2. Academic Validation
  3. Disulfiram mediated anti-tumour effect in pituitary neuroendocrine tumours by inducing cuproptosis

Disulfiram mediated anti-tumour effect in pituitary neuroendocrine tumours by inducing cuproptosis

  • Int Immunopharmacol. 2024 Apr 30:134:112159. doi: 10.1016/j.intimp.2024.112159.
Ning Huang 1,  Yao Feng 2,  Yanting Liu 2,  Yong Zhang 3,  Li Liu 4,  Bo Zhang 2,  Tao Zhang 4,  Zhipeng Su 5,  Li Xue 6,  Zhe Bao Wu 7
Affiliations

Affiliations

  • 1 Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Department of Neurosurgery, Center of Pituitary Tumour, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Department of Neurosurgery, Center of Pituitary Tumour, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 5 Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. Electronic address: drsuzhipeng@163.com.
  • 6 Department of Neurosurgery, Center of Pituitary Tumour, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Center for Brain Science and Brain-Inspired Technology, Shanghai, China. Electronic address: royxueli@126.com.
  • 7 Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Department of Neurosurgery, Center of Pituitary Tumour, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: wzb11748@rjh.com.cn.
PMID: 38692018 DOI: 10.1016/j.intimp.2024.112159
Abstract

Context: Medical treatment plays a critical role in pituitary neuroendocrine tumour (PitNET) treatment. Dopamine agonists and Somatostatin Receptor agonists are the only known drugs for effectively treating PitNET. Thus, the identification of potential therapeutic targets and drugs is urgently needed.

Objective: To discover potential drugs that can suppress PitNET growth and to further investigate the underlying mechanism involved.

Methods: High-throughput drug screening of primary cultures of 17 patient-derived PitNETs was performed to identify potential therapeutic compounds. Cell viability assays, Western blot analysis and flow cytometry were used to investigate pituitary neuroendocrine tumour cell lines and patient-derived PitNET cultures in vitro. In vivo drug efficacy was examined in a mouse xenograft model.

Results: Seventeen primary PitNET samples were collected for high-throughput drug screening, and a class of copper ionophores that can effectively inhibit cell growth, such as zinc pyrithione, elesclomol, and disulfiram (DSF), was identified. Subsequent experiments initially validated the dose-dependent cell growth-suppressing effect of these copper ionophores on AtT20, GH3, and MMQ cells and several primary PitNET cell lines. Moreover, we confirmed that the cytotoxic effect of DSF depends on the presence of copper. Additionally, we determined that cell death occurs via Cuproptosis, with events such as Fe-S cluster protein loss, dihydrolipoyl transacetylase oligomerization and heat shock protein 70 upregulation. Finally, we verified the cytotoxic effects of DSF in vivo.

Conclusion: The present study revealed copper ionophores as a potential class of drugs for PitNET treatment. DSF induced PitNET cell death via Cuproptosis and might be a promising option for PitNET therapy.

Keywords

Cuproptosis; Disulfiram; High-throughput screening; Pituitary neuroendocrine tumour.

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