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Updated: Aug 1, 2025
An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 18, 2013
Repurposing ketotifen as a therapeutic strategy for neuroendocrine prostate cancer by targeting the IL-6/STAT3
1Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200120, China.
Purpose:
Neuroendocrine prostate cancer (NEPC), a highly aggressive subtype of prostate cancer displaying resistance to hormone therapy, presents a poor prognosis and limited therapeutic options. Here, we aimed to find novel medication therapies for NEPC and explore the underlying mechanism.
Methods:
A high-throughput drug screening utilizing an FDA-approved drug library was performed and ketotifen, an antihistamine agent, was identified as a potential therapeutic candidate for NEPC. The whole-transcriptome sequencing analysis was conducted to explore mechanism of ketotifen inhibitory in NEPC. Multiple cell biology and biochemistry experiments were performed to confirm the inhibitory effect of ketotifen in vitro. A spontaneous NEPC mice model (PBCre4:Ptenf/f;Trp53f/f;Rb1f/f) was used to reveal the inhibitory effect of ketotifen in vivo.
Results:
Our in vitro experiments demonstrated that ketotifen effectively suppressed neuroendocrine differentiation, reduced cell viability, and reversed the lineage switch via targeting the IL-6/STAT3 pathway. Our in vivo results showed that ketotifen significantly prolonged overall survival and reduced the risk of distant metastases in NEPC mice model.
Conclusion:
Our findings repurpose ketotifen for antitumor applications and endorse its clinical development for NEPC therapy, offering a novel and promising therapeutic strategy for this formidable cancer subtype.
Insights
Ketotifen, an antihistamine, shows promise in treating neuroendocrine prostate cancer (NEPC). This drug suppressed tumor growth and metastasis in preclinical models, offering a new therapeutic avenue for this aggressive cancer.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Neuroendocrine prostate cancer (NEPC) is an aggressive subtype resistant to hormone therapy.
- NEPC has a poor prognosis and limited treatment options.
- Novel therapeutic strategies are urgently needed for NEPC.
Purpose of the Study:
- To identify novel drug therapies for NEPC.
- To explore the underlying mechanisms of potential NEPC treatments.
- To repurpose existing drugs for NEPC therapy.
Main Methods:
- High-throughput screening of an FDA-approved drug library identified ketotifen as a candidate.
- Whole-transcriptome sequencing elucidated ketotifen's mechanism of action.
- In vitro and in vivo experiments in NEPC cell lines and a mouse model confirmed ketotifen's efficacy.
Main Results:
- Ketotifen suppressed neuroendocrine differentiation and cell viability in vitro.
- Ketotifen reversed lineage plasticity by targeting the IL-6/STAT3 pathway.
- In vivo, ketotifen significantly improved survival and reduced metastasis in NEPC mice.
Conclusions:
- Ketotifen demonstrates significant antitumor activity against NEPC.
- Repurposing ketotifen offers a promising therapeutic strategy for NEPC.
- Clinical development of ketotifen for NEPC is warranted.
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