Unshielding Multidrug Resistant Cancer through Selective Iron Depletion of P-Glycoprotein-Expressing Cells

Cancer Res. 2020 Feb 15;80(4):663-674. doi: 10.1158/0008-5472.CAN-19-1407. Epub 2019 Dec 30.


Clinical evidence shows that following initial response to treatment, drug-resistant cancer cells frequently evolve and, eventually, most tumors become resistant to all available therapies. We compiled a focused library consisting of >500 commercially available or newly synthetized 8-hydroxyquinoline (8OHQ) derivatives whose toxicity is paradoxically increased rather than decreased by the activity of P-glycoprotein (Pgp), a transporter conferring multidrug resistance (MDR). Here, we deciphered the mechanism of action of NSC297366 that shows exceptionally strong Pgp-potentiated toxicity. Treatment of cells with NSC297366 resulted in changes associated with the activity of potent anticancer iron chelators. Strikingly, iron depletion was more pronounced in MDR cells due to the Pgp-mediated efflux of NSC297366-iron complexes. Our results indicate that iron homeostasis can be targeted by MDR-selective compounds for the selective elimination of multidrug resistant cancer cells, setting the stage for a therapeutic approach to fight transporter-mediated drug resistance. SIGNIFICANCE: Modulation of the MDR phenotype has the potential to increase the efficacy of anticancer therapies. These findings show that the MDR transporter is a "double-edged sword" that can be turned against resistant cancer.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cell Line, Tumor
  • Drug Resistance, Multiple / drug effects
  • Drug Resistance, Neoplasm / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Iron / metabolism*
  • Iron Chelating Agents / pharmacology*
  • Iron Chelating Agents / therapeutic use
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Oxyquinoline / analogs & derivatives
  • Oxyquinoline / pharmacology*
  • Oxyquinoline / therapeutic use


  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • Iron Chelating Agents
  • Oxyquinoline
  • Iron