Electrochemical Reduction of Copper (II) As a Potent and Versatile Approach for Tumor Cell Eradication

At the advanced stages of the disease, tumor cells acquire pleiotropic resistance to a variety of treatment modalities. In these situations, targeted therapies become no longer efficient. Inactivation of non-apoptotic mechanisms of cell survival remains a strategy of choice. Pursuing the role of oxidative damage in killing pleiotropically resistant tumor cells, we developed a series of copper(II) containing inorganic and organic compounds with an idea of Cu²⁺-to-Cu¹⁺ electrochemical transition in the presence of physiological reducing agents cysteine and ascorbate. Rapid generation of reactive oxygen species (ROS) as a result of Cu(II) reduction triggered multiple mechanisms of cell death including direct damage of the plasma membrane and mitochondria. This effect was specific for copper but not for other transition metals; however, the organic ligand may negatively influence the availability of the metal cation to the reducing agent. In cell-based experiments, the combinations of Cu (II)–organic complexes and cysteine potently killed mammalian tumor cells regardless of tissue origin, including multidrug resistant variants. This effect was achievable at non-toxic concentrations of each component of the combination. To attenuate general toxicity, we focused on the delivery of copper to the sites of potential metastasis, e.g., the bone. Our new Cu(II) complex of zoledronic acid, an FDA-approved drug for prevention of bone destruction, represented a ratio of oligomers/monomers in which two organic moieties were coordinated by three metal cations. Combinations of water-soluble Cu-zoledronate formulations and cysteine (at sub-toxic concentrations) triggered a non-apoptotic death of chronic myelogenous leukemia cell line otherwise resistant to the 3rd generation Bcr-Abl inhibitor vamotinib in the medium conditioned by bone marrow-derived fibroblasts. Overall, local oxidative burst upon Cu(II) reduction emerges as a promising approach to eradicate tumor cells, alone and in the microenvironment.