A radiosensitizing effect of artesunate in glioblastoma cells is associated with a diminished expression of the inhibitor of apoptosis protein survivin.

Abstract

BACKGROUND AND PURPOSE:

Novel strategies to overcome an irradiation resistant phenotype may help to increase therapeutic efficacy in glioblastoma multiforme. The present study aimed to elucidate radiation sensitizing properties of artesunate, a semi synthetic derivate of artemisinin and to assess factors involved in this effect.

MATERIALS AND METHODS:

LN229 and U87MG cells were treated with various concentrations of artesunate and radiation response was determined by a colony forming assay. Cell numbers, apoptosis induction, cell cycle distribution, and DNA repair following combined modality treatment were monitored by MTT-, caspase 3/7 assay, cytofluorometry, and γ-H2AX foci formation. Expression of survivin, survivin-GFP fusion protein, XIAP, cellular (c)IAP1 and cIAP2 was monitored by Western immunoblotting.

RESULTS:

Treatment of glioma cells with artesunate and irradiation resulted in an increased apoptotic fraction, pronounced G2/M arrest and increased DNA damage as demonstrated by an elevated amount of γ-H2AX foci/nucleus. Incubation with artesunate lowers survivin expression in a time and dose-dependent manner, whereas expression of XIAP, cIAP1 and cIAP2 was not affected. In clonogenic assays, treatment with artesunate revealed a significantly reduced surviving fraction, whereas stable over expression of a survivin-GFP protein reversed artesunate-mediated radiosensitization.

CONCLUSION:

Artesunate selectively down regulates survivin that contributes to a radio-sensitization of glioma cells by an increased induction of apoptosis, cell cycle arrest, and a hampered DNA damage response.

• Authors: Sebastian Reichert, Vera Reinboldt, Stephanie Hehlgans, Thomas Efferth, Claus Rödel, Franz Rödel
• Journal: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology (Radiother Oncol) Vol. 103 Issue 3 Pg. 394-401 (Jun 2012) ISSN: 1879-0887 [Electronic] Ireland
• PMID: 22560712 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Artemisinins
• BIRC5 protein, human
• Inhibitor of Apoptosis Proteins
• Neoplasm Proteins
• Radiation-Sensitizing Agents
• Survivin
• Artesunate

Topics

• Apoptosis (drug effects)
• Artemisinins (pharmacology)
• Artesunate
• Brain Neoplasms (genetics, metabolism, radiotherapy)
• Cell Cycle (radiation effects)
• Cell Line, Tumor
• Cell Survival (radiation effects)
• DNA Repair (drug effects)
• Dose-Response Relationship, Drug
• Down-Regulation
• Glioblastoma (genetics, metabolism, radiotherapy)
• Humans
• Inhibitor of Apoptosis Proteins (metabolism)
• Neoplasm Proteins (metabolism)
• Radiation-Sensitizing Agents (pharmacology)
• Survivin