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Silibinin suppresses EMT-driven erlotinib resistance by reversing the high miR-21/low miR-200c signature in vivo

2013; Nature Portfolio; Volume: 3; Issue: 1 Linguagem: Inglês

10.1038/srep02459

2045-2322

Sílvia Cufí, Rosa Bonavia, Alejandro Vázquez‐Martín, Cristina Oliveras‐Ferraros, Bruna Corominas-Faja, Elisabet Cuyàs, Begoña Martı́n-Castillo, Enrique Barrajón‐Catalán, Joana Visa, Antonio Segura‐Carretero, Jorge Joven, Joaquim Bosch‐Barrera, Vicente Micol, Javier A. Menéndez,

Lung Cancer Research Studies

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.