Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:EXPT01586 (G418)
 2,237 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-8 (IL-8) is a chemokine for neutrophils and an angiogenic factor. Human tumors that express IL-8 may exhibit intense neutrophil infiltration and increased vascularization. Mutatect cells are a murine fibrosarcoma that can be grown as subcutaneous tumors in syngeneic C57BL/6 mice. Since neutrophils are a source of cytotoxic and genotoxic species, we constructed Mutatect cell lines that constitutively express human IL-8 to explore the involvement of neutrophils in tumor biology and genetic instability. An IL-8/neo expression plasmid was stably transfected into Mutatect MC17-51 cells and clone MIL-4 was isolated. Tumors initiated with 5x10(5) MIL-4 cells grew very slowly compared with tumors from pure MC17-51 cells or from 0.5 to 4x10(5) MIL-4 cells mixed with 5x10(5) MC17-51 cells. Over 95% of cells recovered from slow-growing pure MIL-4 tumors lost the transgene as measured by loss of (i) resistance to G418, (ii) expression of IL-8 protein and (iii) IL-8-specific DNA sequences. When tumors from mixed cell types were examined, loss of the transgene did not occur; rather, IL-8 producing cells appeared to have some growth advantage. The neutrophil content of tumors (as measured by myeloperoxidase) was directly proportional to the level of IL-8 expressed at the time tumors were excised. As reported earlier, the frequency of mutations at the hypoxanthine phosphoribosyltransferase locus was also directly proportional to neutrophil content. To explain some of these biological findings, we postulate that early in development of pure MIL-4 tumors, genotoxic/cytotoxic neutrophils are attracted by IL-8, which in turn leads to loss of the transgene and to localized cytotoxicity of IL-8 producing cells. In mixed tumors, where the initial IL-8 concentration may be lower, tumors might become established more readily because fewer neutrophils may be attracted. This relatively simple experimental paradigm has revealed some of the complex biological changes that can occur as a result of IL-8 in tumors.
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PMID:Constitutive expression of interleukin-8 by Mutatect cells markedly affects their tumor biology. 1118 44

Recently, it has been suggested that chemokine/receptor interactions determine the destination of the invasive tumor cells in several types of cancer. It has also been proposed that the stromal cell-derived factor-1 (SDF-1; CXCL12)/CXCR4 system might be involved lymph node metastasis in oral squamous cell carcinoma (SCC). In order to further clarify the role of the SDF-1/CXCR4 system in oral SCC, we generated CXCR4 stable transfectants (IH-CXCR4) using oral SCC cells, and compared them to IH, which did not express CXCR4 and which did not have lymph node metastatic potentials in vivo. We introduced enhanced green fluorescent protein (GFP) fused-CXCR4 into IH cells, and detected the GFP fluorescence in the cytoplasm and cell membrane in approximately 60% of the G418-resistant cells. This bulk-transfectant expressed a high level of CXCR4 mRNA and protein, and exhibited the characteristic calcium fluxes and chemotactic activity observed in treatment with SDF-1. SDF-1 biphasically activated extracellular signal-regulated kinase (ERK)1/2, but continuously activated Akt/protein kinase B (PKB) in IH-CXCR4 cells. Most importantly, IH-CXCR4 cells frequently metastasized to the cervical lymph node, but not to the distant organs in the orthotopic inoculation of nude mice. Furthermore, these lymph node metastases were inhibited by the treatment of a mitogen-activated protein kinase/ERK kinase inhibitor, U0126, or a phosphatidylinositol 3 kinase inhibitor, wortmannin. These results indicate that SDF-1/CXCR4 signaling mediates the establishment of lymph node metastasis in oral SCC via ERK1/2 or Akt/PKB pathway.
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PMID:Acquisition of lymph node, but not distant metastatic potentials, by the overexpression of CXCR4 in human oral squamous cell carcinoma. 1549 52

Chemokine receptors belong to a superfamily of proteins that signal through coupled heterotrimeric G proteins. Chemokine receptor CCR5 is the major co-receptor essential for HIV entry into host cells, and now chemokine CCR5 receptor has become an important target in searching for anti-HIV drugs. Here, we describe the establishment of a human embryonic kidney (HEK) 293/CCR5-HA cell line stably expressing CCR5 receptor with influenza hemagglutinin (HA) tag at the N termini on the membrane surface of HEK293 cells. Plasmid pcDNA3.0-CCR5-HA was transfected into HEK293 cells, and monoclonal HEK293 cell lines expressing CCR5 receptor were generated under G418 selection. The expression of functional CCR5 receptor was tested by GTP?S assay, and the results showed about 5 monoclonal HEK293 cell lines expressed functional CCR5 receptor, and of which No.7 monoclonal cell line is the best. The FACS analysis results further confirmed that CCR5 receptor was positive in 96.89% of No.7 monoclonal HEK293/CCR5-HA cell line. Further results showed that RANTES significantly stimulated GTP?S binding in the dose-dependent manner, and CCR5 antagonist Sch-351125 inhibited RANTES stimulated GTP?S binding in the dose-dependent manner in No.7 monoclonal HEK293/CCR5-HA cell line. Our results suggest that the established HEK293/CCR5-HA cell line is suitable for highthroughput screening and is feasible to identify CCR5 receptor antagonists.
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PMID:Establishment of a new cell line for high-throughput evaluation of chemokine CCR5 receptor antagonists. 2249 60