Journal Article

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

Cheng, Tai‐Shan, Huang, Chi‐Ying F., Chen, Kuan‐Yu, Wu, Cheng‐Wen, Chang, Peter Mu‐Hsin, Huang, Tse‐Hung, Lin, Kuan‐Ting, Lai, Chia‐Jou, Hsieh, Hao‐Wen, Wu, Alexander T. H.

2019

Overview

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.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: A549 Cells / Animals / Anti-Bacterial Agents - pharmacology / Apoptosis / cancer stem cell / Cancer therapies / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - metabolism / Carcinoma, Non-Small-Cell Lung - pathology / Cell growth / Cell Line, Tumor / Cell migration / Cell Movement - drug effects / Cell Movement - genetics / Cell Proliferation - drug effects / Cell Proliferation - genetics / Cell Survival - drug effects / Cell Survival - genetics / Chemotherapy / Computer Simulation / Disease / Disease control / Disease resistance / Drug development / Drug resistance / Epithelial-Mesenchymal Transition - drug effects / Epithelial-Mesenchymal Transition - genetics / epithelial‐to‐mesenchymal transition / Gemcitabine / Gene expression / Gene Expression Profiling - methods / Gene Expression Regulation, Neoplastic - drug effects / Humans / Hung Huang / Lung cancer / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lung Neoplasms - pathology / Mesenchyme / Metastases / Mice, Inbred NOD / Mice, SCID / MicroRNAs - genetics / miR‐98 / Nanog Homeobox Protein - genetics / Nanog Homeobox Protein - metabolism / Neoplastic Stem Cells - metabolism / Neoplastic Stem Cells - pathology / Non-small cell lung carcinoma / non–small‐cell lung cancer / Original / Protein-tyrosine kinase / Signal Transduction - drug effects / Signal Transduction - genetics / Spheres / Stem cells / Thiostrepton / Thiostrepton - pharmacology / Treatment resistance / Tumors / Xenograft Model Antitumor Assays - methods