Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protein-bound polysaccharide isolated from basidiomycetes (PSK) is a biological response modifier capable of exhibiting various biological activities, such as antitumor and antimicrobial effects. In the present study, we found that PSK suppressed interleukin (IL)-6 production in murine peritoneal macrophages stimulated with endotoxic lipopolysaccharide (LPS) and its synthetic lipid A (compound 506). Nitric oxide production and p38 mitogen-associated protein kinase phosphorylation induced in a murine macrophage cell line, J774-A1, by LPS and compound 506 were also inhibited by PSK. Further, PSK distinctly suppressed nuclear factor-kappaB activation in Ba/F3 cells expressing mouse Toll-like receptor 4 and MD-2, following stimulation with LPS and compound 506, however, not with Taxol. These PSK-induced inhibitory activities were caused by inhibition of the physical associations of LPS with LPS-binding protein (LBP) and CD14. PSK also protected mice from LPS-induced lethality, presumably by down-regulating IL-6 and tumor necrosis factor-alpha concentrations in serum. These findings indicate that PSK, which also has an ability to regulate LBP/CD14 functions, may be useful for clinical control of endotoxic sepsis.
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PMID:Protein-bound polysaccharide isolated from basidiomycetes inhibits endotoxin-induced activation by blocking lipopolysaccharide-binding protein and CD14 functions. 1560 41

We have found that the synthetic compound CC-5079 potently inhibits cancer cell growth in vitro and in vivo by a novel combination of molecular mechanisms. CC-5079 inhibits proliferation of cancer cell lines from various organs and tissues at nanomolar concentrations. Its IC(50) value ranges from 4.1 to 50 nmol/L. The effect of CC-5079 on cell growth is associated with cell cycle arrest in G(2)-M phase, increased phosphorylation of G(2)-M checkpoint proteins, and apoptosis. CC-5079 prevents polymerization of purified tubulin in a concentration-dependent manner in vitro and depolymerizes microtubules in cultured cancer cells. In competitive binding assays, CC-5079 competes with [(3)H]colchicine for binding to tubulin; however, it does not compete with [(3)H]paclitaxel (Taxol) or [(3)H]vinblastine. Our data indicate that CC-5079 inhibits cancer cell growth with a mechanism of action similar to that of other tubulin inhibitors. However, CC-5079 remains active against multidrug-resistant cancer cells unlike other tubulin-interacting drugs, such as Taxol and colchicine. Interestingly, CC-5079 also inhibits tumor necrosis factor-alpha (TNF-alpha) secretion from lipopolysaccharide-stimulated human peripheral blood mononuclear cells (IC(50), 270 nmol/L). This inhibitory effect on TNF-alpha production is related to its inhibition of phosphodiesterase type 4 enzymatic activity. Moreover, in a mouse xenograft model using HCT-116 human colorectal tumor cells, CC-5079 significantly inhibits tumor growth in vivo. In conclusion, our data indicate that CC-5079 represents a new chemotype with novel mechanisms of action and that it has the potential to be developed for neoplastic and inflammatory disease therapy.
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PMID:The synthetic compound CC-5079 is a potent inhibitor of tubulin polymerization and tumor necrosis factor-alpha production with antitumor activity. 1642 30

Paclitaxel (Taxol) is an antineoplastic agent that specifically targets microtubules and arrests cells at the G2/M phase of the cell cycle. In addition to mitotic arrest, the activation of c-Jun N-terminal kinase (JNK) signaling pathway has been demonstrated to be involved in the process leading to apoptosis. In an attempt to explore what genes are transcriptionally regulated by the activated JNK signaling pathway upon paclitaxel treatment, we used cDNA microarrays to analyse the changes of gene expression in human ovarian cancer cells that were treated with paclitaxel and/or the JNK inhibitor SP600125. Among 20 genes that were specifically regulated by the paclitaxel-activated JNK pathway, interleukin (IL)-6 was shown to elicit function through the JAK-STAT signaling pathway in an autocrine and/or paracrine fashion. Subsequently, we identified that 87.5% of eight tested ovarian cancer lines secreted detectable levels of IL-6, which could be further upregulated 2-3.2 fold by 1 microM paclitaxel. Dissection on regulatory pathways for IL-6 indicated that (i) when ovarian cancer cells were treated with paclitaxel at low but clinically achievable concentrations (exemplified by 1 microM in this study), the JNK signaling pathway was the major stimulator of IL-6 gene regulation and (ii) at suprapharmacologically high concentrations (exemplified by 50 microM), paclitaxel exerted lipopolysaccharide-like effects, most likely through the Toll-like receptor 4 signaling pathway. Collectively, these results suggest that paclitaxel upregulates functional IL-6 expression in human ovarian cancer cells through multiple signaling pathways.
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PMID:Paclitaxel (Taxol) upregulates expression of functional interleukin-6 in human ovarian cancer cells through multiple signaling pathways. 1654 93

