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72. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Polnischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

06.06. - 09.06.2021

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Azaindole derivatives cause a metabolic reprogramming and have a strong anti-cancer activity in glioblastoma cells in vitro

Azaindol-Derivate verursachen eine Umprogrammierung des Tumorzellmetabolismus und haben eine ausgeprägte anti-neoplastische Aktivität im Glioblastom in vitro

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  • Maximilian Pruss - Universitätsklinikum Ulm, Neurochirurgische Klinik, Ulm, Deutschland
  • Stefan Wiezorek - Institute of Organic Chemistry, Aachen, Deutschland
  • Annika Dwucet - Universitätsklinikum Ulm, Neurochirurgische Klinik, Ulm, Deutschland
  • Michal Hlavac - Universitätsklinikum Ulm, Neurochirurgische Klinik, Ulm, Deutschland
  • Markus David Siegelin - Columbia University Irving Medical Center, Department of Pathology and Cell Biology, New York, NY, Vereinigte Staaten
  • Marc-Eric Halatsch - Universitätsklinikum Ulm, Neurochirurgische Klinik, Ulm, Deutschland
  • Christian Rainer Wirtz - Universitätsklinikum Ulm, Neurochirurgische Klinik, Ulm, Deutschland
  • Mike-Andrew Westhoff - Universitätsklinikum Ulm, Klinik für Pädiatrie, Ulm, Deutschland
  • Carsten Bolm - Institute of Organic Chemistry, Aachen, Deutschland
  • presenting/speaker Georg Karpel-Massler - Universitätsklinikum Ulm, Neurochirurgische Klinik, Ulm, Deutschland

Deutsche Gesellschaft für Neurochirurgie. 72. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Polnischen Gesellschaft für Neurochirurgie. sine loco [digital], 06.-09.06.2021. Düsseldorf: German Medical Science GMS Publishing House; 2021. DocP029

doi: 10.3205/21dgnc317, urn:nbn:de:0183-21dgnc3176

Published: June 4, 2021

© 2021 Pruss et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.

Outline

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Objective: In this study, we screened nine synthetic azaindole derivatives for anti-neoplastic activity in glioblastoma cells in an in vitro setting.

Methods: Cell viability analyses were performed to assess effects on various glioblastoma cells following treatment with nine azaindole derivatives. A selection of the two most promising candidates underwent further testing. Cell count analyses and staining with propidium iodide followed by flow cytometry were performed to characterize effects on the cellular viability. Scratch-induced migration assays and time-lapse analyses were used to examine a potential influence on non-directed movement. Western blot analyses were done to determine specific protein expression of members of the Bcl-2 family of proteins and complexes of the respiratory chain. Extracellular flux analyses were performed to determine effects on oxidative phosphorylation (OCR) and the glycolytic rate (ECAR). Phospho tyrosine kinase arrays were used to detect effects on cell signaling patterns on the phospho protein level.

Results: All azaindoles tested, displayed a significant anti-proliferative activity among U251 and U87MG established glioblastoma cell lines as well as ULM-GBM-PC38 glioblastoma primary cultures. The two most potent derivatives had IC50-values ranging between 0.94 µM and 4.44 µM and were selected for further analyses. Both derivatives led to a significant inhibition of non-directed migration in U251 and ULM-GBM-PC38 glioblastoma cells. Metabolic analyses revealed a diverse response towards the two compounds tested. While compound 1 led to a downregulation of the oxidative consumption rate and an upregulation of the glycolytic rate, compound 2 caused mostly a decreased glycolytic rate. Similar, a diverse response was found with respect to the phospho tyrosine kinase activation pattern among the two derivatives. While compound 1 caused a reduced activation of ERK and RAS, compound 2 led to reduced activation of AKT and increased phosphorylation of p53.

Conclusion: We identified two promising drug candidates with potent anti-proliferative and anti-migratory activity among multiple in vitro models of glioblastoma. The mechanisms that underly the differential metabolic reprogramming warrant further investigation.