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.
