Factors determining sensitivity or resistance of tumor cell lines towards artesunate

Publication type:
Journal article
Metadata:
Autoren
  • Serkan Sertel
  • Tolga Eichhorn
  • Sebastian Sieber
  • Alexandra Sauer
  • Johanna Weiss
  • Peter K Plinkert
  • Thomas Efferth
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000277751300007&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1016/j.cbi.2010.02.002
eISSN
1872-7786
Externe Identifier
  • Clarivate Analytics Document Solution ID: 597IW
  • PubMed Identifier: 20144594
ISSN
0009-2797
Ausgabe der Veröffentlichung
1
Zeitschrift
CHEMICO-BIOLOGICAL INTERACTIONS
Schlüsselwörter
  • Artemisinin
  • Artesunate (ART)
  • Anti-cancer therapy
  • Traditional Chinese medicine (TCM)
  • Molecular pharmacology
  • Multidrug resistance (MDR)
  • Natural products
  • Pharmacogenomics
Paginierung
42 - 52
Datum der Veröffentlichung
2010
Status
Published
Titel
Factors determining sensitivity or resistance of tumor cell lines towards artesunate
Sub types
  • Article
Ausgabe der Zeitschrift
185

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • Serkan Sertel
  • Tolga Eichhorn
  • Sebastian Sieber
  • Alexandra Sauer
  • Johanna Weiss
  • Peter K Plinkert
  • Thomas Efferth
DOI
10.1016/j.cbi.2010.02.002
ISSN
0009-2797
Ausgabe der Veröffentlichung
1
Zeitschrift
Chemico-Biological Interactions
Sprache
en
Paginierung
42 - 52
Datum der Veröffentlichung
2010
Status
Published
Herausgeber
Elsevier BV
Herausgeber URL
http://dx.doi.org/10.1016/j.cbi.2010.02.002
Datum der Datenerfassung
2021
Titel
Factors determining sensitivity or resistance of tumor cell lines towards artesunate
Ausgabe der Zeitschrift
185

Data source: Crossref

Abstract
Clinical oncology is still challenged by the development of drug resistance of tumors that result in poor prognosis for patients. There is an urgent necessity to understand the molecular mechanisms of resistance and to develop novel therapy strategies. Artesunate (ART) is an anti-malarial drug, which also exerts profound cytotoxic activity towards cancer cells. We first applied a gene-hunting approach using cluster and COMPARE analyses of microarray-based transcriptome-wide mRNA expression profiles. Among the genes identified by this approach were genes from diverse functional groups such as structural constituents of ribosomes (RPL6, RPL7, RPS12, RPS15A), kinases (CABC1, CCT2, RPL41), transcriptional and translational regulators (SFRS2, TUFM, ZBTB4), signal transducers (FLNA), control of cell growth and proliferation (RPS6), angiogenesis promoting factors (ITGB1), and others (SLC25A19, NCKAP1, BST1, DBH, FZD7, NACA, MTHFD2). Furthermore, we applied a candidate gene approach and tested the role of resistance mechanisms towards established anti-cancer drugs for ART resistance. By using transfected or knockout cell models we found that the tumor suppressor p16(INK4A) and the anti-oxidant protein, catalase, conferred resistance towards ART, while the oncogene HPV-E6 conferred sensitivity towards ART. The tumor suppressor p53 and its downstream protein, p21, as well as the anti-oxidant manganese-dependent superoxide dismutase did not affect cellular response to ART. In conclusion, our pharmacogenomic approach revealed that response of tumor cells towards ART is multi-factorial and is determined by gene expression associated with either ART sensitivity or resistance. At least some of the functional groups of genes (e.g. angiogenesis promoting factors, cell growth and proliferation-associated genes signal transducers and kinases) are also implicated in clinical responsiveness of tumors towards chemotherapy. It merits further investigation, whether ART is responsive in clinically refractory tumors and whether the genes identified in the present study also determine clinical responsiveness towards ART.
Addresses
  • Department of Otorhinolaryngology, Head & Neck Surgery, University of Heidelberg, Heidelberg, Germany.
Autoren
  • Serkan Sertel
  • Tolga Eichhorn
  • Sebastian Sieber
  • Alexandra Sauer
  • Johanna Weiss
  • Peter K Plinkert
  • Thomas Efferth
  • Thomas Efferth
DOI
10.1016/j.cbi.2010.02.002
eISSN
1872-7786
Externe Identifier
  • PubMed Identifier: 20144594
Open access
false
ISSN
0009-2797
Ausgabe der Veröffentlichung
1
Zeitschrift
Chemico-biological interactions
Schlüsselwörter
  • Cell Line, Tumor
  • Humans
  • Neoplasms
  • Artemisinins
  • Antineoplastic Agents, Phytogenic
  • Antimalarials
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Artesunate
Sprache
eng
Medium
Print-Electronic
Online publication date
2010
Paginierung
42 - 52
Datum der Veröffentlichung
2010
Status
Published
Datum der Datenerfassung
2010
Titel
Factors determining sensitivity or resistance of tumor cell lines towards artesunate.
Sub types
  • Research Support, Non-U.S. Gov't
  • Journal Article
Ausgabe der Zeitschrift
185

