Combination-treatment of glioblastoma multiforme cell lines with the anti-malarial artesunate and the epidermal growth factor receptor tyrosine kinase inhibitor OSI-774

Autoren

Thomas Efferth
Tzutzuy Ramirez
Erich Gebhart
Marc-Eric Halatsch

DOI

10.1016/j.bcp.2003.12.035

ISSN

0006-2952

Ausgabe der Veröffentlichung

9

Zeitschrift

Biochemical Pharmacology

Sprache

en

Paginierung

1689 - 1700

Datum der Veröffentlichung

2004

Status

Published

Herausgeber

Elsevier BV

Herausgeber URL

http://dx.doi.org/10.1016/j.bcp.2003.12.035

Datum der Datenerfassung

2023

Titel

Combination treatment of glioblastoma multiforme cell lines with the anti-malarial artesunate and the epidermal growth factor receptor tyrosine kinase inhibitor OSI-774

Ausgabe der Zeitschrift

67

Data source: Crossref

Abstract

New drugs and combination modalities for otherwise non-responsive brain tumors are urgently required. The anti-malarial artesunate (ART) and the EGFR tyrosine kinase inhibitor OSI-774 reveal profound cytotoxic activity. The effectiveness of a combination treatment and the underlying molecular determinants of cellular response are unknown. In the present investigation, we studied ART and OSI-774 in glioblastoma multiforme (GBM) cell lines. Supra-additive inhibition of cell growth was observed in U-87MG.DeltaEGFR cells transduced with a deletion-mutant constitutively active EGFR gene, while additive effects were present in cells transduced with wild-type EGFR (U-87MG.WT-2N), kinase-deficient EGFR (U-87MG.DK-2N), mock vector controls (U-87MG.LUX), or non-transduced parental U-87MG cells. Among nine other non-transduced GBM cell lines, supra-additive effects were found in two cell lines (G-210GM, G-599GM), while ART and OSI-774 acted in an additive manner in the other seven cell lines (G-211GM, G-750GM, G-1163GM, G-1187GM, G-1265GM, G-1301GM, and G-1408GM). Sub-additive or antagonistic effects were not observed. Genomic gains and losses of genetic material in the non-transduced cell lines as assessed by comparative genomic hybridization were correlated with the IC(50) values for ART and OSI-774 and subsequently subjected to hierarchical cluster analysis and cluster image mapping. A genomic profile of imbalances was detected that predicted cellular response to ART and OSI-774. The genes located at the genomic imbalances of interest may serve as candidate resistance genes of GBM cells towards ART and OSI-774. In conclusion, the combination treatment of ART and OSI-774 resulted in an increased growth inhibition of GBM cell lines as compared to each drug alone.

Addresses

Center for Molecular Biology, University of Heidelberg, Im Neuenheimer Feld 282, Heidelberg 69120, Germany. thomas.efferth@web.de

Autoren

Thomas Efferth
Thomas Efferth
Tzutzuy Ramirez
Erich Gebhart
Marc-Eric Halatsch

DOI

10.1016/j.bcp.2003.12.035

eISSN

1873-2968

Externe Identifier

PubMed Identifier: 15081868

Open access

false

ISSN

0006-2952

Ausgabe der Veröffentlichung

9

Zeitschrift

Biochemical pharmacology

Schlüsselwörter

Cell Line
Tumor Cells, Cultured
Humans
Glioblastoma
Sesquiterpenes
Artemisinins
Quinazolines
Antineoplastic Combined Chemotherapy Protocols
Drug Screening Assays, Antitumor
Cluster Analysis
Nucleic Acid Hybridization
Cell Division
Drug Synergism
ErbB Receptors
Erlotinib Hydrochloride
Artesunate

Sprache

eng

Medium

Print

Paginierung

1689 - 1700

Datum der Veröffentlichung

2004

Status

Published

Datum der Datenerfassung

2004

Titel

Combination treatment of glioblastoma multiforme cell lines with the anti-malarial artesunate and the epidermal growth factor receptor tyrosine kinase inhibitor OSI-774.

Sub types

Research Support, Non-U.S. Gov't
Journal Article

Ausgabe der Zeitschrift

67

Data source: Europe PubMed Central

Abstract

New drugs and combination modalities for otherwise non-responsive brain tumors are urgently required. The anti-malarial artesunate (ART) and the EGFR tyrosine kinase inhibitor OSI-774 reveal profound cytotoxic activity. The effectiveness of a combination treatment and the underlying molecular determinants of cellular response are unknown. In the present investigation, we studied ART and OSI-774 in glioblastoma multiforme (GBM) cell lines. Supra-additive inhibition of cell growth was observed in U-87MG.DeltaEGFR cells transduced with a deletion-mutant constitutively active EGFR gene, while additive effects were present in cells transduced with wild-type EGFR (U-87MG.WT-2N), kinase-deficient EGFR (U-87MG.DK-2N), mock vector controls (U-87MG.LUX), or non-transduced parental U-87MG cells. Among nine other non-transduced GBM cell lines, supra-additive effects were found in two cell lines (G-210GM, G-599GM), while ART and OSI-774 acted in an additive manner in the other seven cell lines (G-211GM, G-750GM, G-1163GM, G-1187GM, G-1265GM, G-1301GM, and G-1408GM). Sub-additive or antagonistic effects were not observed. Genomic gains and losses of genetic material in the non-transduced cell lines as assessed by comparative genomic hybridization were correlated with the IC(50) values for ART and OSI-774 and subsequently subjected to hierarchical cluster analysis and cluster image mapping. A genomic profile of imbalances was detected that predicted cellular response to ART and OSI-774. The genes located at the genomic imbalances of interest may serve as candidate resistance genes of GBM cells towards ART and OSI-774. In conclusion, the combination treatment of ART and OSI-774 resulted in an increased growth inhibition of GBM cell lines as compared to each drug alone.

Date of acceptance

2003

Autoren

Thomas Efferth
Tzutzuy Ramirez
Erich Gebhart
Marc-Eric Halatsch

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/15081868

DOI

10.1016/j.bcp.2003.12.035

ISSN

0006-2952

Ausgabe der Veröffentlichung

9

Zeitschrift

Biochem Pharmacol

Schlüsselwörter

Antineoplastic Combined Chemotherapy Protocols
Artemisinins
Artesunate
Cell Division
Cell Line
Cluster Analysis
Drug Screening Assays, Antitumor
Drug Synergism
ErbB Receptors
Erlotinib Hydrochloride
Glioblastoma
Humans
Nucleic Acid Hybridization
Quinazolines
Sesquiterpenes
Tumor Cells, Cultured

Sprache

eng

Country

England

Paginierung

1689 - 1700

PII

S0006295204000371

Datum der Veröffentlichung

2004

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2004

Titel

Combination treatment of glioblastoma multiforme cell lines with the anti-malarial artesunate and the epidermal growth factor receptor tyrosine kinase inhibitor OSI-774.

Sub types

Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

67

Data source: PubMed

Combination-treatment of glioblastoma multiforme cell lines with the anti-malarial artesunate and the epidermal growth factor receptor tyrosine kinase inhibitor OSI-774

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