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

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.

Relation of Metal-Binding Property and Selective Toxicity of 8-Hydroxyquinoline Derived Mannich Bases Targeting Multidrug Resistant Cancer Cells

“…In a recent study we have described the synthesis and chemical characterization of four closely related 8-hydroxyquinoline Mannich base derivatives [ 60 ]. The series contains structurally related derivatives of the unsubstituted 8-hydroxyquinoline core structure (NSC2039, Q-1 ), including the morpholin-1-yl-methyl derivative NSC662298 ( Q-2 ), the piperidin-1-yl-methyl derivative NSC57969 ( Q-3 ), and Q-4 , that was inspired by its ring-closed derivative NSC297366 [ 19 , 42 ] ( Figure S1 ). To assess the effect of these structural modifications on MDR-selective toxicity, herein we included several cell line pairs consisting of drug-sensitive parental and MDR derivatives.…”

“…Interestingly, at constant metal-to-ligand ratios, MDR-selective toxicity of Q-3 and Q-4 was retained even in the presence of 0.33, 0.5 or 1.0 equivalents of metal ions ( Table S1, Figures S20 and S21 ), suggesting that for a selective rescue of Pgp positive MES-SA/Dx5 cells by iron(III), as well as for the selective copper(II)-induced sensitization of Pgp negative MES-SA cells, an excess of the respective metal ion is needed. This intriguing result may be explained by an altered metal homeostasis of MDR cells (resulting in, e.g., an increased sensitivity to iron depletion [ 42 ]) or a selective induction of downstream toxic effects (such as copper-induced oxidative stress).…”

“…CRL-1977™). ABCB1 was expressed in A431 and MES-SA cells using lentiviral transduction [ 42 , 61 ]. The human cervix carcinoma cell line KB-3-1 and the vinblastine selected KB-v1were kind gifts from Dr. Michael M. Gottesman, National Institutes of Health.…”

“…In that respect, characterization of solution speciation, the relation of complex equilibria and redox properties to cytotoxic activity, revealed key characteristics governing complex formation and anticancer activity [ 37 , 38 , 39 , 40 , 41 ]. Recently, we have shown that the MDR-selective toxicity of NSC297366 is linked to cellular iron depletion, which is exacerbated by Pgp [ 42 ]. Due to their increased proliferation, cancer cells have an excessive demand for iron [ 43 , 44 ] and copper [ 45 , 46 ], and this vulnerability can be exploited by chelator-based cancer treatment strategies [ 37 , 39 , 47 , 48 , 49 ].…”

An inventory of lysosomal ABC transporters

“…Once sorted to ILVs, P‐gp molecules are doomed to destruction by acid hydrolases present in the lysosomal lumen. Incorporation of P‐gp into the membrane of cytoplasmic vesicles may be the consequence of the high‐level expression of P‐gp in MDR cells selected for extreme MDR [146]. Indeed, selected cell lines express very high P‐gp levels, reaching 20% of the total plasma membrane proteins in Chinese hamster cells selected with doxorubicin [147].…”