and in combination with gemcitabine, in an orthotopic model of metastatic pancreatic cancer. Nude mice (nine to 10/group) were injected orthotopically with 1x10(6) L3.6pl human pancreatic cancer cells. Eight days later, treatment was initiated with vehicle only, gemcitabine (100 mg/kg intraperitoneal twice weekly), ZD6474 (50 mg/kg oral once daily) or a combination of the two treatments. Animals were killed on day 24 posttreatment initiation. The phosphorylation status level of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor as well as the phosphorylation level of AKT and extracellular signal-regulated kinase-1/2 in different human pancreatic carcinoma cells and in human umbilical vein endothelial cells was analyzed by Western blotting. Compared with controls (1231 mg), the mean weight of treated tumors was reduced to 836, 541 and 308 mg in the gemcitabine, ZD6474 and combination groups, respectively. Lymph node metastasis was significantly reduced in both the ZD6474 alone and combined treatment groups, with 3/10 and 1/5 animals developing metastases, compared with 10/10 and 9/9 in the control and gemcitabine groups (P<0.003 and <0.0003, respectively). Microvessel density and cell proliferation were significantly reduced in the ZD6474 and combined treatment groups (P<0.02). Immunohistochemistry of tumor samples following treatment with ZD6474 resulted in a reduction of the activated and phosphorylated epidermal growth factor receptor, whereas total epidermal growth factor receptor levels were comparable with control tumors. On the basis of Western blot analysis, ZD6474 provides inhibition of tumor angiogenesis through an anti-vascular endothelial growth factor receptor-2 mechanism and inhibition of cancer cell growth through an anti-epidermal growth factor receptor mechanism. ZD6474 decreased primary pancreatic tumor growth and reduced lymph node and liver metastases compared with controls or gemcitabine alone. Tumor growth was inhibited further in animals receiving ZD6474 and gemcitabine in combination.
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PMID:Antiangiogenic and antitumor activity of a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor ZD6474 in a metastatic human pancreatic tumor model. 1741 26

Sorafenib, an inhibitor of multiple tyrosine kinases including vascular endothelial growth factor receptor and Raf/mitogen-activated protein kinase, increases progression-free survival in metastatic renal cell carcinoma (RCC) compared with placebo. The efficacy and toxicity of combined sorafenib and radiation therapy (RT) in the treatment of RCC are unknown. This is a retrospective report of 3 consecutive patients with metastatic or locally recurrent RCC treated with palliative RT while undergoing sorafenib therapy. All 3 patients experienced disease progression on sorafenib and remained on the drug without dose reduction during the RT plus sorafenib regimen. They were followed for toxicity and response by clinical history, physical examination, and contrast-enhanced computed tomography scans. Soon after completion of palliative RT, all 3 patients experienced complete pain relief without the need for narcotic pain medication. Posttreatment imaging revealed partial response with > 50% regression of tumor in all patients. None reported significant acute or late side effects at follow-up of 3, 6, and 8 months after RT and sorafenib. In the 3 patients with recurrent or metastatic RCC in this report, the combination of RT and sorafenib was well tolerated and resulted in excellent clinical and radiologic responses. This combination is promising and requires further study.
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PMID:Radiation therapy and sorafenib: clinical data and rationale for the combination in metastatic renal cell carcinoma. 1755 11

