Unshielding multidrug resistant cancer through selective iron depletion of p-glycoprotein-expressing cells

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 Szákacs

Research output: Contribution to journalArticle

Abstract

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 inMDRcells 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.

Original languageEnglish
Pages (from-to)663-674
Number of pages12
JournalCancer Research
Volume80
Issue number4
DOIs
Publication statusPublished - Feb 15 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Cserepes, M., Türk, D., Tóth, S., Pape, V. F. S., Gaál, A., Gera, M., Szabó, J. E., Kucsma, N., Várady, G., Vértessy, B. G., Streli, C., Szabó, P. T., Tovari, J., Szoboszlai, N., & Szákacs, G. (2020). Unshielding multidrug resistant cancer through selective iron depletion of p-glycoprotein-expressing cells. Cancer Research, 80(4), 663-674. https://doi.org/10.1158/0008-5472.CAN-19-1407