Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor beta (TGFbeta) is a pleiotropic factor that regulates cell proliferation, angiogenesis, metastasis, and immune suppression. Dysregulation of the TGFbeta pathway in tumor cells often leads to resistance to the antiproliferative effects of TGFbeta while supporting other cellular processes that promote tumor invasiveness and growth. In the present study, SD-208, a 2,4-disubstituted pteridine, ATP-competitive inhibitor of the TGFbeta receptor I kinase (TGFbetaRI), was used to inhibit cellular activities and tumor progression of PANC-1, a human pancreatic tumor line. SD-208 blocked TGFbeta-dependent Smad2 phosphorylation and expression of TGFbeta-inducible proteins in cell culture. cDNA microarray analysis and functional gene clustering identified groups of TGFbeta-regulated genes involved in metastasis, angiogenesis, cell proliferation, survival, and apoptosis. These gene responses were inhibited by SD-208. Using a Boyden chamber motility assay, we demonstrated that SD-208 inhibited TGFbeta-stimulated invasion in vitro. An orthotopic xenograft mouse model revealed that SD-208 reduced primary tumor growth and decreased the incidence of metastasis in vivo. Our findings suggest mechanisms through which TGFbeta signaling may promote tumor progression in pancreatic adenocarcinoma. Moreover, they suggest that inhibition of TGFbetaRI with a small-molecule inhibitor may be effective as a therapeutic approach to treat human pancreatic cancer.
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PMID:Inhibition of transforming growth factor beta signaling reduces pancreatic adenocarcinoma growth and invasiveness. 1740 Jul 64

Gliomas are the most malignant of the primary brain tumors. Nucleotides represent an important class of extracellular molecules that are crucial for the normal function of the nervous system. ATP and adenosine can stimulate cell proliferation in different glioma cell lines; the events induced by extracellular adenine nucleotides are controlled by the action of ecto-nucleotidases, which hydrolyze ATP into adenosine in the extracellular space. Recent studies have shown that quercetin has an anti-proliferative effect on the U138MG glioma cell line. Since evidence suggests that purinergic signaling is involved in the growth and progression of glioma and, taking into consideration the anti-proliferative effect elicited by quercetin in this tumor type, the aim of the present study was to better investigate the extracellular metabolism of AMP and evaluate the effect of quercetin on this system in the human U138MG glioma cell line. The adenine products secreted by glioma cells were first characterized; extracellular AMP was efficiently metabolized by the glioma culture, demonstrating a very active ecto-5'-NT/CD73. Quercetin was able to inhibit the ecto-5'-NT/CD73 activity and modulate its expression. In addition, the cell treatment with APCP (alpha,beta-methyleneadenosine-5'-diphosphate), an ecto-5'-NT/CD73 inhibitor, led to a significant reduction in glioma cell proliferation. We suggest that the inhibition of ecto-5'-NT/CD73 may result in a decrease in extracellular adenosine production with a consequent reduction in tumor progression.
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PMID:Ecto-5'-nucleotidase/CD73 inhibition by quercetin in the human U138MG glioma cell line. 1764 26

Autotaxin (ATX) is an approximately 125kDa transmembrane protein known as a tumor progression factor based on its lysophospholipase D (lysoPLD) activity. There are many reports of the biological and biochemical properties of ATX, but crystallographic or structural studies have not been reported because a large-scale production process using prokaryotic cells has not been established. Here we report a bulk purification process and soluble expression of the recombinant human ATX (rhATX S48) from prokaryotic cells. The extracellular domain of human ATX cDNA was cloned into a pET101/D-TOPO vector and transformed to an Escherichia coliBL21 strain which was co-transformed with a pTF16 chaperone plasmid. The rhATX S48 was purified with chaperone and it was removed by Mg(2+)-ATP treatment. The final yield of purified rhATX S48 was approximately 3.5mg/l culture of recombinant strain. The rhATX S48 shows lysoPLD enzymatic activity and effectively stimulates the growth and motile activity of the human tumor cells as well as native ATX. This is a first report for scalable purification of the ATX molecule and the rhATX S48 should be a good tool for immunization of anti-ATX or crystallographic analysis of ATX.
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PMID:Scalable purification and characterization of the extracellular domain of human autotaxin from prokaryotic cells. 1824 59

