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

SIMPLE SUMMARY: Effective treatment of cancer is often limited by the resistance of cancer cells to chemotherapy. A well-described mechanism supporting multidrug resistance (MDR) relies on the efflux of toxic drugs from cancer cells, mediated by P-glycoprotein (Pgp). Circumventing Pgp-mediated resistance is expected to make a significant contribution to improved therapy of malignancies. Interestingly, MDR cells exhibit paradoxical hypersensitivity towards a diverse set of anticancer chelators. In this study we explore the relation of chemical and structural properties influencing metal binding and toxicity of a set of 8-hydroxyquinoline derivatives to reveal key characteristics governing “MDR-selective” activity. We find that subtle changes in the stability and redox activity of the biologically relevant metal complexes significantly influence MDR-selective toxicity. Our results underline the importance of chelation in MDR-selective toxicity, suggesting that the collateral sensitivity of MDR cells may be targeted by preferential iron deprivation or the formation of redox-active copper(II) complexes. ABSTRACT: Resistance to chemotherapeutic agents is a major obstacle in cancer treatment. A recently proposed strategy is to target the collateral sensitivity of multidrug resistant (MDR) cancer. Paradoxically, the toxicity of certain metal chelating agents is increased, rather than decreased, by the function of P-glycoprotein (Pgp), which is known to confer resistance by effluxing chemotherapeutic compounds from cancer cells. We have recently characterized and compared the solution’s chemical properties including ligand protonation and the metal binding properties of a set of structurally related 8-hydroxyquinoline derived Mannich bases. Here we characterize the impact of the solution stability and redox activity of their iron(III) and copper(II) complexes on MDR-selective toxicity. Our results show that the MDR-selective anticancer activity of the studied 8-hydroxyquinoline derived Mannich bases is associated with the iron deprivation of MDR cells and the preferential formation of redox-active copper(II) complexes, which undergo intracellular redox-cycling to induce oxidative stress.