Glutathione-related enzymes contribute to resistance of tumor cells and low toxicity in normal organs to artesunate

Publication type:
Journal article
Metadata:
Autoren
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000227883600028&DestLinkType=FullRecord&DestApp=WOS_CPL
eISSN
1791-7549
Externe Identifier
  • Clarivate Analytics Document Solution ID: 909TM
  • PubMed Identifier: 15796179
ISSN
0258-851X
Ausgabe der Veröffentlichung
1
Zeitschrift
IN VIVO
Schlüsselwörter
  • artesunate
  • cluster analysis
  • drug resistance
  • glutathione-related enzymes
  • immunohistochemistry
  • microarrays
  • transfected cell lines
Paginierung
225 - 232
Datum der Veröffentlichung
2005
Status
Published
Titel
Glutathione-related enzymes contribute to resistance of tumor cells and low toxicity in normal organs to artesunate
Sub types
  • Article
Ausgabe der Zeitschrift
19

Data source: Web of Science (Lite)

Other metadata sources:
Abstract
The anti-malarial artesunate (ART) also inhibits the growth of cancer cells. The active moiety is an endoperoxide bridge whose cleavage generates reactive oxygen species and free radicals. We analyzed whether glutathione-related enzymes contribute to tumor resistance to ART and to the low toxicity of ART towards normal organs. The microarray-based mRNA expression of dihydrodiol dehydrogenase, gamma-glutamylcysteine synthase (gamma-GCS), glutathione S-transferases GSTM4, GSTT2, GSTZ1, and microsomal glutathione S-transferase MGST3 showed significant relationships (p <0.05) to cellular response to ART in 55 cell lines of the National Cancer Institute, USA. A tendency for correlation (0.05<p<0.1) was observed for GSTA1, GSTA2, GSTP1 and MGST1. A further 12 glutathione-related genes were not linked to ART resistance. MSC-HL13 cells transfected with cDNAs for heavy and light subunits of gamma-GCS were more resistant to ART than mock control vector-transfected MSV-PC4 cells. L-buthionine sulfoximine, a gamma-GCS inhibitor that depletes cellular glutathione pools, completely reversed ART resistance in MSV-HL13 cells, while a partial reversion was obtained by ethacrynic acid, an inhibitor of GST. The expression of GST-P was analyzed immunohistochemically in normal rat organs. GST-P immunostaining was found in all organs analyzed, albeit with varying staining intensities and in different histological structures of the organs. GST expression in normal organs may, therefore, contribute to the good tolerability and minimal toxicity of ART in normal organs.
Addresses
  • German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. thomas.efferth@web.de
Autoren
eISSN
1791-7549
Externe Identifier
  • PubMed Identifier: 15796179
Open access
false
ISSN
0258-851X
Ausgabe der Veröffentlichung
1
Zeitschrift
In vivo (Athens, Greece)
Schlüsselwörter
  • Cell Line, Tumor
  • Humans
  • Neoplasms
  • Free Radicals
  • Reactive Oxygen Species
  • Sesquiterpenes
  • Artemisinins
  • Isoenzymes
  • gamma-Glutamyltransferase
  • Glutathione Transferase
  • Buthionine Sulfoximine
  • Glutathione
  • RNA, Messenger
  • Enzyme Inhibitors
  • Antimalarials
  • Oligonucleotide Array Sequence Analysis
  • Immunohistochemistry
  • Transfection
  • Inhibitory Concentration 50
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm
  • Female
  • Male
  • Artesunate
Sprache
eng
Medium
Print
Paginierung
225 - 232
Datum der Veröffentlichung
2005
Status
Published
Datum der Datenerfassung
2005
Titel
Glutathione-related enzymes contribute to resistance of tumor cells and low toxicity in normal organs to artesunate.
Sub types
  • Comparative Study
  • Journal Article
Ausgabe der Zeitschrift
19

Data source: Europe PubMed Central

Abstract
The anti-malarial artesunate (ART) also inhibits the growth of cancer cells. The active moiety is an endoperoxide bridge whose cleavage generates reactive oxygen species and free radicals. We analyzed whether glutathione-related enzymes contribute to tumor resistance to ART and to the low toxicity of ART towards normal organs. The microarray-based mRNA expression of dihydrodiol dehydrogenase, gamma-glutamylcysteine synthase (gamma-GCS), glutathione S-transferases GSTM4, GSTT2, GSTZ1, and microsomal glutathione S-transferase MGST3 showed significant relationships (p <0.05) to cellular response to ART in 55 cell lines of the National Cancer Institute, USA. A tendency for correlation (0.05<p<0.1) was observed for GSTA1, GSTA2, GSTP1 and MGST1. A further 12 glutathione-related genes were not linked to ART resistance. MSC-HL13 cells transfected with cDNAs for heavy and light subunits of gamma-GCS were more resistant to ART than mock control vector-transfected MSV-PC4 cells. L-buthionine sulfoximine, a gamma-GCS inhibitor that depletes cellular glutathione pools, completely reversed ART resistance in MSV-HL13 cells, while a partial reversion was obtained by ethacrynic acid, an inhibitor of GST. The expression of GST-P was analyzed immunohistochemically in normal rat organs. GST-P immunostaining was found in all organs analyzed, albeit with varying staining intensities and in different histological structures of the organs. GST expression in normal organs may, therefore, contribute to the good tolerability and minimal toxicity of ART in normal organs.
Autoren
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/15796179
ISSN
0258-851X
Ausgabe der Veröffentlichung
1
Zeitschrift
In Vivo
Schlüsselwörter
  • Antimalarials
  • Artemisinins
  • Artesunate
  • Buthionine Sulfoximine
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm
  • Enzyme Inhibitors
  • Female
  • Free Radicals
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Glutathione
  • Glutathione Transferase
  • Humans
  • Immunohistochemistry
  • Inhibitory Concentration 50
  • Isoenzymes
  • Male
  • Neoplasms
  • Oligonucleotide Array Sequence Analysis
  • RNA, Messenger
  • Reactive Oxygen Species
  • Sesquiterpenes
  • Transfection
  • gamma-Glutamyltransferase
Sprache
eng
Country
Greece
Paginierung
225 - 232
Datum der Veröffentlichung
2005
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2005
Titel
Glutathione-related enzymes contribute to resistance of tumor cells and low toxicity in normal organs to artesunate.
Sub types
  • Comparative Study
  • Journal Article
Ausgabe der Zeitschrift
19

Data source: PubMed

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