Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

For tumor progression, a cascade of linked sequential biological events is essential. We tried to test whether biological therapy can modulate specific biological phenotypes and increase the anti-tumor effect when combined with chemotherapy. Five human gastric cancer cell lines (YCC-1, YCC-2, YCC-3, YCC-7, AGS) were used in these studies. Pentosan polysulfate (PPS) as a heparin-binding growth factor inhibitor, Tranexamic acid as a plasmin inhibitor, Lovastatin as an adhesion inhibitor and Adriamycin as a chemotherapeutic agent were selected. The effects of each drug on colony formation and tumor cell proliferation were evaluated by soft agar assay and cell proliferation assay, respectively to test direct anti-tumor effect. The expression of uPA, PAI-1 was determined by ELISA, while MMPs activity was evaluated by zymography. PPS suppressed the colony-forming activity as much as Adriamycin did, but it showed only cytostatic effects in cell proliferation assay. Migration capacity using Boyden chamber assay was more closely correlated with adhesive capacity than uPA or MMP-2 expression. The motility inhibitory effect of Tranexamic acid was observed in the YCC-7 cell line, which expressed all the required biological phenotypes for migration. In AGS, with high cell motility and adhesiveness, the adhesion was inhibited by Lovastatin and most of the inhibitory effect was recovered by Mevalonate. When PPS was combined with Adriamycin on the Adriamycin-resistant, midkine (MK) gene expressing YCC-7 cell line, the growth inhibition rate increased up to 84%, while that for a single treatment of PPS or Adriamycin was 40% and 22%, respectively (p=0.001). When we combined Tranexamic acid and Adriamycin, we observed the synergistic effect in YCC-3 and YCC-7, while no combined effect was found in YCC-1. The combination of Lovastatin and Adriamycin did not show any combined effects in any of the cell lines. In conclusion, a synergistic anti-proliferative effect (chemo-sensitization) with combined chemo-biotherapy was found in cancer cells with specific biological target, MK. The anti-motility effect was the greatest when the gastric cancer cells expressed all the specific biological phenotypes.
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PMID:Modulation of biological phenotypes for tumor growth and metastasis by target-specific biological inhibitors in gastric cancer. 1040 90

The fibrinolytic inhibitor plasminogen activator inhibitor type 1 (PAI-1) plays a role in the development of atherothrombosis and is produced by macrophages that infiltrate the atherosclerotic vessel wall. Because statins are effective in reducing atherosclerosis, we investigated if they modulate the synthesis of PAI-1 in human monocytes/macrophages. To this end, we studied the effect of atorvastatin in different models of monocyte/macrophage differentiation, such as differentiated human promyelocytic cell line HL-60 and human peripheral blood monocyte-derived macrophages. HL-60 cells were differentiated along monocyte lineage by phorbol myristate acetate (PMA) or a mixture of transforming growth factor-beta type 1 (TGF-beta1)/1alpha,25-dihydroxyvitamin D3 (D3). In these conditions, PAI-1 synthesis was strongly induced and atorvastatin upregulated this synthesis, especially during TGF-beta1/D3-induced differentiation. Recombinant human tumor necrosis factor-alpha (TNF-alpha) strongly upregulated PAI-1 synthesis in PMA- or TGF-beta1/D3-differentiated cells, and the potentiating effect of atorvastatin was of the same order as in the absence of TNF-alpha. Mevalonate reversed the enhancing effect of atorvastatin. In mature human monocyte-derived macrophages, atorvastatin, alone or in combination with TNF-alpha, TGF-beta1, or PMA, did not exert any significant effect on PAI-1 synthesis. Basal production of urokinase (uPA), which was below detection limits in HL-60 cells and very low in human monocyte-derived macrophages, was not altered by atorvastatin. These results show that atorvastatin upregulates PAI-1 synthesis during the early stages of monocyte/macrophage differentiation, but has no effect on PAI-1 and uPA synthesis in mature human monocyte-derived macrophages. Atorvastatin did not significantly interact with the upregulating action of TNF-alpha on PAI-1 synthesis during differentiation.
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PMID:Effect of atorvastatin on plasminogen activator inhibitor type-1 synthesis in human monocytes/macrophages. 1139 73