Identification by High-throughput In Silico Screening of Radio-protecting Compounds Targeting the DNA-binding Domain of the Tumor Suppressor p53

Publication type:
Journal article
Metadata:
Autoren
  • Tolga Eichhorn
  • Corinna Hiller
  • Kerstin Hirschfelder
  • Martin Frank
  • R Luise Krauth-Siegel
  • Rolf Mueller
  • Rolf Mertens
  • Thomas Efferth
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000339392800004&DestLinkType=FullRecord&DestApp=WOS_CPL
eISSN
1790-6245
Externe Identifier
  • Clarivate Analytics Document Solution ID: AL8MI
  • PubMed Identifier: 23382585
ISSN
1109-6535
Ausgabe der Veröffentlichung
1
Zeitschrift
CANCER GENOMICS & PROTEOMICS
Schlüsselwörter
  • p53
  • molecular docking
  • pharmacogenomics
  • radioprotection
  • tumor suppressor
  • virtual drug screening
  • in silico screening
Paginierung
35 - 45
Datum der Veröffentlichung
2013
Status
Published
Titel
Identification by High-throughput <i>In Silico</i> Screening of Radio-protecting Compounds Targeting the DNA-binding Domain of the Tumor Suppressor p53
Sub types
  • Article
Ausgabe der Zeitschrift
10

Data source: Web of Science (Lite)

Other metadata sources:
Abstract
Therapies targeting p53 mostly concentrate on (re)activation of the p53 protein, to further induce apoptosis in cancer cells. In the present investigations, the focus was on the identification of small molecules that block the DNA-binding domain of p53 and thus inhibit its function. Using high-throughput in silico screening of approximately 300,000 compounds, we identified eight putatively interacting with the DNA-binding domain of p53. Subsequently, HCT116 p53 wild-type (p53(+/+)) and knockout (p53(-/-)) cells were irradiated with 16 Gy and treated with these compounds. Among the eight compounds, NSC 23175 offered the best protection against γ-irradiation-mediated injury. Microarray-based mRNA expression profiling revealed many downstream p53-dependent genes in irradiated and NSC 23175-treated p53(+/+) cells. Using a luciferase reporter assay, we showed that NSC 23175 suppressed p53 binding to the promoter of EGR1, a p53-regulated gene. The fact that NSC 23175 protected p53(+/+) cells implicates a putative protective effect of the compound during radiotherapy of p53-mutated tumors. The role of NSC 23175 as protecting agent, in reducing radiotherapy-related side-effects merits future investigation.
Addresses
  • Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
Autoren
  • Tolga Eichhorn
  • Corinna Hiller
  • Kerstin Hirschfelder
  • Martin Frank
  • R Luise Krauth-Siegel
  • Rolf Müller
  • Rolf Mertens
  • Thomas Efferth
eISSN
1790-6245
Externe Identifier
  • PubMed Identifier: 23382585
Open access
false
ISSN
1109-6535
Ausgabe der Veröffentlichung
1
Zeitschrift
Cancer genomics & proteomics
Schlüsselwörter
  • HCT116 Cells
  • Humans
  • Neoplasms
  • Radiation Injuries
  • Ethanolamines
  • Fluorenes
  • Luciferases, Renilla
  • Radiation-Protective Agents
  • Cell Proliferation
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Binding Sites
  • Protein Binding
  • Genes, Reporter
  • Models, Biological
  • Models, Molecular
  • Computer Simulation
  • Tumor Suppressor Protein p53
  • High-Throughput Screening Assays
  • Transcriptome
Sprache
eng
Medium
Print
Paginierung
35 - 45
Datum der Veröffentlichung
2013
Status
Published
Datum der Datenerfassung
2013
Titel
Identification by high-throughput in silico screening of radio-protecting compounds targeting the DNA-binding domain of the tumor suppressor p53.
Sub types
  • Research Support, Non-U.S. Gov't
  • Journal Article
Ausgabe der Zeitschrift
10

Data source: Europe PubMed Central

Abstract
Therapies targeting p53 mostly concentrate on (re)activation of the p53 protein, to further induce apoptosis in cancer cells. In the present investigations, the focus was on the identification of small molecules that block the DNA-binding domain of p53 and thus inhibit its function. Using high-throughput in silico screening of approximately 300,000 compounds, we identified eight putatively interacting with the DNA-binding domain of p53. Subsequently, HCT116 p53 wild-type (p53(+/+)) and knockout (p53(-/-)) cells were irradiated with 16 Gy and treated with these compounds. Among the eight compounds, NSC 23175 offered the best protection against γ-irradiation-mediated injury. Microarray-based mRNA expression profiling revealed many downstream p53-dependent genes in irradiated and NSC 23175-treated p53(+/+) cells. Using a luciferase reporter assay, we showed that NSC 23175 suppressed p53 binding to the promoter of EGR1, a p53-regulated gene. The fact that NSC 23175 protected p53(+/+) cells implicates a putative protective effect of the compound during radiotherapy of p53-mutated tumors. The role of NSC 23175 as protecting agent, in reducing radiotherapy-related side-effects merits future investigation.
Autoren
  • Tolga Eichhorn
  • Corinna Hiller
  • Kerstin Hirschfelder
  • Martin Frank
  • R Luise Krauth-Siegel
  • Rolf Müller
  • Rolf Mertens
  • Thomas Efferth
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/23382585
eISSN
1790-6245
Ausgabe der Veröffentlichung
1
Zeitschrift
Cancer Genomics Proteomics
Schlüsselwörter
  • Binding Sites
  • Cell Proliferation
  • Computer Simulation
  • Ethanolamines
  • Fluorenes
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Genes, Reporter
  • HCT116 Cells
  • High-Throughput Screening Assays
  • Humans
  • Luciferases, Renilla
  • Models, Biological
  • Models, Molecular
  • Neoplasms
  • Protein Binding
  • Radiation Injuries
  • Radiation-Protective Agents
  • Transcriptome
  • Tumor Suppressor Protein p53
Sprache
eng
Country
Greece
Paginierung
35 - 45
PII
10/1/35
Datum der Veröffentlichung
2013
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2013
Titel
Identification by high-throughput in silico screening of radio-protecting compounds targeting the DNA-binding domain of the tumor suppressor p53.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
10

Data source: PubMed

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