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Compounds potentially targeting CSCs have been recently developed. This study shows how melatonin, an endogenous hormone synthesised by the pineal gland, and its derivative suppress CSC\u2010like phenotypes of human non\u2010small cell lung cancer (NSCLC) cell lines, H460, H23, and A549. The effects of MLT and its derivative, acetyl melatonin (ACT), on CSC\u2010like phenotypes were investigated using assays for anchorage\u2010independent growth, three\u2010dimensional spheroid formation, scratch wound healing ability, and CSC marker and upstream protein signalling expression. Enriched CSC spheroids were used to confirm the effect of both compounds on lung cancer cells. MLT and ACT inhibited CSC\u2010like behaviours by suppression of colony and spheroid formation in NSCLC cell lines. Their effects on spheroid formation were confirmed in CSC\u2010enriched H460 cells. CSC markers, CD133 and ALDH1A1, were depleted by both compounds. The behaviour and factors associated to epithelial\u2013mesenchymal transition, as indicated by cell migration and the protein vimentin, were also decreased by MLT and ACT. Mechanistically, MLT and ACT decreased the expression of stemness proteins Oct\u20104, Nanog, and \u03b2\u2010catenin by reducing active AKT (phosphorylated AKT). Suppression of the AKT pathway was not mediated through melatonin receptors. This study demonstrates a novel role, and its underlying mechanism, for MLT and its derivative ACT in suppression of CSC\u2010like phenotypes in NSCLC cells, indicating that they are potential candidates for lung cancer treatment.<\/jats:p>","DOI":"10.1111\/1440-1681.13572","type":"journal-article","created":{"date-parts":[[2021,8,16]],"date-time":"2021-08-16T08:10:46Z","timestamp":1629101446000},"page":"1712-1723","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Melatonin and its derivative disrupt cancer stem\u2010like phenotypes of lung cancer cells via AKT downregulation"],"prefix":"10.1111","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4106-4716","authenticated-orcid":false,"given":"Preeyaporn Plaimee","family":"Phiboonchaiyanan","sequence":"first","affiliation":[{"name":"College of Pharmacy Rangsit University Pathumthani Thailand"},{"name":"Cosmeceutical Research, Development and Testing 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