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

Food Chem Toxicol. 2013 Oct;60:360-8. doi: 10.1016/j.fct.2013.07.063. Epub 2013 Aug 1.

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.

Keywords: EMT; Gefitinib; Lung cancer; Milk thistle; Silibinin; Silibinin meglumine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antioxidants / pharmacology
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chromatography, High Pressure Liquid
  • Drug Resistance, Neoplasm
  • Epithelial-Mesenchymal Transition / drug effects*
  • ErbB Receptors
  • Gefitinib
  • Humans
  • Meglumine / chemistry
  • Meglumine / pharmacology*
  • Mice
  • Mice, Inbred NOD
  • Milk Thistle / chemistry*
  • Plant Extracts / chemistry
  • Plant Extracts / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Quinazolines / pharmacology
  • Seeds / chemistry
  • Silybin
  • Silymarin / chemistry
  • Silymarin / pharmacology*
  • Tandem Mass Spectrometry
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Antioxidants
  • Plant Extracts
  • Protein Kinase Inhibitors
  • Quinazolines
  • Silymarin
  • Silybin
  • Meglumine
  • ErbB Receptors
  • Gefitinib