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High-throughput drug screening identifies fluoxetine as a potential therapeutic agent for neuroendocrine prostate
1Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Introduction:
Neuroendocrine 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.
Methods:
We 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.
Results:
Our 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.
Discussion:
This work repurposed fluoxetine for antitumor application, and supported its clinical development for NEPC therapy, which may provide a promising therapeutic strategy.
Insights
Fluoxetine, an antidepressant, shows promise in treating neuroendocrine prostate cancer (NEPC). It inhibits NEPC growth and metastasis by targeting the AKT pathway, offering a new therapeutic option.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Neuroendocrine prostate cancer (NEPC) is an aggressive subtype with poor prognosis.
- Current therapeutic options for NEPC are limited due to resistance to hormone therapy.
Purpose of the Study:
- To identify and evaluate novel therapeutic agents for NEPC.
- To investigate the potential of repurposing existing drugs for NEPC treatment.
Main Methods:
- High-throughput drug screening was employed to identify potential NEPC therapeutics.
- In vitro and in vivo experiments were conducted to assess fluoxetine's efficacy and mechanism in NEPC models.
Main Results:
- Fluoxetine demonstrated significant inhibition of neuroendocrine differentiation and cell viability in NEPC models.
- Targeting the AKT pathway was identified as a key mechanism of fluoxetine's action.
- Preclinical studies in NEPC mice models showed prolonged survival and reduced distant metastases with fluoxetine treatment.
Conclusions:
- Fluoxetine repurposing shows significant antitumor potential for NEPC.
- The findings support the clinical development of fluoxetine as a novel therapeutic strategy for NEPC.
- Targeting the AKT pathway with fluoxetine offers a promising approach for NEPC treatment.
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