BH3 Profiling Identifies Apoptotic Priming by SREBP-1/-2 Inhibition and Synergistic Anti-Glioblastoma Activity When Combined with ABT-263 In Vitro.
5 affiliations
- 1Department of Neurosurgery, Ulm University Medical Center, 89081 Ulm, Germany.
- 2Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University Medical Center Regensburg, 93053 Regensburg, Germany.
- 3Institute of Neurogenetics, University of Lübeck, 23562 Lübeck, Germany.
- 4Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, 89081 Ulm, Germany.
- 5Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
Abstract
Background/Objectives: Glioblastoma exhibits profound therapy resistance driven in part by complex pro-survival signaling. We hypothesized that targeting lipid metabolism via SREBP-1/2 inhibition (fatostatin) might alter the apoptotic phenotype and facilitate an apoptotic response driven by BH3 mimetics (ABT-263) in glioblastoma in vitro. Methods: Dynamic BH3 profiling was performed to detect apoptotic priming. The combined inhibition of SREBP-1/2 and Bcl-xL/Bcl-2 was evaluated across 2- and 3-dimensional culture models. The cell lines used included established cell lines as well as primary cultures and glioma stem-like cells. Extracellular flux analysis was used to assess metabolic effects. Changes in migration were evaluated through time-lapse analysis, scratch, and Transwell assays. Results: BH3 profiling showed that treatment with fatostatin increased Bcl-xL/Bcl-2 reliance, while ABT-263 increased Mcl-1 dependence. The combination showed potent synergy in inhibiting viability and spheroid growth, driven at least in part by enhanced caspase-dependent apoptosis. Mechanistically, fatostatin induced dose-dependent Mcl-1 downregulation, sensitizing cells to ABT-263. Dual treatment suppressed oxidative phosphorylation and impaired cell migration, while exhibiting low toxicity in non-pathological cells. Conclusions: This study indicates that combined inhibition of SREBP-1/2 and Bcl-xL/Bcl-2 represents a promising therapeutic strategy for the treatment of glioblastoma. The efficacy of this dual approach potentially lies in the downregulation of Mcl-1 induced by fatostatin and suppression of oxidative phosphorylation. Further studies are warranted.
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BibTeX
@article{tosin2026profiling,
title = {{BH3 Profiling Identifies Apoptotic Priming by SREBP-1/-2 Inhibition and Synergistic Anti-Glioblastoma Activity When Combined with ABT-263 In Vitro.}},
author = {Davide Tosin and Felix Seyfried and Annika Hajosch and Dominik Schlotter and Letizia Santinelli and Mike-Andrew Westhoff and Markus Siegelin and Christian Rainer Wirtz and Georg Karpel-Massler},
journal = {Pharmaceutics},
year = {2026},
month = oct,
doi = {10.3390/pharmaceutics18101327},
url = {https://europepmc.org/article/MED/42942857},
note = {CC BY},
}
RIS
TY - JOUR
TI - BH3 Profiling Identifies Apoptotic Priming by SREBP-1/-2 Inhibition and Synergistic Anti-Glioblastoma Activity When Combined with ABT-263 In Vitro.
AU - Davide Tosin
AU - Felix Seyfried
AU - Annika Hajosch
AU - Dominik Schlotter
AU - Letizia Santinelli
AU - Mike-Andrew Westhoff
AU - Markus Siegelin
AU - Christian Rainer Wirtz
AU - Georg Karpel-Massler
PY - 2026
DA - 2026/10/20
JO - Pharmaceutics
DO - 10.3390/pharmaceutics18101327
UR - https://europepmc.org/article/MED/42942857
AB - Background/Objectives: Glioblastoma exhibits profound therapy resistance driven in part by complex pro-survival signaling. We hypothesized that targeting lipid metabolism via SREBP-1/2 inhibition (fatostatin) might alter the apoptotic phenotype and facilitate an apoptotic response driven by BH3 mimetics (ABT-263) in glioblastoma in vitro. Methods: Dynamic BH3 profiling was performed to detect apoptotic priming. The combined inhibition of SREBP-1/2 and Bcl-xL/Bcl-2 was evaluated across 2- and 3-dimensional culture models. The cell lines used included established cell lines as well as primary cultures and glioma stem-like cells. Extracellular flux analysis was used to assess metabolic effects. Changes in migration were evaluated through time-lapse analysis, scratch, and Transwell assays. Results: BH3 profiling showed that treatment with fatostatin increased Bcl-xL/Bcl-2 reliance, while ABT-263 increased Mcl-1 dependence. The combination showed potent synergy in inhibiting viability and spheroid growth, driven at least in part by enhanced caspase-dependent apoptosis. Mechanistically, fatostatin induced dose-dependent Mcl-1 downregulation, sensitizing cells to ABT-263. Dual treatment suppressed oxidative phosphorylation and impaired cell migration, while exhibiting low toxicity in non-pathological cells. Conclusions: This study indicates that combined inhibition of SREBP-1/2 and Bcl-xL/Bcl-2 represents a promising therapeutic strategy for the treatment of glioblastoma. The efficacy of this dual approach potentially lies in the downregulation of Mcl-1 induced by fatostatin and suppression of oxidative phosphorylation. Further studies are warranted.
SN - 1999-4923
ER -