Article
The anti-malaria drug Chloroquine activates p53 transcriptional response and cell death in human glioma cells
Das Antimalariamedikament Chloroquine aktiviert die transkriptionelle Antwort von p53 und Zelltod in menschlichen Gliomzellen
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Authors
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J. Leppert
- Department of Neurosurgery, University of Schleswig-Holstein, Campus Lübeck
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R. Wüstenberg
- Department of Neurosurgery, University of Schleswig-Holstein, Campus Lübeck
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S. Schlaffer
- Department of Neurosurgery, University of Schleswig-Holstein, Campus Lübeck
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E. Pawlak
- Department of Neurosurgery, University of Schleswig-Holstein, Campus Lübeck
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E. Reusche
- Department of Neuropathology, University of Schleswig-Holstein, Campus Lübeck
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E. Kim
- Department of Neurosurgery, University of Schleswig-Holstein, Campus Lübeck
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A. Giese
- Department of Neurosurgery, University of Schleswig-Holstein, Campus Lübeck
| Published: | May 4, 2005 |
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Outline
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Objective
Functional inactivation of p53 is the common mechanism underlying tumour progression in different types of cancers including gliomas. The major mechanism underlying p53 functions as a tumour suppressor is transcriptional activation of a large number of p53 responsive genes, which are involved in cell cycle control, DNA repair or apoptosis. The search for new compound-inducers of the p53 transcriptional activity has been an intensively developing area of research in the last decade. The identification of compounds that would be non-toxic at a dose effective for p53 activation is a matter of crucial importance as far as clinical applications are concerned. We have found that chloroquine, a known anti-malaria drug, is a potent inducer of the p53 transcriptional response in glioma cells with wild type p53.
Methods
Established human glioma cell lines with known p53 status were treated with increasing concentrations of chloroquine to study the effect on cell growth, proliferation and colony formation. Cell death was determined using trypan blue exclusion, histone-complexed DNA fragmentation, DNA histograms and determination of the mitochondrial membrane potential. p53 transactivation was examined by western blot, RT-PCR and chromatin immunprecipitation and the p53/DNA interaction was analyzed by EMSA.
Results
We found that the antimalarial agent chloroquine activates sequence-specific DNA binding and transcriptional activity of p53 in glioma-derived cell lines to the extent comparable to that induced by gamma-irradiation. However, the mechanism of p53 activation induced by chloroquine appears to be distinct from the one underlying p53 activation by gamma-irradiation, which induces ATM-dependant p53 phosphorylation at Ser15. Chloroquine treatment induces death of glioma cells accompanied by characteristic morphological and biochemical changes indicative of apoptosis. Furthermore, chloroquine treatment sensitises glioma cells to gamma-irradiation and to other drugs used for glioma treatment such as BCNU.
Conclusions
We demonstrate as a first report that the orally available anti-malaria drug chloroquine is a potent inducer of the p53 pathway and of cell death in human glioma cells. Chloroquine treatment sensitises glioma cells to drug-induced apoptosis. The efficacy in killing tumour cells, the low cost and long pre-history of safe clinical use make chloroquine an attractive candidate drug that may be used to complement existing glioma therapies.