Data source: Europe PubMed Central

Abstract
Clinical oncology is still challenged by the development of drug resistance of tumors that result in poor prognosis for patients. There is an urgent necessity to understand the molecular mechanisms of resistance and to develop novel therapy strategies. Artesunate (ART) is an anti-malarial drug, which also exerts profound cytotoxic activity towards cancer cells. We first applied a gene-hunting approach using cluster and COMPARE analyses of microarray-based transcriptome-wide mRNA expression profiles. Among the genes identified by this approach were genes from diverse functional groups such as structural constituents of ribosomes (RPL6, RPL7, RPS12, RPS15A), kinases (CABC1, CCT2, RPL41), transcriptional and translational regulators (SFRS2, TUFM, ZBTB4), signal transducers (FLNA), control of cell growth and proliferation (RPS6), angiogenesis promoting factors (ITGB1), and others (SLC25A19, NCKAP1, BST1, DBH, FZD7, NACA, MTHFD2). Furthermore, we applied a candidate gene approach and tested the role of resistance mechanisms towards established anti-cancer drugs for ART resistance. By using transfected or knockout cell models we found that the tumor suppressor p16(INK4A) and the anti-oxidant protein, catalase, conferred resistance towards ART, while the oncogene HPV-E6 conferred sensitivity towards ART. The tumor suppressor p53 and its downstream protein, p21, as well as the anti-oxidant manganese-dependent superoxide dismutase did not affect cellular response to ART. In conclusion, our pharmacogenomic approach revealed that response of tumor cells towards ART is multi-factorial and is determined by gene expression associated with either ART sensitivity or resistance. At least some of the functional groups of genes (e.g. angiogenesis promoting factors, cell growth and proliferation-associated genes signal transducers and kinases) are also implicated in clinical responsiveness of tumors towards chemotherapy. It merits further investigation, whether ART is responsive in clinically refractory tumors and whether the genes identified in the present study also determine clinical responsiveness towards ART.
Date of acceptance
2010
Autoren
  • Serkan Sertel
  • Tolga Eichhorn
  • Sebastian Sieber
  • Alexandra Sauer
  • Johanna Weiss
  • Peter K Plinkert
  • Thomas Efferth
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/20144594
DOI
10.1016/j.cbi.2010.02.002
eISSN
1872-7786
Ausgabe der Veröffentlichung
1
Zeitschrift
Chem Biol Interact
Schlüsselwörter
  • Antimalarials
  • Antineoplastic Agents, Phytogenic
  • Artemisinins
  • Artesunate
  • Cell Line, Tumor
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Humans
  • Neoplasms
Sprache
eng
Country
Ireland
Paginierung
42 - 52
PII
S0009-2797(10)00070-0
Datum der Veröffentlichung
2010
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2010
Titel
Factors determining sensitivity or resistance of tumor cell lines towards artesunate.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
185

Data source: PubMed

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