Delivery of miR-200c Mimic with Poly(amido amine) CXCR4 Antagonists for Combined Inhibition of Cholangiocarcinoma Cell Invasiveness

Mol Pharm. 2016 Mar 7;13(3):1073-80. doi: 10.1021/acs.molpharmaceut.5b00894. Epub 2016 Feb 8.

Abstract

Cholangiocarcinoma is the second most common primary liver malignancy with extremely poor prognosis due to early invasion and widespread metastasis. The invasion and metastasis are regulated by multiple factors including CXCR4 chemokine receptor and multiple microRNAs. The goal of this study was to test the hypothesis that inhibition of CXCR4 combined with the action of miR-200c mimic will cooperatively enhance the inhibition of the invasion of human cholangiocarcinoma cells. The results show that CXCR4-inhibition polycation PCX can effectively deliver miR-200c mimic and that the combination treatment consisting of PCX and miR-200c results in cooperative antimigration activity, most likely by coupling the CXCR4 axis blockade with epithelial-to-mesenchymal transition inhibition in the cholangiocarcinoma cells. The ability of the combined PCX/miR-200c treatment to obstruct two migratory pathways represents a promising antimetastatic strategy in cholangiocarcinoma.

Keywords: CXCR4; cholangiocarcinoma; microRNA; poly(amido amine); polyplexes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Benzylamines
  • Bile Duct Neoplasms / drug therapy*
  • Bile Duct Neoplasms / genetics
  • Bile Duct Neoplasms / pathology
  • Bile Ducts, Intrahepatic / drug effects*
  • Bile Ducts, Intrahepatic / metabolism
  • Bile Ducts, Intrahepatic / pathology
  • Blotting, Western
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cholangiocarcinoma / drug therapy*
  • Cholangiocarcinoma / genetics
  • Cholangiocarcinoma / pathology
  • Cyclams
  • Drug Delivery Systems*
  • Drug Therapy, Combination
  • Heterocyclic Compounds / pharmacology
  • Humans
  • MicroRNAs / administration & dosage
  • MicroRNAs / genetics*
  • Neoplasm Invasiveness
  • Polyamines / chemistry*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, CXCR4 / antagonists & inhibitors*
  • Receptors, CXCR4 / genetics
  • Receptors, CXCR4 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured

Substances

  • Benzylamines
  • CXCR4 protein, human
  • Cyclams
  • Heterocyclic Compounds
  • MIRN200 microRNA, human
  • MicroRNAs
  • Poly(amidoamine)
  • Polyamines
  • RNA, Messenger
  • Receptors, CXCR4
  • plerixafor