VEGF (vascular endothelial growth factor), a potent angiogenic molecule specific for vascular endothelial cells, is overexpressed in most tumours including MM (multiple myeloma) and closely associated with tumour growth and prognosis. It has been shown that a soluble fragment of the VEGF receptor Flt-1 (Fms-like tyrosine kinase-1) [sFlt-1 (soluble Flt-1)] has antiangiogenic properties by way of its antagonist activity against VEGF. VEGF and its receptors have been shown to be targets for treating tumours. In the present study, sFlt-1 gene was expressed in Pichia pastoris and the product was applied for studying the effect on KM3 MM cells. sFlt-1 gene was inserted into the pPICZalphaA vector and the expressed product was analysed by SDS/PAGE, immunoblot and ELISA. The sFlt-1 protein was expressed by 0.5% (v/v) methanol induction and it accumulated up to 23% of total proteins in the supernatant. The product was further purified with metal-chelating resin [Ni-NTA (Ni(2+)-nitrilotriacetate)]. The functional analysis of the sFlt-1 protein was performed with HUVEC (human umbilical-vein endothelial cells) proliferation assay. We next showed that the sFlt-1 protein acted directly on MM cells and inhibited the VEGF-induced proliferation of MM cells with MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] and (3)H uptake assay. The sFlt-1 protein blocked VEGF-induced ERK (extracellular-signal-regulated kinase) phosphorylation and inhibited the MAPK (mitogen-activated protein kinase) signalling cascades. The present study demonstrated that anti-MM activity of the sFlt-1 protein, coupled with its antiangiogenic effects, provides the basis for clinical trials of this agent to improve the outcome in MM.
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PMID:Expression of soluble Flt-1 gene in Pichia pastoris and the effect of the product on multiple-myeloma cells in vitro. 1761 89

The Shb adapter protein is an Src homology 2-domain containing signaling intermediate operating downstream of several tyrosine kinase receptors, including vascular endothelial growth factor receptor-2. Shb is multifunctional and apoptosis is one response that Shb regulates. Inhibition of angiogenesis can be used in cancer therapy, and one way to achieve this is by inducing endothelial cell apoptosis. The angiosarcoma cell line SVR is of endothelial origin and can be used as a tool for studying in vivo inhibition of angiogenesis, and we thus employed an Shb-knockdown strategy using an inducible lentiviral system to reduce Shb levels in SVR cells and to study their responses. Shb knockdown increases the susceptibility of SVR cells to the apoptotic agents, cisplatin and staurosporine. Simultaneously, Shb knockdown causes reduced focal adhesion kinase (FAK) activation, monitored as phosphorylation of the regulatory residues tyrosines 576/577. No detectable effects on Akt or extracellular signal-regulated kinase activity were noted. The altered FAK activity coincided with an elongated cell phenotype that was particularly noticeable in the presence of staurosporine. In order to relate the effects of Shb knockdown to in vivo tumorigenicity, cells were exposed to the angiogenesis inhibitor honokiol, and again the cells with reduced Shb content exhibited increased apoptosis. Tumor growth in vivo was strongly reduced in the Shb-knockdown cells upon honokiol treatment. It is concluded that Shb regulates apoptosis and cell shape in tumor endothelial cells via FAK, and that Shb is a potential target for inhibition of angiogenesis.
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PMID:Shb gene knockdown increases the susceptibility of SVR endothelial tumor cells to apoptotic stimuli in vitro and in vivo. 1791 55

The kringle 1 domain of human hepatocyte growth factor (HGFK1) was previously shown to inhibit bovine aortic endothelial cell proliferation, suggesting that it might be an antiangiogenic molecule. Here, we evaluated the in vivo efficacy of a recombinant adenoassociated virus carrying HGFK1 (rAAV-HGFK1) for the treatment of hepatocellular carcinoma (HCC) in a rat orthotopic HCC model and explored its molecular mechanisms in vitro in both endothelial and tumor cells. We first showed that rAAV-HGFK1 treatment significantly prolonged the survival time of rats transplanted with tumor cells. Treatment with rAAV-HGFK1 inhibited tumor growth, decreased tumor microvessel density, and completely prevented intrahepatic, lung, and peritoneal metastasis in this in vivo model. In vitro, rAAV-HGFK1 exhibited both antiangiogenic and antitumor cell effects, inhibiting the proliferation of both murine microvascular endothelial cells (MEC) and tumor cells, and inducing apoptosis and G(0)-G(1) phase arrest in these cells. To our surprise, rAAV-HGFK1 did not act through the hepatocyte growth factor/hepatocyte growth factor receptor pathway. Instead, it worked mainly through epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR) signaling, with more minor contributions from vascular endothelial growth factor/vascular endothelial growth factor receptor and beta fibroblast growth factor (bFGF)/beta fibroblast growth factor receptor (bFGFR) signaling. In both MECs and tumor cells, rAAV-HGFK1 acted through two pathways downstream of EGFR, namely inhibition of extracellular signal-regulated kinase activation and stimulation of p38 mitogen-activated protein kinase/c-Jun-NH(2)-kinase activation. These results suggest for the first time that HGFK1 exerts both antiangiogenic and antitumor cell activities mainly through EGF/EGFR signaling, and may thus be considered as a novel therapeutic strategy for the treatment of HCC.
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PMID:The kringle 1 domain of hepatocyte growth factor has antiangiogenic and antitumor cell effects on hepatocellular carcinoma. 1819 34

