The colony-stimulating factor-1 receptor inhibitor edicotinib counteracts multidrug resistance in cancer cells by inhibiting ABCG2-mediated drug efflux

Biomed Pharmacother. 2024 Nov:180:117554. doi: 10.1016/j.biopha.2024.117554. Epub 2024 Oct 15.

Abstract

Chemotherapy treatment faces a major obstacle with the emergence of multidrug resistance (MDR), often attributed to the elevated expression of ATP-binding cassette (ABC) transporters such as ABCG2 and ABCB1 in cancer cells. These transporters hinder the efficacy of cytotoxic drugs via ATP hydrolysis-dependent efflux, leading to diminished intracellular drug levels. The scarcity of approved treatments for multidrug resistant cancers necessitates exploration of alternative strategies, including drug repositioning of molecular targeted agents to counteract ABCG2-mediated MDR in multidrug-resistant cancer cells. This study investigates the potential of edicotinib, a selective colony-stimulating factor-1 receptor (CSF-1R) tyrosine kinase inhibitor that is currently undergoing clinical trials for various diseases, to reverse MDR in ABCG2-overexpressing cancer cells. Our findings reveal that by attenuating the drug-efflux function of ABCG2 without altering its expression, edicotinib improves drug-induced apoptosis and reverses MDR in ABCG2-overexpressing multidrug-resistant cancer cells at non-toxic concentrations. Through ATPase activity analysis and molecular docking, potential interaction sites for edicotinib on ABCG2 were identified. These results underscore an additional pharmacological benefit of edicotinib against ABCG2 activity, suggesting its potential incorporation into combination therapies for patients with ABCG2-overexpressing tumors. Further research is warranted to validate these findings and explore their clinical implications.

Keywords: ABC transporter; ABCG2; drug repositioning; edicotinib; multidrug resistance.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2* / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily G, Member 2* / metabolism
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Drug Resistance, Multiple* / drug effects
  • Drug Resistance, Neoplasm* / drug effects
  • Humans
  • Molecular Docking Simulation
  • Neoplasm Proteins* / antagonists & inhibitors
  • Neoplasm Proteins* / metabolism
  • Protein Kinase Inhibitors / pharmacology

Substances

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ABCG2 protein, human
  • Neoplasm Proteins
  • Antineoplastic Agents
  • Protein Kinase Inhibitors