Drug Repurposing Screen Identifies Pimozide as a ROS ‐Inducing Therapy With Anti‐Tumor Efficacy in HNSCC PDX Models
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Le résumé fourni par la source
Redox regulation is a key mechanism supporting tumor survival and an attractive therapeutic target. In this study, we screened 1161 FDA-approved compounds to identify agents that induce reactive oxygen species (ROS) accumulation in head and neck squamous cell carcinoma (HNSCC) cells. Pimozide, a dopamine D2 receptor antagonist, emerged as the most potent ROS inducer. It selectively suppresses the growth of HNSCC cells with high oxidative stress resistance while exhibiting only modest effects on less resistant cells and normal keratinocytes. Notably, pimozide exhibited anti-tumor effects as a monotherapy and in combination with paclitaxel at clinically relevant doses. Mechanistic analysis revealed that pimozide rapidly induced ROS accumulation via a mechanism distinct from its known action on dopamine D2 receptors and STAT3/5. To identify markers of ROS-induced responses, we examined ROS-responsive genes and found that early growth response 1 (EGR1) was selectively induced in sensitive cells and correlated with pimozide responsiveness. Functional analysis revealed that EGR1 knockdown suppressed pimozide-induced cytotoxicity, suggesting its role as a functional pharmacodynamic marker of pimozide sensitivity. In a patient-derived xenograft model of HNSCC, pimozide significantly reduced the tumor burden alone and in combination with paclitaxel. While tumor volume reduction in the combination group was not statistically greater than that in the monotherapy group, fluorescence immunohistochemistry revealed a marked decrease in undifferentiated tumor cells, indicating enhanced therapeutic effects of combination treatment. Taken together, these findings indicate that pimozide is a promising candidate for repurposing as a novel therapeutic agent against HNSCC.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- Drug Repurposing Screen Identifies Pimozide as a <scp>ROS</scp> ‐Inducing Therapy With Anti‐Tumor Efficacy in <scp>HNSCC PDX</scp> Models
- Date Crossref
- 20/11/2025
- Éditeur
- Wiley
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Nihon University Department of Microbiology and Immunology pays non établi dans la noticeUniversité ou école supérieure
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Keio University Department of Otolaryngology-Head and Neck Surgery pays non établi dans la noticeUniversité ou école supérieure
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Kyushu University Department of Hematology pays non établi dans la noticeUniversité ou école supérieure
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Kyushu University Hospital pays non établi dans la noticeÉtablissement de santé
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Tokyo Medical University Institute of Medical Science pays non établi dans la noticeUniversité ou école supérieure
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Tokyo University of Science Division of Cell Fate Regulation pays non établi dans la noticeUniversité ou école supérieure
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Fujita Health University Division of Gene Regulation pays non établi dans la noticeUniversité ou école supérieure
Department of Microbiology and Immunology — Nihon University, Department of Otolaryngology-Head and Neck Surgery — Keio University et Department of Hematology — Kyushu University, avec 4 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.