gms | German Medical Science

73. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Griechischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

29.05. - 01.06.2022, Köln

Combined inhibition of Bcl-xL/Bcl-2 and SREBP-1 results in a synergistic anti-neoplastic activity in glioblastoma cells in vitro

Die kombinierte Hemmung von Bcl-xL/Bcl-2 und SREBP-1 führt zu einer synergistischen anti-neoplastischen Aktivität im Glioblastom in vitro

Meeting Abstract

  • Davide Tosin - Universitätsklinikum Ulm, Neurochirurgie, Ulm, Deutschland
  • Dominik Schlotter - Universitätsklinikum Ulm, Neurochirurgie, Ulm, Deutschland
  • Annika Dwucet - Universitätsklinikum Ulm, Neurochirurgie, Ulm, Deutschland
  • Michal Hlavac - Universitätsklinikum Ulm, Neurochirurgie, Ulm, Deutschland
  • Mike-Andrew Westhoff - Universitätsklinikum Ulm, Kinder- und Jugendmedizin, Ulm, Deutschland
  • Markus David Siegelin - Columbia University, Department of Pathology and Cell Biology, New York, NY, Vereinigte Staaten
  • Christian Rainer Wirtz - Universitätsklinikum Ulm, Neurochirurgie, Ulm, Deutschland
  • presenting/speaker Georg Karpel-Massler - Universitätsklinikum Ulm, Neurochirurgie, Ulm, Deutschland

Deutsche Gesellschaft für Neurochirurgie. 73. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Griechischen Gesellschaft für Neurochirurgie. Köln, 29.05.-01.06.2022. Düsseldorf: German Medical Science GMS Publishing House; 2022. DocV175

doi: 10.3205/22dgnc170, urn:nbn:de:0183-22dgnc1707

Veröffentlicht: 25. Mai 2022

© 2022 Tosin et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.


Gliederung

Text

Objective: A cellular homeostasis that is shifted away from apoptosis and a reprogramming of the lipid metabolism are both, features that are frequently encountered in glioblastoma. This study aimed at investigating whether a combined reprogramming of the apoptotic machinery and the lipid metabolism results in a synergistic anti-glioblastoma activity in vitro.

Methods: Established (U251) and primary-cultured glioblastoma cells (PC38, PC40 and PC128) as well as glioblastoma stem-like cells (SC38 and SC40) were treated with the Bcl-xL/Bcl-2 inhibitor ABT-263 (navitoclax) and/or the SREBP-1 inhibitor Fatostatin. MTT-assays were performed to assess effects of the combination therapy on the cell viability. Isobolograms were calculated to characterize the nature of the drug-drug interaction. Spheroids were used to determine anti-proliferative effects in a 3-dimensional setting. Staining with annexin V/propidium iodide and flowcytometric analysis were performed to assess pro-apoptotic effects. For molecular analyses, Western blots and specific knock-down experiments with siRNA were performed.

Results: A simultaneous treatment with ABT-263 and Fatostatin resulted in a synergistic anti-proliferative effect on established, primary-cultured and glioblastoma stem-like cells as well as spheroids. The prevailing form of cell death after combined treatment with ABT-263 and Fatostatin was shown to be apoptosis, which occurred in a caspase-dependent manner. On the molecular level, treatment with increasing concentrations of Fatostatin led to a downregulation of Mcl-1 in a dose-dependent manner.

Conclusion: Our study indicates that combined inhibition of Bcl-xL/Bcl-2 and interference with the lipid metabolism targeting SREBP-1 synergistically induces caspase-dependent apoptosis in glioblastoma cells. This effect can also be observed in more complex 3-dimensional glioblastoma cell formations. Further studies will focus on deciphering the drug-induced alterations of the metabolic pathways that are responsible for the synergistic effect of this therapeutic strategy.