Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined whether several newly synthesized derivatives of kojic acid, a compound with known antiinflammatory, anti-proliferative, and anti-oxidative properties, were able to modulate glioma cell proliferation and Toll-like receptor (TLR) 4-mediated functional activation of macrophage-managed tumor microenvironments. Anti-cancer effects on C6 glioma and SYF cells were examined by cell proliferation assays, DNA laddering assays, nuclear staining experiments, and Western blot analysis. The anti-inflammatory activities of the derivatives were assessed by measuring the production of nitric oxide (NO) and cytokine expression in macrophages (RAW264.7 cells) stimulated with the TLR 4 ligand lipopolysacchride (LPS). Among the various derivatives tested, RHS-0110 exhibited the strongest inhibitory activity on the proliferation of C6 glioma cells, with an IC50 value of 4.7 microM. However, the inhibitory effect of this compound was abrogated with respect to the proliferation of SYF cells, a cell line lacking Src, Yes, and Fyn kinases, similar to effects observed with the Src kinase inhibitor PP2. In agreement with these findings, RHS-0110 decreased the expression of Src but not the activation of Yes and Fyn. Based on DNA laddering tests and nucleus staining experiments, the anti-proliferative effects of RHS-0110 appeared to be due to a necrotic pathway. Kojic acid derivatives also suppressed LPS-induced NO production and interleukin (IL)-6 expression in RAW264.7 cells under lowered or non-cytotoxic concentrations of compounds. Because of their anti-proliferative and anti-TLR4-mediated microenvironmental formation features, our results suggest that kojic acid derivatives, including RHS-0110, may be useful as novel anti-cancer drugs.
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PMID:A modulatory effect of novel kojic acid derivatives on cancer cell proliferation and macrophage activation. 2043 22

Glioblastoma (GBM) is a high-grade glioma with a complex microenvironment, including various inflammatory cells and mast cells (MCs) as one of them. Previously we had identified glioma grade-dependent MC recruitment. In the present study we investigated the role of plasminogen activator inhibitor 1 (PAI-1) in MC recruitment.PAI-1, a primary regulator in the fibrinolytic cascade is capable of forming a complex with fibrinolytic system proteins together with low-density lipoprotein receptor-related protein 1 (LRP1). We found that neutralizing PAI-1 attenuated infiltration of MCs. To address the potential implication of LRP1 in this process, we used a LRP1 antagonist, receptor-associated protein (RAP), and demonstrated the attenuation of MC migration. Moreover, a positive correlation between the number of MCs and the level of PAI-1 in a large cohort of human glioma samples was observed. Our study demonstrated the expression of LRP1 in human MC line LAD2 and in MCs in human high-grade glioma. The activation of potential PAI-1/LRP1 axis with purified PAI-1 promoted increased phosphorylation of STAT3 and subsequently exocytosis in MCs.These findings indicate the influence of the PAI-1/LRP1 axis on the recruitment of MCs in glioma. The connection between high-grade glioma and MC infiltration could contribute to patient tailored therapy and improve patient stratification in future therapeutic trials.
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PMID:Glioma-derived plasminogen activator inhibitor-1 (PAI-1) regulates the recruitment of LRP1 positive mast cells. 2616 7