@prefix this: . @prefix sub: . @prefix beldoc: . @prefix rdfs: . @prefix rdf: . @prefix xsd: . @prefix dct: . @prefix dce: . @prefix pav: . @prefix np: . @prefix belv: . @prefix prov: . @prefix go: . @prefix Protein: . @prefix hgnc: . @prefix geneProductOf: . @prefix hasAgent: . @prefix species: . @prefix occursIn: . @prefix orcid: . sub:Head { this: np:hasAssertion sub:assertion; np:hasProvenance sub:provenance; np:hasPublicationInfo sub:pubinfo; a np:Nanopublication . } sub:assertion { sub:_1 hasAgent: sub:_2; a go:0042789 . sub:_2 geneProductOf: hgnc:6349; a Protein: . sub:_3 hasAgent: sub:_4; a go:0042789 . sub:_4 geneProductOf: hgnc:6348; a Protein: . sub:_5 occursIn: species:9606; rdf:object sub:_3; rdf:predicate belv:decreases; rdf:subject sub:_1; a rdf:Statement . sub:assertion rdfs:label "tscript(p(HGNC:KLF5)) -| tscript(p(HGNC:KLF4))" . } sub:provenance { beldoc: dce:description "Approximately 61,000 statements."; dce:rights "Copyright (c) 2011-2012, Selventa. All rights reserved."; dce:title "BEL Framework Large Corpus Document"; pav:authoredBy sub:_8; pav:version "1.4" . sub:_6 dce:identifier "Cellular and Molecular Biology 26: Transcription Factor Function Abstract 1692"; dce:title "Cellular and Molecular Biology 26: Transcription Factor Function Abstract 1692"; dce:type "Other" . sub:_7 prov:value "A group of 2-indolyl imidazol [4,5-d] phenanthroline derivatives with potent and selective anti-proliferative activity against several types of human cancer has been developed. A pattern of particular tumor-type selectivity was shown in the in vitro anti-tumor screening of the National Cancer Institute (NCI) Developmental Therapeutics Program. Lead compounds showed potent and selective growth inhibition of colon cancer [N= 6 cell lines; GI50 0.53 +- 0.11 (uM)], leukemia [N=3 cell lines; GI50 0.17 +- 0.09 (uM)], non-small cell lung cancer [NSCLC N = 8 cell lines; GI50 0.95 +- 0.4 (uM)], and prostate cancer [N= 2 cell lines; GI50 0.22 +- 0.05 (uM)]. These compounds also exhibited in vivo activity in the Hollow Fiber Assay, and in xenograft models of human colon carcinoma (HT-29) and NSCLC (H460) in athymic \\\"nude\\\" mice. These studies demonstrated significant tumor growth inhibition and in vivo cytocidal effect on implanted cancer cells. Dose-schedule studies defined oral and intraperitoneal therapeutic dosages ranging from 40 mg/Kg to 100 mg/Kg daily x 5 days (tumor volume change ratio T/C = 15-45 %) with no signs of apparent toxicity. Analysis of gene expression by quantitative RT-PCR in tumor xenograft tissue from treated mice showed strong induction of the tumor suppressor gene Kruppel -like factor 4 (KLF4) and decreased expression of the cell cycle associated gene Cyclin D1. Cell cycle analysis by flow cytometry showed that these compounds block the cell cycle progression of HT-29 cells at G1 phase. Additional mechanism of action studies demonstrated that they reduce the concentration of available intracellular zinc, reflected by decreased fluorescent count using the zinc-sensitive dye zinquin, and decreased gene expression of the zinc-storage protein metallothionein 1A. Further studies showed that this effect translated into a series of events that included: (1) reduced gene expression of the metal-responsive transcription factor 1 (MTF-1), as determined by RT-PCR; (2) down-regulation of the KLF4- transcriptional antagonist Kruppel-like factor 5 (KLF5) and induction of KLF4, as determined by RT-PCR and Western blot; and (3) altered expression of several known KLF-4-regulated genes involved in cell cycle progression, including cyclin D1. Taken together, the results indicate intracellular zinc depletion leading to induction of KLF4 as a key process involved in the mechanism of anti-tumor activity of these novel compounds. Additional mechanism of action studies demonstrated that they reduce the concentration of available intracellular zinc, reflected by decreased fluorescent count using the zinc-sensitive dye zinquin, and decreased gene expression of the zinc-storage protein metallothionein 1A. Further studies showed that this effect translated into a series of events that included: (1) reduced gene expression of the metal-responsive transcription factor 1 (MTF-1), as determined by RT-PCR; (2) down-regulation of the KLF4- transcriptional antagonist Kruppel-like factor 5 (KLF5) and induction of KLF4, as determined by RT-PCR and Western blot; and (3) altered expression of several known KLF-4-regulated genes involved in cell cycle progression, including cyclin D1."; prov:wasQuotedFrom sub:_6 . sub:_8 rdfs:label "Selventa" . sub:assertion prov:hadPrimarySource sub:_6; prov:wasDerivedFrom beldoc:, sub:_7 . } sub:pubinfo { this: dct:created "2014-07-03T14:29:43.303+02:00"^^xsd:dateTime; pav:createdBy orcid:0000-0001-6818-334X, orcid:0000-0002-1267-0234 . }