Rutin as A Novel c-Met Inhibitory Lead for The Control of Triple Negative Breast Malignancies

Nutr Cancer. 2017 Nov-Dec;69(8):1256-1271. doi: 10.1080/01635581.2017.1367936. Epub 2017 Oct 30.

Abstract

Triple negative breast cancer (TNBC) has high metastatic and mortality potential and lacks effective and selective therapeutic options. Aberrant dysregulation of the receptor tyrosine kinase c-Met promotes TNBC progression, motility and survival and therefore considered a valid therapeutic target. Among various identified anticancer agents, plant polyphenols (PPs) including flavonoids, have been shown to be safe and proven for their antitumor activity through modulating diverse macromolecular targets. This study reports the bioassay-guided identification of the common flavonol glycoside rutin as breast cancer cell proliferation, migration and invasion inhibitor. The cell free Z'-LYTE kinase assay, Western blot and in silico docking experiments uncovered, for the first time, c-Met kinase as a potential mechanistic target for rutin-mediated anticancer effects on TNBC cell lines. Likewise, the intraperitoneal injection of rutin at 30 mg/kg, 3X/week, significantly reduced the growth of the TNBC MDA-MB-231/GFP orthotopic xenograft in nude mouse model. These results clearly designate the functional dietary flavonoid rutin as a potential lead for the prevention and control of c-Met-dependent breast malignancies.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Fabaceae / chemistry
  • Female
  • Flavonoids / pharmacology
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • L-Lactate Dehydrogenase / genetics
  • L-Lactate Dehydrogenase / metabolism
  • MCF-7 Cells
  • Mice
  • Mice, Knockout
  • Mice, Nude
  • Molecular Docking Simulation
  • Plant Extracts / pharmacology
  • Polyphenols / pharmacology
  • Protein Conformation
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism
  • Rutin / pharmacology*
  • Triple Negative Breast Neoplasms / drug therapy*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Flavonoids
  • Plant Extracts
  • Polyphenols
  • Rutin
  • Hepatocyte Growth Factor
  • L-Lactate Dehydrogenase
  • Proto-Oncogene Proteins c-met