journal contribution posted on 2023-03-31, 03:25 authored by Mihály Cserepes, Dóra Türk, Szilárd Tóth, Veronika F.S. Pape, Anikó Gaál, Melinda Gera, Judit E. Szabó, Nóra Kucsma, György Várady, Beáta G. Vértessy, Christina Streli, Pál T. Szabó, Jozsef Tovari, Norbert Szoboszlai, Gergely Szakács
Supplementary tables and figures, supplementary materials and methods
Hungarian Academy of Sciences
Austrian Science Fund
National Research Development and Innovation Office
Research and Technology Innovation Fund of Hungary
National Excellence Program
2019 Thematic Excellence Program
ARTICLE ABSTRACTClinical 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.
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.