Most cancers are dependent on the growth of tumor blood vessels and inhibition of tumor angiogenesis may thus provide an efficient strategy to retard or block tumor growth. Recently, tumor vascular targeting has expanded to include not only endothelial cells (ECs) but also smooth muscle cells (SMCs), which contribute to a mature and functional vasculature. We have reported previously that delphinidin, a major biologically active constituent of berries, inhibits the vascular endothelial growth factor-induced phosphorylation of vascular endothelial growth factor receptor-2 and blocks angiogenesis in vitro and in vivo. In the present study, we show that delphinidin also inhibits activation of the platelet-derived growth factor (PDGF)-BB receptor-beta [platelet-derived growth factor receptor-beta (PDGFR-beta)] in SMC and that this inhibition may contribute to its antitumor effect. The inhibitory effect of delphinidin on PDGFR-beta was very rapid and led to the inhibition of PDGF-BB-induced activation of extracellular signal-regulated kinase (ERK)-1/2 signaling and of the chemotactic motility of SMC, as well as the differentiation and stabilization of EC and SMC into capillary-like tubular structures in a three-dimensional coculture system. Using an anthocyan-rich extract of berries, we show that berry extracts were able to suppress the synergistic induction of vessel formation by basic fibroblast growth factor-2 and PDGF-BB in the mouse Matrigel plug assay. Oral administration of the berry extract also significantly retarded tumor growth in a lung carcinoma xenograft model. Taken together, these results provide new insight into the molecular mechanisms underlying the antiangiogenic activity of delphinidin that will be helpful for the development of dietary-based chemopreventive strategies.
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PMID:Delphinidin, a dietary anthocyanidin, inhibits platelet-derived growth factor ligand/receptor (PDGF/PDGFR) signaling. 1833 83

Cell therapy has been extensively studied as an approach to repair damage in nervous system diseases. Multipotent stromal cells [MSCs] are well known to have neuroprotective effects and neural differentiation potential. The ability to induce migration of MSCs near nervous system damage via direct transplantation or via intravenous injections and increase the secretion of neurotrophic factors from MSCs might improve our ability to repair damage to the nervous system through cell therapy. In the present study, we investigated whether recombinant human erythropoietin [rhEPO], known to have a hematopoietic effect, could increase the motility of human bone marrow [hBM]-MSCs and enhance production of neurotrophic factors from hBM-MSCs. Based on the results of our MTT assay, trypan blue staining, and bromodeoxyuridine ELISA, rhEPO treatment increases the viability of MSCs but not their proliferation. With a migration assay kit, we demonstrated that the motility of hBM-MSCs was enhanced in rhEPO-treated cells. Immunoblotting assays revealed increased expression of phospho-Akt, phospho-GSK-3beta, phospho-extracellular signal-regulated kinase (ERK), beta PAK-interacting exchange factor (PIX), CXCR4, phospho tyrosine kinase B (TrkB), and vascular endothelial growth factor receptor-2 [VEGFR-2] in rhEPO-treated cells. Reverse transcription-polymerase chain reaction and gelatin zymography demonstrated that rhEPO treatment induces MMP-2 mRNA level and activity. In the studies using ELISAs, we found that rhEPO could increase levels of stromal cell-derived factor-1alpha, VEGF, and brain-derived neurotrophic factors. These findings suggest that rhEPO can increase the viability and motility of hBM-MSCs by affecting various intracellular signals including Akt, ERK, beta-PIX, CXCR4, TrkB, VEGFR-2, and MMP-2 and can enhance the production of neurotrophic factors from hBM-MSCs.
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PMID:Erythropoietin increases the motility of human bone marrow-multipotent stromal cells (hBM-MSCs) and enhances the production of neurotrophic factors from hBM-MSCs. 1859 Mar 75

