Artikel
An old psychiatric drug, olanzapine, provides antineoplastic activity against glioblastoma cells when applied as a single-agent or in combination with temozolomide
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Autoren
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Georg Karpel-Massler
- Klinik für Neurochirurgie, Universität Ulm, Ulm, Deutschland; Klinik für Kinder- und Jugendmedizin, Universität Ulm, Ulm, Deutschland
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Richard Eric Kast
- IIAIGC Headquarters, Dean of Studies, Burlington, Vermont, U.S.A.
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Mike-Andrew Westhoff
- Klinik für Kinder- und Jugendmedizin, Universität Ulm, Ulm, Deutschland
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Annika Dwucet
- Klinik für Neurochirurgie, Universität Ulm, Ulm, Deutschland
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Nathalie Welscher
- Klinik für Neurochirurgie, Universität Ulm, Ulm, Deutschland
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Lisa Nonnenmacher
- Klinik für Kinder- und Jugendmedizin, Universität Ulm, Ulm, Deutschland
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Michal Hlavac
- Klinik für Neurochirurgie, Universität Ulm, Ulm, Deutschland
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Markus David Siegelin
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, U.S.A.
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Christian Rainer Wirtz
- Klinik für Neurochirurgie, Universität Ulm, Ulm, Deutschland
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Klaus-Michael Debatin
- Klinik für Kinder- und Jugendmedizin, Universität Ulm, Ulm, Deutschland
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Marc-Eric Halatsch
- Klinik für Neurochirurgie, Universität Ulm, Ulm, Deutschland
| Veröffentlicht: | 2. Juni 2015 |
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Gliederung
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Objective: The continuously poor prognosis of patients with glioblastoma urges the discovery of more effective therapeutics. Repurposing of already existing drugs involves the clinical application of old agents with previously not known or not utilized anti-cancer activity and represents a strategy to diminish costs and to save preclinical development time. This study aimed at elucidating whether the neuroleptic olanzapine may provide anti-cancer activity against glioblastoma either alone or in combination with temozolomide, the standard chemotherapeutic agent used against this disease.
Method: Anti-proliferative effects of olanzapine were assessed by MTT assays and cell count analysis. Soft-agar assays were performed to examine the drug's effect on glioblastoma cells' colony-forming ability. Transwell® assays were used in U87MG and A172MG cells to analyze anti-migratory effects. Apoptosis or cytostasis was detected by staining for annexin V/propidium iodide or carboxyfluorescein succinimidyl ester prior to flow cytometric analysis.
Results: Single-agent treatment with olanzapine inhibited proliferation of U87MG (IC50=49.1 microM) and A172 (IC50=27.9 microM) glioblastoma cell lines. Moreover, combined treatment with olanzapine and temozolomide resulted in an additive antiproliferative effect on U87MG and A172 cells. In U87MG cells, anchorage-independent growth was dose-dependently inhibited. In A172 cells, treatment with olanzapine yielded a dose-dependent anti-migratory effect. On the cellular level, olanzapine was shown to exert a cell line-dependent pleomorphism with respect to the induction of apoptosis, necrosis and/or cytostasis.
Conclusions: Our data confirm that olanzapine enhances the anti-tumor activity of temozolomide against glioblastoma cell lines. In addition, olanzapine on its own provides anti-cancer activity in glioblastoma and is known to cross the blood-brain-barrier. Therefore, olanzapine should be seriously considered for repurposing in glioblastoma.
