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Cancer Res. 2019 Dec 30. pii: canres.1407.2019. doi: 10.1158/0008-5472.CAN-19-1407. [Epub ahead of print]

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

Author information

1
Experimental Pharmacology, National Institute of Oncology.
2
Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences.
3
Institute of Materials and Enviromental Chemistry, Biological Nanochemistry Research Group, Research Centre for Natural Sciences.
4
bAtominstitut, Technische Universitaet.
5
Instrumentation Centre, Research Center for Natural Sciences.
6
Department of Experimental Pharmacology, National Institute of Oncology.
7
Institute of Chemistry, Eötvös Loránd University.
8
Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences szakacs.gergely@ttk.mta.hu.

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 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.

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