CD147 is a multifunctional transmembrane protein and promotes cancer progression. We found that the anti-human CD147 mouse monoclonal antibody MEM-M6/1 strongly induces necrosis-like cell death in LoVo, HT-29, WiDr, and SW620 colon cancer cells and A2058 melanoma cells, but not in WI-38 and TIG-113 normal fibroblasts. Silencing or overexpression of CD147 in LoVo cells enhanced or decreased the MEM-M6/1 induced cell death, respectively. CD147 is known to form complex with proton-linked monocarboxylate transporters (MCTs), which is critical for lactate transport and intracellular pH (pHi) homeostasis. In LoVo cells, CD147 and MCT-1 co-localized on the cell surface, and MEM-M6/1 inhibited the association of these molecules. MEM-M6/1 inhibited lactate uptake, lactate release, and reduced pHi. Further, the induction of acidification was parallel to the decrease of the glycolytic flux and intracellular ATP levels. These effects were not found in the normal fibroblasts. As cancer cells depend on glycolysis for their energy production, CD147 inhibition might induce cell death specific to cancer cells.
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PMID:Blocking CD147 induces cell death in cancer cells through impairment of glycolytic energy metabolism. 1861 31

The receptor tyrosine kinase Met is crucial for the genetic program causing cancer progression and metastasis. Its nodal function during aggressiveness and resistance acquisition poses Met inhibition as an obligatory step in anti-cancer targeted therapy. Here, we applied a "Met-focussed" forward chemical biological screen to discover new agents antagonizing Met-triggered biological functions. The identified new scaffold, JLK1360, has a dual mechanism of action towards Met: it impairs Met signalling and also prevents its restoration after degradation. Docking and molecular dynamics provide evidences on the interacting mode of JLK1360 within the Met ATP-binding pocket. Moreover, computational and biochemical studies also highlighted that JLK1360 has a good degree of selectivity towards Met than other RTKs tested. Altogether, these findings demonstrate that the approach we have applied is a powerful strategy to identify compounds with combined properties towards a chosen target. Our studies show how integration of chemistry, biology and computational analysis can provide robust strategies to identify new inhibitory scaffolds suitable for further development of anti-cancer targeted therapies.
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PMID:A new Met inhibitory-scaffold identified by a focused forward chemical biological screen. 1870 15

Hsp90 (heat shock protein 90) is a molecular chaperone that modulates the stability and/or transport of a diverse set of critical cellular regulatory, metabolism, organization, and signaling proteins. Binding to Hsp90 is required for normal function of many proteins. In addition, Hsp90 has an extra-cellular function. It is found in two isotypes: alpha which is inducible and beta which is constitutive. Tumor cells frequently over express Hsp90alpha, and Hsp90 is implicated in cancer progression. Hence Hsp90 has emerged as a potential target for cancer treatment. A variety of agents have been found to interfere with Hsp function, mainly by binding to an ATP binding site on the molecule. More recent agents interfere with protein binding or the dimerization of Hsp90 needed for function. Preclinical studies have demonstrated that disruption of the many client proteins chaperoned by Hsp90 is achievable and associated with significant growth inhibition, both in vitro and in tumor xenografts. As a result, agents which interfere with this protein's function are being tested in the clinic as a targeted method of interfering with malignant growth. We review the current clinical status of therapeutic efforts to perturb this pathway and discuss future directions.
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PMID:The heat shock protein 90 chaperone complex: an evolving therapeutic target. 1878 98

