Regorafenib antagonizes BCRP-mediated multidrug resistance in colon cancer

Cancer Lett. 2019 Feb 1:442:104-112. doi: 10.1016/j.canlet.2018.10.032. Epub 2018 Oct 28.

Abstract

Overexpression of breast cancer resistance protein (BCRP) has been shown to produce multidrug resistance (MDR) in colon cancer, leading to major obstacles for chemotherapy. In this study, we evaluated the effect of regorafenib, an oral multi-kinase inhibitor, in inhibiting BCRP-mediated MDR in silico, in vitro and in vivo. We found that regorafenib significantly sensitized MDR colon cancer cells to BCRP substrates by increasing their intracellular accumulation. There are no significant changes in the expression level or the subcellular distribution of BCRP in the cells exposed to regorafenib. Investigation of the mechanism revealed that regorafenib stimulated BCRP ATPase activity. Our induced-fit docking and molecular dynamics simulations suggested the existence of a strong and stable interaction between regorafenib and the transmembrane domain of human crystalized BCRP. In vivo tumor xenograft study revealed that the combination of regorafenib and topotecan exhibited synergistic effects on mitoxantrone-resistant S1-M1-80 xenograft tumors. In conclusion, our studies indicate that regorafenib would be beneficial in combating MDR in colon cancer.

Keywords: Combination chemotherapy with regorafenib; Reversal of multidrug resistance; Synergy.

Publication types

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

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / agonists*
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / chemistry
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Binding Sites
  • Cell Line, Tumor
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Dose-Response Relationship, Drug
  • Drug Resistance, Multiple / drug effects*
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Synergism
  • Humans
  • Male
  • Mice, Nude
  • Mitoxantrone / pharmacology
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Neoplasm Proteins / agonists*
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Phenylurea Compounds / chemistry
  • Phenylurea Compounds / pharmacology*
  • Protein Binding
  • Protein Conformation
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Topotecan / pharmacology
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Antineoplastic Agents
  • Neoplasm Proteins
  • Phenylurea Compounds
  • Pyridines
  • regorafenib
  • Topotecan
  • Mitoxantrone