Repurposed Antipsychotics as Potential Anticancer Agents: Clozapine Efficacy and Dopaminergic Pathways in Neuroblastoma and Glioblastoma

Neuro-oncology focuses on the diagnosis and treatment of brain tumors, which, despite their rarity, are associated with high mortality due to their invasiveness and limited treatment options. Emerging evidence suggests that dopamine (DA), a neurotransmitter crucial for cognitive and emotional processes, and its receptors may influence tumor growth and the tumor microenvironment. This study aimed to evaluate the potential anticancer effects of repurposed antipsychotic dopamine-targeting drugs (Clozapine, CLZ; Pimozide, PIM; Olanzapine, OLZ; and Risperidone, RIS) and antiemetic drugs (Domperidone, DOM; Droperidol, DRO) on neuroblastoma (SH-SY5Y) and glioblastoma (A172) cell lines, and to assess whether their efficacy is modulated by oxidative stress and DA synthesis. The drugs were first tested individually, followed by co-treatment with tyrosine (Tyr), a dopamine precursor, and hydrogen peroxide (H₂O₂), an inducer of oxidative stress. Additionally, drug activity was evaluated in the simultaneous presence of H₂O₂ and Tyr. CLZ exhibited the highest cytotoxicity in both cell lines, suggesting strong anticancer potential and also synergism among the different combinations, particularly in SH-SY5Y. Liquid chromatography of the extracellular medium showed greater Tyr consumption in SH-SY5Y compared to A172 cells, indicating a higher dependence on extracellular Tyr to mitigate drug- and/or stress-induced cytotoxicity. In summary, several of the repurposed antipsychotics demonstrated cytotoxic effects on central nervous system tumor cells, with CLZ showing the most promising activity, even under oxidative stress conditions. These findings support further investigation into dopamine-targeting drugs as potential therapeutic agents in neuro-oncology.