Excessive neutrophil elastase (NE) activity and altered vascular endothelial growth factor (VEGF) signaling have independently been implicated in the development and progression of pulmonary emphysema. In the present study, we investigated the potential link between NE and VEGF. We noted that VEGF(165) is a substrate for NE. Digestion of purified VEGF(165) with NE generated a partially degraded disulfide-linked fragment of VEGF. Mass spectrometric analysis revealed that NE likely cleaves VEGF(165) at both the NH(2) and COOH termini to produce VEGF fragment chains approximately 5 kDa reduced in size. NE treatment of VEGF-laden endothelial cell cultures and smooth muscle cells endogenously expressing VEGF generated VEGF fragments similar to those observed with purified VEGF(165). NE-generated VEGF fragment showed significantly reduced binding to VEGF receptor 2 and heparin yet retained the ability to bind to VEGF receptor 1. Interestingly, VEGF fragment showed altered signaling in pulmonary artery endothelial cells compared with intact VEGF(165). Specifically, treatment with VEGF fragment did not activate extracellular-regulated kinases 1 and 2 (ERK1/2), yet resulted in enhanced activation of protein kinase B (Akt). Treatment of monocyte/macrophage RAW 264.7 cells with VEGF fragment, on the other hand, led to both Akt and ERK1/2 activation, increased VEGFR1 expression, and stimulated chemotaxis. These findings suggest that the tissue response to NE-mediated injury might involve the generation of diffusible VEGF fragments that stimulate inflammatory cell recruitment and activation via VEGF receptor 1.
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PMID:Neutrophil elastase cleaves VEGF to generate a VEGF fragment with altered activity. 1913 76

Epithelial ovarian cancer (EOC) is the fifth most common cancer in women and is characterized by a low 5-year survival rate. One strategy that can potentially improve the overall survival rate in ovarian cancer is the use of antitumor agents such as ABT-510. ABT-510 is a small mimetic peptide of the naturally occurring antiangiogenic compound thrombospondin-1 and has been shown to significantly reduce tumor growth and burden in preclinical mouse models and in naturally occurring tumors in dogs. This is the first evaluation of ABT-510 in a preclinical model of human EOC. Tumorigenic mouse surface epithelial cells were injected into the bursa of C57BL/6 mice that were treated with either 100 mg/kg ABT-510 or an equivalent amount of PBS. ABT-510 caused a significant reduction in tumor size, ascites fluid volume, and secondary lesion dissemination when compared with PBS controls. Analysis of the vasculature of ABT-510-treated mice revealed vascular remodeling with smaller diameter vessels and lower overall area, increased number of mature vessels, and decreased tissue hypoxia. Tumors of ABT-510-treated mice had a significantly higher proportion of apoptotic tumor cells compared with the PBS-treated controls. Immunoblot analysis of cell lysates revealed a reduction in vascular endothelial growth factor, vascular endothelial growth factor receptor-2, and proliferating cell nuclear antigen protein expression as well as expression of members of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase survival pathways. In vitro, ABT-510 induced tumor cell apoptosis in mouse and human ovarian cancer cells. This study shows ABT-510 as a promising candidate for inhibiting tumor growth and ascites formation in human EOC.
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PMID:ABT-510 induces tumor cell apoptosis and inhibits ovarian tumor growth in an orthotopic, syngeneic model of epithelial ovarian cancer. 1913 14


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