title: Silibinin suppresses EMT-driven erlotinib resistance by reversing the high miR-21/low miR-200c signature in vivo.
abstract: The flavolignan silibinin was studied for its ability to restore drug sensitivity to EGFR-mutant NSCLC xenografts with epithelial-to-mesenchymal transition (EMT)-driven resistance to erlotinib. As a single agent, silibinin significantly decreased the tumor volumes of erlotinib-refractory NSCLC xenografts by approximately 50%. Furthermore, the complete abrogation of tumor growth was observed with the co-treatment of erlotinib and silibinin. Silibinin fully reversed the EMT-related high miR-21/low miR-200c microRNA signature and repressed the mesenchymal markers SNAIL, ZEB, and N-cadherin observed in erlotinib-refractory tumors. Silibinin was sufficient to fully activate a reciprocal mesenchymal-to-epithelial transition (MET) in erlotinib-refractory cells and prevent the highly migratogenic phenotype of erlotinib-resistant NSCLC cells. Given that the various mechanisms of resistance to erlotinib result from EMT, regardless of the EGFR mutation status, a water-soluble, silibinin-rich milk thistle extract might be a suitable candidate therapy for upcoming clinical trials aimed at preventing or reversing NSCLC progression following erlotinib treatment.
authors: Metabolism & Cancer Group, Translational Research Laboratory, Catalan Institute of Oncology, Girona, Catalonia, Spain.
authors: Sílvia
authors: S
authors: Cufí
authors: Rosa
authors: R
authors: Bonavia
authors: Alejandro
authors: A
authors: Vazquez-Martin
authors: Cristina
authors: C
authors: Oliveras-Ferraros
authors: Bruna
authors: B
authors: Corominas-Faja
authors: Elisabet
authors: E
authors: Cuyàs
authors: Begoña
authors: B
authors: Martin-Castillo
authors: Enrique
authors: E
authors: Barrajón-Catalán
authors: Joana
authors: J
authors: Visa
authors: Antonio
authors: A
authors: Segura-Carretero
authors: Jorge
authors: J
authors: Joven
authors: Joaquim
authors: J
authors: Bosch-Barrera
authors: Vicente
authors: V
authors: Micol
authors: Javier A
authors: JA
authors: Menendez
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage*; D000077385:Silybin; D012838:Silymarin / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: C533896:MIRN200 microRNA, human; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012838:Silymarin; D000077385:Silybin; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors
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