Repurposing trifluoperazine for glioblastoma treatment

Abstract

Glioblastoma (GBM) remains a therapeutic challenge due to its heterogeneity and plasticity, which drive treatment resistance, especially when compounded by interactions with the brain microenvironment. Recent preclinical evidence indicates that trifluoperazine (TFP) inhibits treatment-induced malignant reprogramming of tumour cells, potentially helping to reduce tumour plasticity. TFP targets calmodulin, dopamine receptors, and stress-responsive proteins (nuclear protein 1, NUPR1). Through these mechanisms, TFP has been shown to reduce tumour growth, sensitise tumours to chemoradiotherapy, and prolong survival in xenograft animal models. The clinical safety profile of TFP is well known from its use as an antipsychotic, and recent preclinical evidence further indicates that TFP has low toxicity to healthy neurons and glia despite transient functional effects on dopamine receptors. This Opinion explores TFP mechanisms of action and clinical activity to assess its suitability as a repurposed therapeutic option for GBM.

Keywords: GBM; NUPR1; antipsychotics; brain cancer; calmodulin; chemotherapy; dopamine; ferroptosis; glioma; multidrug resistance; phenothiazine; trifluoperazine.