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

Autor:	Cserepes M; Institute of Enzymology, Research Centre of Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.; Department of Experimental Pharmacology, National Institute of Oncology, Budapest, Hungary., Türk D; Institute of Enzymology, Research Centre of Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.; Department of Experimental Pharmacology, National Institute of Oncology, Budapest, Hungary., Tóth S; Institute of Enzymology, Research Centre of Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary., Pape VFS; Institute of Enzymology, Research Centre of Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary., Gaál A; Institute of Enzymology, Research Centre of Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.; Institute of Chemistry, Eötvös Loránd University, Budapest, Hungary., Gera M; Institute of Enzymology, Research Centre of Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary., Szabó JE; Institute of Enzymology, Research Centre of Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary., Kucsma N; Institute of Enzymology, Research Centre of Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary., Várady G; Institute of Enzymology, Research Centre of Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary., Vértessy BG; Institute of Enzymology, Research Centre of Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.; Department of Applied Biotechnology and Food Sciences, BME Budapest University of Technology and Economics, Budapest, Hungary., Streli C; Atominstitut, Technische Universitaet Wien, Vienna, Austria., Szabó PT; Instrumentation Centre, Research Centre of Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary., Tovari J; Department of Experimental Pharmacology, National Institute of Oncology, Budapest, Hungary., Szoboszlai N; Institute of Chemistry, Eötvös Loránd University, Budapest, Hungary., Szakács G; Institute of Enzymology, Research Centre of Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary. szakacs.gergely@ttk.mta.hu.; Institute of Cancer Research, Medical University of Vienna, Vienna, Austria.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2020 Feb 15; Vol. 80 (4), pp. 663-674. Date of Electronic Publication: 2019 Dec 30.
DOI:	10.1158/0008-5472.CAN-19-1407
Abstrakt:	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. (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
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