Artikel
Combined treatment with ABT-263 and vacquinol exhibits synergistic anti-glioblastoma activity in vitro which can be further enhanced by inhibition of autophagy
Die kombinierte Behandlung mit ABT-263 und Vacquinol zeigt synergistische Aktivität gegen Glioblastomzellen in vitro und kann durch Hemmung von Autophagie verstärkt werden
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Autoren
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Jenson Anthonymuthu
- Universitätsklinikum Ulm, Ulm, Deutschland
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Carolin Golla
- Universitätsklinikum Ulm, Ulm, Deutschland
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Annika Dwucet
- Universitätsklinikum Ulm, Ulm, Deutschland
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Maximilian Pruss
- Universitätsklinikum Ulm, Ulm, Deutschland
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Michal Hlavac
- Universitätsklinikum Ulm, Ulm, Deutschland
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Richard Eric Kast
- IIAIGC Study Center, Burlington, VT, United States
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Christian Rainer Wirtz
- Universitätsklinikum Ulm, Ulm, Deutschland
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Marc-Eric Halatsch
- Universitätsklinikum Ulm, Ulm, Deutschland
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Markus David Siegelin
- Columbia University, New York, NY, United States
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Mike-Andrew Westhoff
- Universitätsklinikum Ulm, Ulm, Deutschland
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Georg Karpel-Massler
- Universitätsklinikum Ulm, Ulm, Deutschland
| Veröffentlicht: | 26. Juni 2020 |
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| Veröffentlicht mit Erratum: | 14. September 2020 |
Gliederung
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Objective: Vacquinol represents an experimental anti-malaria drug which has been previously described to provide anti-glioma activity.The purpose of this study was to examine whether treatment with vacquinol would enhance the pro-apoptotic reprogramming of glioblastoma cells following selective Bcl-2/Bcl-xL inhibition by ABT-263.
Methods: Drug testing was performed on primary cultured ULM-GBM-PC38 and ULM-GBM-PC128 glioblastoma cells. MTT assays were used to provide a rigorous characterization of the drug-drug interaction of vacquinol and ABT-263 including isobologram analyses. Annexin-V/PI and TMRE staining followed by flow cytometric analyses were done to assess pro-apoptotic effects. Western blot analyses were performed to assess the expression of anti-apoptotic members of the Bcl-2 family of proteins and to determine the LC3 conversion.
Results: Combined treatment with vacquinol and ABT-263 resulted in synergistic anti-proliferative and pro-apoptotic effects in ULM-GBM-PC38 and ULM-GBM-PC128 cells. Mechanistically, the pro-apoptotic effect of the combination treatment was associated with a significant decrease of the mitochondrial outer membrane potential and a decreased expression of Bcl-2 and Bcl-xL in ULM-GBM-PC38 cells. Western blot analyses showed that the combination treatment led to increased LC3 conversion. Additional treatment with an inhibitor of autophagy (chloroquine) resulted in increased anti-proliferative and pro-apoptotic effects.
Conclusion: Our data suggest that combined treatment with vacquinol and ABT-263 has superior anti-glioblastoma activity compared to single agent treatments. However, this potential therapeutic approach is associated with the induction of protective autophagy in our setting and should be complemented by an inhibitor of autophagy. The promising results of this study warrant further investigation.
