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Author Spotlight: Assessing the Impact of Novel Iron Chelators on Cancer Cell Metabolism
Published on: February 23, 2024
Unshielding Multidrug Resistant Cancer through Selective Iron Depletion of P-Glycoprotein-Expressing Cells
Mihály Cserepes1,2, Dóra Türk1,2, Szilárd Tóth1
1Institute of Enzymology, Research Centre of Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
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. 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.
Insights
Drug-resistant cancers often develop resistance to therapies. New 8-hydroxyquinoline derivatives selectively kill multidrug-resistant (MDR) cancer cells by targeting iron metabolism, exploiting the MDR transporter to enhance toxicity.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Cancer cells frequently develop resistance to therapies, limiting treatment efficacy.
- Multidrug resistance (MDR) is often mediated by transporters like P-glycoprotein (Pgp).
- Targeting MDR phenotypes offers potential to overcome treatment resistance.
Purpose of the Study:
- To investigate 8-hydroxyquinoline (8OHQ) derivatives for selective toxicity against MDR cancer cells.
- To decipher the mechanism of action of NSC297366, a potent Pgp-potentiated 8OHQ derivative.
- To explore targeting iron homeostasis as a strategy against MDR cancer.
Main Methods:
- Compiled and screened a library of over 500 8-hydroxyquinoline derivatives.
- Investigated the mechanism of action of NSC297366 in cancer cells.
- Assessed iron levels and Pgp-mediated efflux of drug-iron complexes.
Main Results:
- Identified 8OHQ derivatives with Pgp-potentiated toxicity against cancer cells.
- NSC297366 exhibited strong Pgp-potentiated toxicity, inducing iron depletion.
- MDR cells showed more pronounced iron depletion due to Pgp-mediated efflux of NSC297366-iron complexes.
Conclusions:
- Iron homeostasis can be targeted by MDR-selective compounds.
- MDR-associated transporters can be exploited to selectively eliminate drug-resistant cancer cells.
- This approach offers a novel therapeutic strategy against transporter-mediated drug resistance.
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