Characterising Triflupromazine as a potential agent to treat glioblastoma multiforme

Glioblastoma Multiforme (GBM) is an aggressive brain tumour with poor prognosis, accounting for up to 50% of all gliomas. For decades, treatment of this tumour has been limited to surgery with concurrent radiation and chemotherapy with temozolomide (TMZ). However, recurrence is inevitable and resistance develops rapidly despite aggressive treatment regimens leading to a high mortality with a median survival of approximately 15 months. New approaches in drug discovery are needed to facilitate treatment strategies for GBM, hence drug repurposing offers the possibility of rediscovering new off target actions for FDA approved drugs. This is particularly pertinent in the absence of new drugs in clinical practice and the development of resistance in GBM. During my doctoral studies, I have taken forward a drug screen project aimed to identify small molecule inhibitors that sensitise glioma neural stem cells to cell death. My findings identified Triflupromazine, a brain-penetrant phenothiazine as a potent inducer of significant cell death in multiple glioma stem cells lines. Further experiments on its underlying molecular action suggested an unexploited off-target mechanism that is separate from its known dopamine antagonism. Following lysosomal accumulation, Triflupromazine induces a dysregulation in lipid homoeostasis leading to the build-up of cholesterol and various lipid species and inducing necroptosis as a mode of cell death. I propose additional key players in the polypharmacology of Triflupromazine and a novel role for ceramide in the induced mechanism of cell death. Of notable discovery is the potential direct interaction with ASAH1, the rate limiting enzyme in the conversion of ceramide to sphingosine. Along with ASAH1, PGAM5, NPC1, and SPNS1 were identified as crucial players in the phenotypes induced by Triflupromazine, suggesting an intricate and overlapping mechanism of action for this phenothiazine. Taken together, the polypharmacology and clinical properties of Triflupromazine strongly supports its repurposing for the adjuvant treatment of GBM.

Grantor dc:publisher

The University of Edinburgh

Year dc:date.issued

2025

Author dc:creator

• Abualetham, Najib Jeries

Advisors dc:contributor.advisor

• Von Kriegsheim, Alex
• Gammoh, Noor

• Glioblastoma Multiforme
• GBM
• autophagy
• Triflupromazine
• ceramide

Language dc:language.iso

en

Identifier URI

http://dx.doi.org/10.7488/era/6027

OAI identifier oai:identifier

oai:era.ed.ac.uk:1842/43491