Repurposing ketotifen as a therapeutic strategy for neuroendocrine prostate cancer by targeting the IL-6/STAT3 pathway

  • Cell Oncol (Dordr). 2023 Apr 29. doi: 10.1007/s13402-023-00822-9.
Yiyi Ji  #  1 ,  Bo Liu  #  1 ,  Lei Chen  #  1 ,  Ang Li  1 ,  Kai Shen  1 ,  Ruopeng Su  1 ,  Weiwei Zhang  1 ,  Yinjie Zhu  2 ,  Qi Wang  3  4 ,  Wei Xue  5
Affiliations
  • 1. Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200120, China.
  • 2. Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200120, China. [email protected].
  • 3. Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200120, China. [email protected].
  • 4. Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200120, China. [email protected].
  • 5. Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200120, China. [email protected].
  • # Contributed equally.
PMID: 37120492 DOI: 10.1007/s13402-023-00822-9
Abstract

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.

Keywords
Drug repurposing; High-throughput drug screening; IL-6/STAT3 pathway; Ketotifen; Lineage switch; NEPC.
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