2. Academic Validation
  3. Chloroxine inhibits pancreatic cancer progression through targeted antagonization of the PI3K/AKT/mTOR signaling pathway

Chloroxine inhibits pancreatic cancer progression through targeted antagonization of the PI3K/AKT/mTOR signaling pathway

  • Clin Transl Oncol. 2023 Oct 18. doi: 10.1007/s12094-023-03328-w.
Miaomiao Lin 1,  Yanyi Xiao 2,  Yile Dai 2,  Yefan Mao 2,  Liming Xu 2,  Qiyu Zhang 3,  Zhe Chen 4
Affiliations

Affiliations

  • 1 The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, People's Republic of China.
  • 2 Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, People's Republic of China.
  • 3 Department for Hepato-Biliary-Pancreatic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, People's Republic of China. qiyu_zhang@wmu.edu.cn.
  • 4 Department for Hepato-Biliary-Pancreatic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, People's Republic of China. chenzhedr@wmu.edu.cn.
PMID: 37848695 DOI: 10.1007/s12094-023-03328-w
Abstract

Background: Patients with pancreatic Cancer have a dismal prognosis due to tumor cell infiltration and metastasis. Many reports have documented that EMT and PI3K-AKT-mTOR axis control pancreatic Cancer cell infiltration and metastasis. Chloroxine is an artificially synthesized Antibacterial compound that demonstrated anti-pancreatic Cancer effects in our previous drug-screening trial. We have explored the impact of chloroxine on pancreatic Cancer growth, infiltration, migration, and Apoptosis.

Methods: The proliferation of pancreatic Cancer cell lines (PCCs) treated with chloroxine was assessed through real-time Cell Analysis (RTCA), colony formation assay, CCK-8 assay, as well as immunofluorescence. Chloroxine effects on the infiltrative and migratory capacities of PCCs were assessed via Transwell invasion and scratch experiments. To assess the contents of EMT- and apoptosis-associated proteins in tumor cells, we adopted Western immunoblotting as well as immunofluorescence assays, and flow cytometry to determine chloroxine effects on PCCs Apoptosis. The in vivo chloroxine antineoplastic effects were explored in nude mice xenografts.

Results: Chloroxine repressed pancreatic Cancer cell growth, migration, and infiltration in vitro, as well as in vivo, and stimulated Apoptosis of the PCCs. Chloroxine appeared to inhibit PCC growth by Ki67 downregulation; this targeted and inhibited aberrant stimulation of the PI3K-AKT-mTOR signaling cascade, triggered Apoptosis in PCC via mitochondria-dependent Apoptosis, and modulated the EMT to inhibit PCC infiltration and migration.

Conclusions: Chloroxine targeted and inhibited the PI3K-AKT-mTOR cascade to repress PCCs growth, migration, as well as invasion, and triggered cellular Apoptosis. Therefore, chloroxine may constitute a potential antineoplastic drug for the treatment of pancreatic Cancer.

Keywords

Chloroxine; Epithelial–mesenchymal transition (EMT); PI3K–AKT–mTOR; Pancreatic ductal adenocarcinoma (PDAC).

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