Adaptaquin is selectively toxic to glioma stem cells through disruption of iron and cholesterol metabolism
Glioma stem cells (GSCs) from this aggressive brain cancer have been subject to nononcogene addiction therapeutic strategies, in particular targeting iron and cholesterol metabolic pathways. In this study, we show the small molecule Adaptaquin (AQ) has anti-GSC effects while sparing neurons, mature oligodendrocytes and astrocytes. Transcriptomic analysis of AQ-treated GSCs showed dramatic upregulation of iron transport genes and downregulation of genes involved in cholesterol biosynthesis. Indeed, we found cytotoxic effects of AQ on GSCs were potentiated when combined with the iron chelator deferoxamine (DFO). Notably, these effects were independent of PHD2 and HIF1α regulation, indicating a distinct pathway of action. Furthermore, we observed that the heme analogue, hemin, protects GSCs from AQ-mediated cell death, suggesting the presence of a functional heme transporter in GSCs, an observation confirmed by uptake of heme analogues. Importantly, we found that AQ treatment alone or in combination with iron chelators impaired cholesterol homeostasis in GSCs, leading to mitochondrial fragmentation and cell death. These findings suggest AQ in combination with iron chelators results in lethal disruption of cholesterol metabolism in glioma stem cells.
Authors
- Gabriel Balmus (ORCID: https://orcid.org/0000-0003-2872-4468)
- John H. Stockley (ORCID: https://orcid.org/0000-0002-7385-8310)
- Rajiv R. Ratan (ORCID: https://orcid.org/0000-0002-9081-2701)
- Eliane E.S. Brechbühl (ORCID: https://orcid.org/0000-0003-1386-4601)
- Kevin Michael Brindle (ORCID: https://orcid.org/0000-0003-3883-6287)
- James A. Nathan (ORCID: https://orcid.org/0000-0002-0248-1632)
- Gemma C. Girdler
- Rachel Seear
- David H. Rowitch (ORCID: https://orcid.org/0000-0002-0079-0060)
- Laura Morcom (ORCID: https://orcid.org/0000-0001-6683-4356)
- Michael McNicholas (ORCID: https://orcid.org/0000-0002-6920-9924)
- Adrien Vaquié (ORCID: https://orcid.org/0000-0003-1463-0153)
- Manav Pathania (ORCID: https://orcid.org/0000-0001-5635-5028)
- Darshil U. Shah (ORCID: https://orcid.org/0000-0002-8078-6802)
- Diana Gold Diaz
- Harry Bulstrode (ORCID: https://orcid.org/0000-0002-3480-108X)
- Zhaoyang Xu
Institutions
- Cedars-Sinai Medical Center (US)
- Cornell University (US)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- Cancer Research UK (GB)
- Cancer Research UK Cambridge Center (GB)
- MIND Research Institute (US)
- Brain Tumour Research (GB)
- Burke Medical Research Institute (US)
- UK Dementia Research Institute (GB)
- Romanian Institute of Science and Technology (RO)
Publication Details
- Journal
- Molecular Oncology
- Published
- 2025-09-21
- DOI
- https://doi.org/10.1002/1878-0261.70128
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- University of Cambridge