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 .
}