The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TKI258), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFRbeta with IC(50) values <0.1 microM. On the basis of its favorable in vitro and in vivo properties, compound 5 was selected for clinical evaluation and is currently in phase I clinical trials.
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PMID:Design, structure-activity relationships and in vivo characterization of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones: a novel class of receptor tyrosine kinase inhibitors. 1911 66

Cyclin-dependent kinases (CDKs) play important roles in regulating cell cycle progression, and altered cell cycles resulting from over-expression or abnormal activation of CDKs observed in many human cancers. As a result, CDKs have become extensive studied targets for developing chemical inhibitors for cancer therapies; however, protein kinases share a highly conserved ATP binding pocket at which most chemical inhibitors bind, therefore, a major challenge in developing kinase inhibitors is achieving target selectivity. To identify cell growth inhibitors with potential applications in cancer therapy, we used an integrated approach that combines one-pot chemical synthesis in a combinatorial manner to generate diversified small molecules with new chemical scaffolds coupled with growth inhibition assay using developing zebrafish embryos. We report the successful identification of a novel lead compound that displays selective inhibitory effects on CDK2 activity, cancer cell proliferation, and tumor progression in vivo. Our approaches should have general applications in developing cell proliferation inhibitors using an efficient combinatorial chemical genetic method and integrated biological assays. The novel cell growth inhibitor we identified should have potential as a cancer therapeutic agent.
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PMID:Identifying tumor cell growth inhibitors by combinatorial chemistry and zebrafish assays. 1919 8

Hepatocyte growth factor (HGF) is an important regulator of normal development and homeostasis, and dysregulated signaling through the HGF receptor, Met, contributes to tumorigenesis, tumor progression, and metastasis in numerous human malignancies. The development of selective small-molecule inhibitors of oncogenic tyrosine kinases (TK) has led to well-tolerated, targeted therapies for a growing number of cancer types. To identify selective Met TK inhibitors, we used a high-throughput virtual screen of the 13.5 million compound ChemNavigator database to find compounds most likely to bind to the Met ATP binding site and to form several critical interactions with binding site residues predicted to stabilize the kinase domain in its inactive conformation. Subsequent biological screening of 70 in silico hit structures using cell-free and intact cell assays identified three active compounds with micromolar IC(50) values. The predicted binding modes and target selectivity of these compounds are discussed and compared to other known Met TK inhibitors.
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PMID:Directed discovery of agents targeting the Met tyrosine kinase domain by virtual screening. 1919 50

Because transient receptor potential (TRP) channels have been implicated in tumor progression, we have investigated the potential role of TRPM7 channel in breast cancer cell proliferation. Under whole cell patch clamp, a Mg(2+)-inhibited cationic (MIC) current was observed in MCF-7 cells. This current was characterized by an inward current and a strong outward rectifying current that were both inhibited in a concentration-dependent manner by the presence of intracellular Mg(2+) or Mg(2+)-ATP. The inward current was reduced by La(3+), and the outward current was sensitive to 2-aminoethoxydiphenyl borate (2-APB), spermine, La(3+), and flufenamic acid. Importantly, a similar MIC current was also recorded in the primary culture of human breast cancerous epithelial cells (hBCE). Moreover, TRPM7 transcripts were found in both hBCE and MCF-7 cells. In MCF-7 cells, the MIC current was inhibited by TRPM7 small interfering RNA. Interestingly, we found that cell proliferation and intracellular Ca(2+) concentration were also reduced by TRPM7 silencing in MCF-7 cells. TRPM7 channels were also found in both human breast cancer and healthy tissues. Importantly, TRPM7 channel was overexpressed in grade III breast cancer samples associated with important Ki67 or tumor size. Our findings strongly suggest that TRPM7 is involved in the proliferative potentiality of breast cancer cells, probably by regulating Ca(2+) influx.
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PMID:Evidence that TRPM7 is required for breast cancer cell proliferation. 1951 1


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