In silico identification of thiostrepton as an inhibitor of cancer stem cell growth and an enhancer for chemotherapy in non-small-cell lung cancer

J Cell Mol Med. 2019 Dec;23(12):8184-8195. doi: 10.1111/jcmm.14689. Epub 2019 Oct 22.

Abstract

Cancer stem cells (CSCs) play an important role in cancer treatment resistance and disease progression. Identifying an effective anti-CSC agent may lead to improved disease control. We used CSC-associated gene signatures to identify drug candidates that may inhibit CSC growth by reversing the CSC gene signature. Thiostrepton, a natural cyclic oligopeptide antibiotic, was the top-ranked candidate. In non-small-cell lung cancer (NSCLC) cells, thiostrepton inhibited CSC growth in vitro and reduced protein expression of cancer stemness markers, including CD133, Nanog and Oct4A. In addition, metastasis-associated Src tyrosine kinase signalling, cell migration and epithelial-to-mesenchymal transition (EMT) were all inhibited by thiostrepton. Mechanistically, thiostrepton treatment led to elevated levels of tumour suppressor miR-98. Thiostrepton combined with gemcitabine synergistically suppressed NSCLC cell growth and induced apoptosis. The inhibition of NSCLC tumours and CSC growth by thiostrepton was also demonstrated in vivo. Our findings indicate that thiostrepton, an established drug identified in silico, is an inhibitor of CSC growth and a potential enhancer of chemotherapy in NSCLC.

Keywords: cancer stem cell; epithelial-to-mesenchymal transition; miR-98; non-small-cell lung cancer; thiostrepton.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Proliferation / drug effects*
  • Cell Proliferation / genetics
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Computer Simulation
  • Epithelial-Mesenchymal Transition / drug effects
  • Epithelial-Mesenchymal Transition / genetics
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mice, Inbred NOD
  • Mice, SCID
  • MicroRNAs / genetics
  • Nanog Homeobox Protein / genetics
  • Nanog Homeobox Protein / metabolism
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Thiostrepton / pharmacology*
  • Xenograft Model Antitumor Assays / methods

Substances

  • Anti-Bacterial Agents
  • MIRN98 microRNA-98, rat
  • MicroRNAs
  • Nanog Homeobox Protein
  • Thiostrepton