The pathogenesis of acute lung injury includes transendothelial diapedesis of leukocytes into lung tissues and disruption of endothelial/epithelial barriers leading to protein-rich oedema. In vitro studies show that the microtubule network plays a role in the regulation of endothelial permeability as well as in neutrophil locomotion. It was hypothesised that the microtubule-stabilising agent, taxol, might attenuate inflammation and vascular leak associated with acute lung injury in vivo. The effect of intravenously delivered taxol was assessed using a model of murine lung injury induced by intratracheal lipopolysaccharide (LPS) administration. Parameters of lung injury and inflammation were assessed 18 h after treatment. Intravenously delivered taxol significantly reduced inflammatory histological changes in lung parenchyma and parameters of LPS-induced inflammation: infiltration of proteins and inflammatory cells into bronchoalveolar lavage fluid, lung myeloperoxidase activity, and extravasation of Evans blue-labelled albumin into lung tissue. Taxol alone (in the absence of LPS) had no appreciable effect on these parameters. In addition to lung proteins, intravenous taxol reduced accumulation of leukocytes in ascitic fluid in a model of LPS-induced peritonitis. Taken together, the present data demonstrate that microtubule stabilisation with taxol systemically attenuates lipopolysaccharide-induced inflammation and vascular leak.
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PMID:Suppression of endotoxin-induced inflammation by taxol. 1753 65

The 90 kDa heat shock proteins (Hsp90), which are integrally involved in cell signaling, proliferation, and survival, are ubiquitously expressed in cells. Many proteins in tumor cells are dependent upon the Hsp90 protein folding machinery for their stability, refolding, and maturation. Inhibition of Hsp90 uniquely targets client proteins associated with all six hallmarks of cancer. Thus, Hsp90 has emerged as a promising target for the treatment of cancer. Hsp90 exists as a homodimer, which contains three domains. The N-terminal domain contains an ATP-binding site that binds the natural products geldanamycin and radicicol. The middle domain is highly charged and has high affinity for co-chaperones and client proteins. Initial studies by Csermely and co-workers suggested a second ATP-binding site in the C-terminus of Hsp90. This C-terminal nucleotide binding pocket has been shown to not only bind ATP, but cisplatin, novobiocin, epilgallocatechin-3-gallate (EGCG) and taxol. The coumarin antibiotics novobiocin, clorobiocin, and coumermycin A1 were isolated from several streptomyces strains and exhibit potent activity against Gram-positive bacteria. These compounds bind type II topoisomerases, including DNA gyrase, and inhibit the enzyme-catalyzed hydrolysis of ATP. As a result, novobiocin analogues have garnered the attention of numerous researchers as an attractive agent for the treatment of bacterial infection. Novobiocin was reported to bind weakly to the newly discovered Hsp90 C-terminal ATP binding site ( approximately 700 M in SkBr3 cells) and induce degradation of Hsp90 client proteins. Structural modification of this compound has led to an increase of 1000-fold in activity in anti-proliferative assays. Recent studies of structure-activity relationship (SAR) by Renoir and co-workers highlighted the crucial role of the C-4 and/or C-7 positions of the coumarin and removal of the noviose moiety, which appeared to be essential for degradation of Hsp90 client proteins. Unlike the N-terminal ATP binding site, there is no reported co-crystal structure of Hsp90 C-terminus bound to any inhibitor. The Hsp90 C-terminal domain, however, is known to contain a conserved pentapeptide sequence (MEEVD) which is recognized by co-chaperones. Cisplatin is a platinum-containing chemotherapeutic used to treat various types of cancers, including testicular, ovarian, bladder, and small cell lung cancer. Most notably, cisplatin coordinates to DNA bases, resulting in cross-linked DNA, which prohibits rapidly dividing cells from duplicating DNA for mitosis. Itoh and co-workers reported that cisplatin decreases the chaperone activity of Hsp90. This group applied bovine brain cytosol to a cisplatin affinity column, eluted with cisplatin and detected Hsp90 in the eluent. Subsequent experiments indicated that cisplatin exhibits high affinity for Hsp90. Moreover Csermely and co-workers determined that the cisplatin binding site is located proximal to the C-terminal ATP binding site. EGCG is one of the active ingredients found in green tea. EGCG is known to inhibit the activity of many Hsp90-dependent client proteins, including telomerase, several kinases, and the aryl hydrocarbon receptor (AhR). Recently Gasiewicz and co-workers reported that EGCG manifests its antagonistic activity against AhR through binding Hsp90. Similar to novobiocin, EGCG was shown to bind the C-terminus of Hsp90. Unlike previously identified N-terminal Hsp90 inhibitors, EGCG does not appear to prevent Hsp90 from forming multiprotein complexes. Studies are currently underway to determine whether EGCG competes with novobiocin or cisplatin binding. Taxol, a well-known drug for the treatment of cancer, is responsible for the stabilization of microtubules and the inhibition of mitosis. Previous studies have shown that taxol induces the activation of kinases and transcription factors, and mimics the effect of bacterial lipopolysaccharide (LPS), an attribute unrelated to its tubulin-binding properties. Rosen and co-workers prepared a biotinylated taxol derivative and performed affinity chromatography experiments with lysates from both mouse brain and macrophage cell lines. These studies led to identification of two chaperones, Hsp70 and Hsp90, by mass spectrometry. In contrast to typical Hsp90-binding drugs, taxol exhibits a stimulatory response. Recently it was reported that the geldanamycin derivative 17-AAG behaves synergistically with taxol-induced apoptosis. This review describes the different C-terminal inhibitors of Hsp90, with specific emphasis on structure-activity relationship studies of novobiocin and their effects on anti-proliferative activity.
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PMID:Novobiocin and additional inhibitors of the Hsp90 C-terminal nucleotide-binding pocket. 1899 31

