Repurposing neuroleptics: clozapine as a novel, adjuvant therapy for melanoma brain metastases

Area of Science:

• Neuroscience
• Oncology
• Pharmacology

Background:

• The blood-brain barrier and unique brain immunology present challenges for treating intracranial tumors.
• Antipsychotics, including neuroleptics, have shown potential anti-tumoral effects, prompting investigation for brain metastases therapy.

Purpose of the Study:

• To investigate the therapeutic potential of clozapine against melanoma brain metastases (MBM).
• To evaluate clozapine's efficacy and safety profile in human MBM cell lines in vitro.

Main Methods:

• Utilized three human MBM cell lines for in vitro cell culture and viability assays.
• Performed dose-dependent experiments to assess clozapine's effects on migration, proliferation, and colony formation.
• Employed flow cytometry and proteome screening to analyze apoptosis induction and changes in the tumor immunological environment.

Main Results:

• Clozapine demonstrated potent anti-tumoral effects on MBM cells with a favorable therapeutic window compared to normal astrocytes and brain organoids.
• Clozapine significantly inhibited MBM cell migration, proliferation, and colony formation in a dose-dependent manner.
• Clozapine induced apoptosis in MBM cells and upregulated immune-related proteins, including macrophage inflammatory protein-1 alpha (MIP-1α) and interleukin-8 (IL-8).

Conclusions:

• Clozapine exhibits significant and selective anti-melanoma brain metastases activity in vitro.
• The findings support further in vivo studies to explore clozapine's clinical translation for MBM treatment.