Inhibition of epidermal growth factor receptor-overexpressing cancer cells by camptothecin, 20-(N,N-diethyl) glycinate

Publication type:
Journal article
Metadata:
Autoren
  • V Badireenath Konkimalla
  • Thomas Efferth
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000277497600005&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1016/j.bcp.2010.02.022
eISSN
1873-2968
Externe Identifier
  • Clarivate Analytics Document Solution ID: 593XW
  • PubMed Identifier: 20206609
ISSN
0006-2952
Ausgabe der Veröffentlichung
1
Zeitschrift
BIOCHEMICAL PHARMACOLOGY
Schlüsselwörter
  • Chemotherapy
  • Microarray
  • Oncogenes
  • Pharmacology
  • Pharmacogenomics
  • Signal transduction
  • Systems biology
Paginierung
39 - 49
Datum der Veröffentlichung
2010
Status
Published
Titel
Inhibition of epidermal growth factor receptor-overexpressing cancer cells by camptothecin, 20-(N,N-diethyl) glycinate
Sub types
  • Article
Ausgabe der Zeitschrift
80

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • V Badireenath Konkimalla
  • Thomas Efferth
DOI
10.1016/j.bcp.2010.02.022
ISSN
0006-2952
Ausgabe der Veröffentlichung
1
Zeitschrift
Biochemical Pharmacology
Sprache
en
Paginierung
39 - 49
Datum der Veröffentlichung
2010
Status
Published
Herausgeber
Elsevier BV
Herausgeber URL
http://dx.doi.org/10.1016/j.bcp.2010.02.022
Datum der Datenerfassung
2019
Titel
Inhibition of epidermal growth factor receptor-overexpressing cancer cells by camptothecin, 20-(N,N-diethyl) glycinate
Ausgabe der Zeitschrift
80

Data source: Crossref

Abstract
The epidermal growth factor receptor (EGFR) represents a prognostic marker for short survival of patients and therapy resistance of tumors. Despite clinical usefulness of EGFR tyrosine kinase inhibitors, resistance can develop. Therefore, there is an urgent need for novel EGFR inhibitors. Camptothecins have been characterized as inhibitors of DNA topoisomerase I (TOP1), although a correlation between TOP1 expression and activity is not well established in clinical biopsies. Hence, other targets may also be relevant. By molecular docking, we found that camptothecin 20-N,N-glycinate (CPTg) and camptothecin (CPT) bind to the same pharmacophore at EGFR as erlotinib, albeit to partly different amino acids. To validate the in silico results, CPT and CPTg were evaluated for their cytotoxic activity and downstream signaling mechanisms in U87MG glioblastoma cell lines transduced with different expression vectors for EGFR. All transduced cell lines were more susceptible to CPTg or CPT than the non-transduced cells, indicating a preferential activity towards EGFR-expressing tumor cells. Microarray-based mRNA hybridizations were performed in treated a non-treated cell lines. Subsets of genes were commonly regulated between the cell lines. By pathway analyses, we ranked canonical pathways according to differential gene expression after drug treatment. The pathways for G2/M DNA damage checkpoint regulation, aryl hydrocarbon receptor signaling, and xenobiotic metabolism and endoplasmatic reticulum stress were top ranked. In conclusion, binding of CPTg and CPT to the erlotinib pharmacophore and preferential cytotoxicity towards EGFR-overexpressing cells indicate susceptibility towards erlotinib-resistant tumors. Multiple mechanisms may account for cytotoxicity of these camptothecins.
Addresses
  • German Cancer Research Center, Pharmaceutical Biology (C015), Heidelberg, Germany.
Autoren
DOI
10.1016/j.bcp.2010.02.022
eISSN
1873-2968
Externe Identifier
  • PubMed Identifier: 20206609
Funding acknowledgements
  • Dietmar Hopp-Foundation:
Open access
false
ISSN
0006-2952
Ausgabe der Veröffentlichung
1
Zeitschrift
Biochemical pharmacology
Schlüsselwörter
  • Cell Line, Tumor
  • Humans
  • Neoplasms
  • Camptothecin
  • Glycine
  • Antineoplastic Agents, Phytogenic
  • Drug Evaluation, Preclinical
  • ErbB Receptors
Sprache
eng
Medium
Print-Electronic
Online publication date
2010
Paginierung
39 - 49
Datum der Veröffentlichung
2010
Status
Published
Datum der Datenerfassung
2010
Titel
Inhibition of epidermal growth factor receptor-overexpressing cancer cells by camptothecin, 20-(N,N-diethyl) glycinate.
Sub types
  • Research Support, Non-U.S. Gov't
  • Evaluation Study
  • Journal Article
Ausgabe der Zeitschrift
80

Data source: Europe PubMed Central

Abstract
The epidermal growth factor receptor (EGFR) represents a prognostic marker for short survival of patients and therapy resistance of tumors. Despite clinical usefulness of EGFR tyrosine kinase inhibitors, resistance can develop. Therefore, there is an urgent need for novel EGFR inhibitors. Camptothecins have been characterized as inhibitors of DNA topoisomerase I (TOP1), although a correlation between TOP1 expression and activity is not well established in clinical biopsies. Hence, other targets may also be relevant. By molecular docking, we found that camptothecin 20-N,N-glycinate (CPTg) and camptothecin (CPT) bind to the same pharmacophore at EGFR as erlotinib, albeit to partly different amino acids. To validate the in silico results, CPT and CPTg were evaluated for their cytotoxic activity and downstream signaling mechanisms in U87MG glioblastoma cell lines transduced with different expression vectors for EGFR. All transduced cell lines were more susceptible to CPTg or CPT than the non-transduced cells, indicating a preferential activity towards EGFR-expressing tumor cells. Microarray-based mRNA hybridizations were performed in treated a non-treated cell lines. Subsets of genes were commonly regulated between the cell lines. By pathway analyses, we ranked canonical pathways according to differential gene expression after drug treatment. The pathways for G2/M DNA damage checkpoint regulation, aryl hydrocarbon receptor signaling, and xenobiotic metabolism and endoplasmatic reticulum stress were top ranked. In conclusion, binding of CPTg and CPT to the erlotinib pharmacophore and preferential cytotoxicity towards EGFR-overexpressing cells indicate susceptibility towards erlotinib-resistant tumors. Multiple mechanisms may account for cytotoxicity of these camptothecins.
Date of acceptance
2010
Autoren
  • V Badireenath Konkimalla
  • Thomas Efferth
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/20206609
DOI
10.1016/j.bcp.2010.02.022
eISSN
1873-2968
Ausgabe der Veröffentlichung
1
Zeitschrift
Biochem Pharmacol
Schlüsselwörter
  • Antineoplastic Agents, Phytogenic
  • Camptothecin
  • Cell Line, Tumor
  • Drug Evaluation, Preclinical
  • ErbB Receptors
  • Glycine
  • Humans
  • Neoplasms
Sprache
eng
Country
England
Paginierung
39 - 49
PII
S0006-2952(10)00164-4
Datum der Veröffentlichung
2010
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2010
Titel
Inhibition of epidermal growth factor receptor-overexpressing cancer cells by camptothecin, 20-(N,N-diethyl) glycinate.
Sub types
  • Evaluation Study
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
80

Data source: PubMed

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