The prime objective of this study was to develop a combined chemo-immunotherapeutic formulation which could directly kill cancer cells as well as activate the immunosuppressed tumor microenvironment to mount a robust antitumor immune response. Paclitaxel (PTX) and SP-LPS (nontoxic derivative of lipopolysaccharide) were selected as anticancer drug and immunostimulant respectively. Poly(lactic-co-glycolic acid) (PLGA) based PTX and SP-LPS containing nanoparticles (TLNP) were prepared by the double-emulsion method (w/o/w) and characterized in terms of size, zeta potential and transmission electron microscopy (TEM). The release behavior of PTX and SP-LPS from the TLNP exhibited a biphasic pattern characterized by an initial burst followed by slow continuous release. In vitro anticancer activity of TLNP was found to be higher compared to PTX when studied in a tumor cell-splenocyte coculture system. TLNP activated murine monocytes induced the secretion of various proinflammatory cytokines. After iv administration of TLNP in tumor bearing C57BL/6 mice, the amount of PTX in the tumor mass was found to be higher in TLNP treated mice as compared to commercial Taxol group at all time points studied. In vitro studies suggest that nanoparticles containing PTX and SP-LPS have both direct cytotoxicity and immunostimulatory activity. Hence this might have potential as a chemo-immunotherapeutic formulation against cancer with advantage over present day chemotherapy with Taxol, in terms of tumor targeting, less toxicity and immunostimulation.
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PMID:Combined chemo-immunotherapy as a prospective strategy to combat cancer: a nanoparticle based approach. 2082 93

The aim of the present study was to observe the influence of various factors on the nuclear distribution of the RhoA protein in the SGC-7901 human gastric cancer cell line. Immunofluorescence microscopy was used to detect the localization of the RhoA protein, and Western blotting was used to determine the quantity of RhoA in the nucleus, cytosol and membrane. The results showed that H2O2-mediated damage and a lipopolysaccharide (LPS)-mediated inflammatory reaction caused the translocation of RhoA from the cytosol toward the nucleus. A P38 mitogen-activated protein kinase (MAPK) inhibitor effectively hindered the LPS-triggered translocation of RhoA into the nucleus at the initial stage. Furthermore, the microtubule-targeted anticancer drug Taxol triggered the translocation of RhoA from the nucleus toward the cytosol and membrane, and Lysophosphatidic acid (LPA) enhanced this translocation. A protein modification inhibitor and a nucleus export inhibitor had no obvious effect on RhoA distribution in the nucleus. The results revealed that the distribution of RhoA protein in the nucleus was influenced by factors related to cell activities but was not affected by the modification of the protein. The translocation of RhoA into the nucleus was not dependent on the active nuclear import system.
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PMID:Factors influencing RhoA protein distribution in the nucleus. 2185 Mar 73

Recent studies have revealed the localization of RhoA protein in the cell nucleus, in addition to its distribution in the cytosol and cell membrane. The results of previous studies by our group indicated that nuclear RhoA expression is increased, or RhoA is transported into the nucleus, when cells become cancerous or damaged. Furthermore, application of the anticancer agent Taxol appeared to reduce nuclear RhoA localization, indicating an association between the nuclear translocation of RhoA and tumor progression. Bilobol is a traditional Chinese medicine ingredient, however, its anticancer effect has remained unclear. The present study aimed to demonstrate the anticarcinogenic action of bilobol against hepatocellular carcinoma, in order to lay the foundations for subsequent research into the mechanisms underlying its anticancer effects. In the present study, HepG2 cells were treated with lipopolysaccharide (LPS), to induce inflammation, and/or bilobol. By performing an ELISA, it was observed that bilobol was able to suppress the inflammation induced by LPS. In addition, immunofluorescence and western blot analyses indicated that bilobol may reduce the expression of RhoA, suppress translocation of RhoA into the nucleus and inhibit the RhoA/Rho-associated protein kinase signaling pathway. In conclusion, the present study revealed the potential anticancer effects of bilobol.
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PMID:Bilobol inhibits the lipopolysaccharide-induced expression and distribution of RhoA in HepG2 human hepatocellular carcinoma cells. 2662 5


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