High-throughput drug screening identifies fluoxetine as a potential therapeutic agent for neuroendocrine prostate cancer

IntroductionNeuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer with poor prognosis and resistance to hormone therapy, which has limited therapeutic approaches. Therefore, this study aimed to identify a novel treatment for NEPC and provide evidence of its inhibitory effects. MethodsWe performed a high-throughput drug screening and identified fluoxetine, originally an FDA-approved antidepressant, as candidate therapeutic agent for NEPC. We carried out both in vitro and in vivo experiments to demonstrate the inhibitory effects of fluoxetine on NEPC models and its mechanism in detail. ResultsOur results demonstrated that fluoxetine effectively curbed the neuroendocrine differentiation and inhibited cell viability by targeting the AKT pathway. Preclinical test in NEPC mice model (PBCre4: Ptenf/f; Trp53f/f; Rb1f/f) showed that fluoxetine effectively prolonged the overall survival and reduced the risk of tumor distant metastases. DiscussionThis work repurposed fluoxetine for antitumor application, and supported its clinical development for NEPC therapy, which may provide a promising therapeutic strategy.

Automated summary

This study identified fluoxetine, an FDA-approved antidepressant, as a potential therapeutic agent for neuroendocrine prostate cancer (NEPC) through high-throughput drug screening. In vitro and in vivo experiments demonstrated that fluoxetine effectively inhibited neuroendocrine differentiation and cell viability by targeting the AKT pathway. Preclinical tests in NEPC mouse models showed that fluoxetine significantly prolonged overall survival and reduced the risk of tumor distant metastases. These findings repurpose fluoxetine for antitumor application and support its clinical development as a promising therapeutic strategy for NEPC.