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.
Highlights
Lung cancer is the leading cause of cancer‐related death worldwide.[1]
Our findings indicate that thiostrep‐ ton, an established drug identified in silico, is an inhibitor of Cancer stem cells (CSCs) growth and a poten‐ tial enhancer of chemotherapy in Non–small‐cell lung cancer (NSCLC)
Through in vitro and in vivo experiments, we demonstrated that thiostrepton effectively inhibited lung CSC growth by the suppressing cancer stemness and expression of epithelial‐to‐mesenchymal transition (EMT) genes
Summary
Lung cancer is the leading cause of cancer‐related death worldwide.[1]. The five‐year survival rate is approximately 18% for patients with lung cancer and 3.9% for those with advanced stages[2] of the disease, lower than the survival rates for colon (65%), female breast (90%) and prostate (99%) cancers.[3]. Cancer stem cells (CSCs) play an important role in cancer recur‐ rence, progression and drug resistance.[11,12,13] Lung CSCs were first identified as CD133+ cells[14] and isolated in established NSCLC cell lines,[15,16] forming floating spheres in serum‐free conditions These CD133+ lung cancer spheres exhibited self‐renewal abilities, stress/ drug resistance, epithelial‐to‐mesenchymal (EMT) potential and the ability to recapitulate tumour heterogeneity in vivo.[14,15,16,17,18] The drug resistance may be due to features related to the stem cell pathway, expression of high‐level ATP‐binding cassette transporters and spe‐ cific surface biomarkers.[19] Identifying agents to eliminate CSCs has become an important issue for anti‐cancer drug development. Our findings suggest thiostrepton can serve as an anti‐CSC drug and play a beneficial role in lung cancer treatment
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