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Previous reports suggest anti-tumoral effects of antipsychotics, encouraging investigations into potential treatment effects of neuroleptics on brain metastases. For the first time, the therapeutic potential of the antipsychotic drug clozapine in treating melanoma brain metastases (MBM) was investigated using three human MBM cell lines. Through in vitro cell culture and viability experiments, clozapine displayed potent anti-tumoral effects on MBM cells with an exploitable therapeutic window when compared to normal human astrocytes or rat brain organoids. Further, it was shown that clozapine inhibited migration, proliferation, and colony formation in a dose-dependent manner. Through flow cytometry and proteome screening, we found that clozapine induced apoptosis in MBM cells and potentially altered the tumor immunological environment by upregulating proteins such as macrophage inflammatory protein-1 alpha (MIP-1\u03b1) and interleukin-8 (IL-8). In conclusion, clozapine shows significant and selective anti-tumoral effects on MBM cell lines in vitro. Further in vivo experiments are warranted to translate these results into clinical use.<\/jats:p>\n          <jats:p>\n            <jats:bold>Graphical abstract<\/jats:bold>\n          <\/jats:p>","DOI":"10.1007\/s10585-025-10328-3","type":"journal-article","created":{"date-parts":[[2025,1,25]],"date-time":"2025-01-25T03:29:07Z","timestamp":1737775747000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Repurposing neuroleptics: clozapine as a novel, adjuvant therapy for melanoma brain metastases"],"prefix":"10.1007","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2925-6144","authenticated-orcid":false,"given":"Tobias","family":"Wikerholmen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9182-777X","authenticated-orcid":false,"given":"Erlend Moen","family":"Taule","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3824-2040","authenticated-orcid":false,"given":"Emma","family":"Rigg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9095-1910","authenticated-orcid":false,"given":"Birgitte Feginn","family":"Berle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7535-7656","authenticated-orcid":false,"given":"Magnus","family":"S\u00e6ttem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6091-5689","authenticated-orcid":false,"given":"Katharina","family":"Sarnow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6200-8239","authenticated-orcid":false,"given":"Halala Sdik","family":"Saed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6503-7141","authenticated-orcid":false,"given":"Terje","family":"Sundstr\u00f8m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7762-3703","authenticated-orcid":false,"given":"Frits","family":"Thorsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,25]]},"reference":[{"key":"10328_CR1","unstructured":"International W, World Cancer Research Fund International (2022) Skin cancer statistics; [Available from: https:\/\/www.wcrf.org\/cancer-trends\/skin-cancer-statistics\/"},{"key":"10328_CR2","doi-asserted-by":"crossref","unstructured":"Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. 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