title: Silibinin meglumine, a water-soluble form of milk thistle silymarin, is an orally active anti-cancer agent that impedes the epithelial-to-mesenchymal transition (EMT) in EGFR-mutant non-small-cell lung carcinoma cells.
abstract: Silibinin is the primary active constituent of a crude extract (silymarin) from milk thistle plant (Silybum marianum) seeds. We explored the ability of an oral milk thistle extract formulation that was enriched with a water-soluble form of silibinin complexed with the amino-sugar meglumine to inhibit the growth of non-small-cell lung carcinoma (NSCLC) mouse xenografts. As a single agent, oral silibinin meglumine notably decreased the overall volumes of NSCLC tumors as efficiently as did the EGFR tyrosine kinase inhibitor (TKI) gefitinib. Concurrent treatment with silibinin meglumine impeded the regrowth of gefitinib-unresponsive tumors, resulting in drastic tumor growth prevention. Because the epithelial-to-mesenchymal transition (EMT) is required by a multiplicity of mechanisms of resistance to EGFR TKIs, we evaluated the ability of silibinin meglumine to impede the EMT in vitro and in vivo. Silibinin-meglumine efficiently prevented the loss of markers associated with a polarized epithelial phenotype as well as the de novo synthesis of proteins associated with the mesenchymal morphology of transitioning cells. Our current findings with this non-toxic, orally active, and water-soluble silibinin formulation might facilitate the design of clinical trials to test the administration of silibinin meglumine-containing injections, granules, or beverages in combination with EGFR TKIs in patients with EGFR-mutated NSCLC.
authors.affiliation: Metabolism & Cancer Group, Translational Research Laboratory, Catalan Institute of Oncology, Girona, Catalonia, Spain; Girona Biomedical Research Institute (IDIBGi), Girona, Catalonia, Spain.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Cufí
authors.forename: Rosa
authors.initials: R
authors.lastname: Bonavia
authors.forename: Alejandro
authors.initials: A
authors.lastname: Vazquez-Martin
authors.forename: Bruna
authors.initials: B
authors.lastname: Corominas-Faja
authors.forename: Cristina
authors.initials: C
authors.lastname: Oliveras-Ferraros
authors.forename: Elisabet
authors.initials: E
authors.lastname: Cuyàs
authors.forename: Begoña
authors.initials: B
authors.lastname: Martin-Castillo
authors.forename: Enrique
authors.initials: E
authors.lastname: Barrajón-Catalán
authors.forename: Joana
authors.initials: J
authors.lastname: Visa
authors.forename: Antonio
authors.initials: A
authors.lastname: Segura-Carretero
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bosch-Barrera
authors.forename: Jorge
authors.initials: J
authors.lastname: Joven
authors.forename: Vicente
authors.initials: V
authors.lastname: Micol
authors.forename: Javier A
authors.initials: JA
authors.lastname: Menendez
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D066246:ErbB Receptors; D000077156:Gefitinib; D006801:Humans; D008536:Meglumine / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D020944:Silybum marianum / Q000737:chemistry*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D012639:Seeds / Q000737:chemistry; D000077385:Silybin; D012838:Silymarin / Q000737:chemistry / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D010936:Plant Extracts; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012838:Silymarin; D000077385:Silybin; D008536:Meglumine; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: EMT; Gefitinib; Lung cancer; Milk thistle; Silibinin; Silibinin meglumine